Patent Publication Number: US-2021186909-A1

Title: Composition of fused tricyclic gamma-amino acid derivatives and the preparation thereof

Description:
TECHNICAL FIELD 
     The present disclosure relates to a field of medication, in particular, to a pharmaceutical composition of fused tricyclic gamma-amino acid derivatives and the use thereof. 
     BACKGROUND 
     Diabetic peripheral neuralgic pain (DPNP) is a common chronic complication of diabetes. At least 25% of diabetic patients suffered from painful diabetic peripheral neuropathy, and 50% of diabetic patients with a disease history of more than 25 years will develop into neuralgia. Currently, there are more than 10 million DPNP patients in China. 
     Post herpetic neuralgia (PHN) is the most common complication of herpes zoster. The annual incidence of herpes zoster is about 3-5‰, and about 9-34% of patients with herpes zoster will develop into PHN. The incidence of herpes zoster tends to increase with age. About 65% of patients with herpes zoster, aged 60 and above, will develop into PHN, while the number is up to 75% in those aged 70 and above. There is a lack of relevant research data in China. However, according to the above data, it is estimated that there are about 4 million PHN patients in China. 
     Fibromyalgia syndrome (FMs) is a group of clinical syndromes of unknown etiology and characterized by systemic pain and significant physical discomfort. The overall prevalence of FMs is 2.7% in the world, with 2% in the United States and 0.8% in China. 
     At present, drugs for symptomatic treatment of peripheral neuralgia mainly comprise anticonvulsants, tricyclic antidepressants, opioid analgesics, local analgesics and the like. 
     The therapeutic agents approved by FDA include voltage-dependent calcium channel antagonists such as pregabalin, gabapentin, 5-HT/NE reuptake inhibitors such as duloxetine, milnacipran, μ-opioid receptor agonist/NE reuptake inhibitor such as tapentadol, and the topical external-use drugs such as lidocaine patch, capsaicin patch. At present, only pregabalin and gabapentin are approved for PHN treatment by CFDA, while no drug has been approved for treating DPNP and FMs. 
     Voltage-gated calcium channels are composed of α1 subunit and accessory protein α2δ-, β-, γ-subunits. α2δ protein can adjust the density of calcium channel and the calcium-channel voltage-dependent dynamics (Felix et al (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al (1999) J. Neuroscience 19: 684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). It has been demonstrated that compounds that exhibit high affinity binding to the voltage-dependent calcium-channel subunit α2δ are effective in the treatment of pain, such as pregabalin and gabapentin. In mammals, the α2δ protein has 4 subtypes, each of which is encoded by a different gene. The subtype 1 and subtype 2 of α2δ show high affinity with pregabalin, while the subtype 3 and subtype 4 of α2δ have no significant drug-binding capacity. 
     Clinically, pregabalin is administrated three times a day or twice a day, with a low clinical compliance to patients. Pregabalin only has an alleviation effect on pain in about 30-50% of patients, and has poor effects on refractory DPNP and the like. The side effects such as dizziness, drowsiness, weight gain, edema and the like occur in a high rate in the clinical use, which may affect the life quality of patients. 
     SUMMARY OF THE DISCLOSURE 
     According to the present disclosure, there is provided a pharmaceutical composition of a fused tricyclic gamma-amino acid derivative, having a novel structure and a good potency, or a pharmaceutically acceptable salt thereof and the use thereof in the field of analgesia. 
     According to the present disclosure, there is also provided a method of treating and/or preventing pain, comprising administering an effective amount of a fused tricyclic gamma-amino acid derivative or a pharmaceutically acceptable salt thereof. 
     The novel compound of a fused tricyclic gamma-amino acid derivative (of formula (I) structure or a pharmaceutically acceptable salt thereof) provided in the present disclosure is a calcium-ion-channel α2δ antagonist, which can competitively bind to a calcium-ion-channel α2δ subunit. The compound is associated with the endogenous inhibitory neurotransmitter, GABA, which is associated with the regulation of brain neuron activity, has a therapeutic effect on peripheral neuralgia caused by diabetes, post herpetic neuralgia and fibromyalgia, and thus is expected to overcome the defect of pregabalin. 
     According to the present disclosure, there is provided a pharmaceutical composition comprising a compound represented by formula (I) as below or a pharmaceutically acceptable salt thereof. 
     
       
         
         
             
             
         
       
     
     According to the present disclosure, there is provided a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (II) as below. 
     
       
         
         
             
             
         
       
     
     In an embodiment, optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 1-100 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 2-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 2-60 mg. 
     Optionally, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is included in an amount of 2-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5-40 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5-30 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5-20 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5-10 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 10-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 10-60 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 10-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 20-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 20-60 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 20-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 30-50 mg. 
     In a specific embodiment, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg. 
     In any one of the aforesaid embodiments, the pharmaceutically acceptable salt is selected from a benzene sulfonate. 
     There is also provided a method of treating and/or preventing pain, comprising administering an effective amount of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein the effective amount ranges optionally from 1 to 100 mg, or from 2 to 80 mg, or from 2 to 60 mg, or from 2 to 50 mg, or from 5 to 50 mg, or from 5 to 40 mg, or from 5 to 30 mg, or from 5 to 20 mg, or from 10 to 80 mg, or from 10 to 70 mg, or from 10 to 60 mg, or from 10 to 50 mg, or from 10 to 45 mg, or from 15 to 70 mg, or from 15 to 60 mg, or from 15 to 50 mg, or from 15 to 45 mg, or from 20 to 70 mg, or from 20 to 60 mg, or from 20 to 50 mg, or from 20 to 45 mg. 
     Preferably, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is a benzene sulfonate thereof. 
     When the pharmaceutically acceptable salt is administered as an active ingredient, the effective dose is a value converted to a free base. 
     In one variation, it is administrated orally. 
     In one variation, the pain comprises: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or arthrorheumatism, lower back pain, sciatica, dental pain, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-associated neuralgia, AIDS-associated neuralgia, cancer-associated neuralgia or non-neuropathic pain, acute or chronic tension headache, postoperative pain or fibromyalgia. In a particular variation, the pain comprises: postherpetic neuralgia, pain caused by diabetic neuropathy, or fibromyalgia. 
     There is also provided the use of the aforesaid pharmaceutical composition in the preparation of a medication for treating and/or preventing pain. Preferably, the pain comprises: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or arthrorheumatism, lower back pain, sciatica, dental pain, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-associated neuralgia, AIDS-associated neuralgia, cancer-associated neuralgia or non-neuropathic pain, acute or chronic tension headache, postoperative pain or fibromyalgia. 
     There is also provided the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a medication for treating and/or preventing pain. 
     In an embodiment, optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 1-100 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 2-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 2-60 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 2-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 5-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 5-40 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 5-30 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 5-20 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 5-10 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 10-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 10-60 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 10-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 20-80 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 20-60 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 20-50 mg. 
     Optionally, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is administrated in a single dose of 30-50 mg. 
     In a specific embodiment, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is included in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg. 
     In each of the above embodiments or variations about the use, the pharmaceutically acceptable salt is selected from benzene sulfonates. 
     In each of the above embodiments or variation of the use, when the pharmaceutically acceptable salt of the compound represented by formula (I) or (II) is used in the preparation of the medication for treating and/or preventing pain, the single dose is a value converted to a free base. 
     Another object of the present disclosure is to improve the stability of the formulation and to solve the problem of content uniformity in the production of the formulation, thereby obtaining a formulation having a qualified content uniformity and a good chemical stability. According to the present disclosure, there is provided a formulation containing the compound of formula (I) or formula (II) as an active ingredient, which can be in a form of tablets, capsules, granules and the like. 
     The formulation, as provided by the present disclosure, is quick in dissolution, and good in chemical stability, safe, effective and few in side effects. 
     According to the present disclosure, there is provided a pharmaceutical composition, which, based on the total weight of the pharmaceutical composition (100%), comprises:
         (i) an active material having a structure as represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in an amount of 1% to 45% by weight, or in an amount of 1% to 40% by weight in some embodiments, or in an amount of 1% to 35% by weight in some embodiments, or in an amount of 1% to 30% by weight in some embodiments, or in an amount of 1% to 25% by weight in some embodiments, or in an amount of 5% to 45% by weight in some embodiments, or in an amount of 5% to 40% by weight in some embodiments, or in an amount of 5% to 35% by weight in some embodiments, or in an amount of 5% to 30% by weight in some embodiments, or in an amount of 5% to 25% by weight in some embodiments, or in an amount of 5% to 21% by weight in some embodiments;   (ii) optionally one or more filler in an amount of 50% to 95% by weight, or in an amount of 55% to 94% by weight in some embodiments, or in an amount of 79% to 94% by weight in some embodiments;   (iii) optionally one or more lubricating agents in an amount of 0.1% to 6% by weight, or in an amount of 0.1% to 5.5% by weight in some embodiments, or in an amount of 0.1% to 2% by weight in some embodiments, or in an amount of 0.1% to 1.5% by weight in some embodiments, or in an amount of 0.5% to 1.5% by weight in some embodiments, or in an amount of 0.5% to 1% by weight in some embodiments, or in an amount of 0.5% to 0.9% by weight in some embodiments, or in an amount of 0.5% to 0.8% by weight in some embodiments, or in an amount of 0.5% to 0.7% by weight in some embodiments, or in an amount of 0.5% to 0.6% by weight in some embodiments;   wherein the above ranges may be arbitrarily combined, provided that the sum of weight percents of the all components is 100%; and   wherein the structure of formula (I) is as follows.       

     
       
         
         
             
             
         
       
     
     The pharmaceutical composition according to the present disclosure, wherein the structure of formula (I) is as follows. 
     
       
         
         
             
             
         
       
     
     The pharmaceutical composition according to the present disclosure, wherein the pharmaceutically acceptable salt of the compound of formula (I) has a structure as follows. 
     
       
         
         
             
             
         
       
     
     The pharmaceutically acceptable salt of the compound of formula (I) has a structure in a crystal form, and has characteristic diffraction peaks in the 2θ angles of 9.72°±0.2°, 14.00°±0.2°, 16.33°±0.2°, 19.32°±0.2°, 20.46°±0.2°, 21.69°±0.2° and 25.33°±0.2° in the X-ray powder-diffraction spectrum using Cu-Kα for radiation. It further has characteristic diffraction peaks in the 2θ angles of 11.21°±0.2°, 15.16°±0.2°, 18.87°±0.2°, 19.88°±0.2°, 23.47°±0.2° and 27.96°±0.2° in the X-ray powder-diffraction spectrum using Cu-Kα for radiation. It further has characteristic diffraction peaks in the 2θ angles of 21.30°±0.2°, 25.40°±0.2°, 29.82°±0.2° in the X-ray powder-diffraction spectrum. Further, the crystal of the pharmaceutically acceptable salt of the compound of formula (I) has an X-ray powder-diffraction spectrum, using Cu-Kα for radiation, as shown in  FIG. 4 . Further, the TGA/DSC spectrum of the crystal of the pharmaceutically acceptable salt of the compound of formula (I) is shown in  FIG. 5 . Moreover, the pharmaceutically acceptable salt of the compound of formula (I) has a single-crystal diffraction spectrum as shown in  FIG. 6 , wherein the pharmaceutically acceptable salt of the compound of formula (I) has a structure as follows: 
     
       
         
         
             
             
         
       
     
     The composition according to the present disclosure may be a pharmaceutical formulation in a form of tablets, granules, microcapsules, pills or capsules. It is in a form of tablets or capsules in certain embodiments. Further, it is in a form of capsules in certain embodiments. 
     The composition according to the present disclosure includes the active material in an amount of 1% to 45% by weight, or in an amount of 1% to 40% by weight in certain embodiments, or in an amount of 1% to 35% by weight in certain embodiments, or in an amount of 1% to 30% by weight in certain embodiments, or in an amount of 1% to 25% by weight in certain embodiments, or in an amount of 5% to 45% by weight in certain embodiments, or in an amount of 5% to 40% by weight in certain embodiments, or in an amount of 5% to 35% by weight in certain embodiments, or in an amount of 5% to 30% by weight in certain embodiments, or in an amount of 5% to 25% by weight in certain embodiments, or in an amount of 5% to 21% by weight in certain embodiments, or in an amount of 5.5% to 21% by weight in certain embodiments, or in an amount of 5.5% to 20.5% by weight in certain embodiments, or in an amount of 5.5% to 20% by weight in certain embodiments. 
     The filler in the composition of the present disclosure is one or more selected from mannitol, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. In certain embodiments, the filler is selected from one or more of mannitol and microcrystalline cellulose. In certain embodiments, it is a combination of mannitol and microcrystalline cellulose. 
     The filler in the composition of the present disclosure is selected from a combination of mannitol and microcrystalline cellulose with a content of mannitol of 9% to 40% by weight. In certain embodiments, the content of mannitol is 9% to 35% by weight; in certain embodiments, the content of mannitol is 10% to 28% by weight; in certain embodiments, the content of mannitol is 9% to 25% by weight; in certain embodiments, the content of mannitol is 9% to 20% by weight; in certain embodiments, the content of mannitol is 15% to 35% by weight; in certain embodiments, the content of mannitol is 15% to 30% by weight; in certain embodiments, the content of mannitol is 15% to 28% by weight; in certain embodiments, the content of mannitol is 15% to 25% by weight; in certain embodiments, the content of mannitol is 15% to 20% by weight. 
     The filler in the composition according to the present disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein said microcrystalline cellulose comprises microcrystalline cellulose A and microcrystalline cellulose B. The microcrystalline cellulose A is selected from microcrystalline cellulose PH14, microcrystalline cellulose PH12, microcrystalline cellulose 12 or microcrystalline cellulose 14. In certain embodiments, the microcrystalline cellulose A is selected from microcrystalline cellulose 12; in certain embodiments, the microcrystalline cellulose A is selected from microcrystalline cellulose PH12; in certain embodiments, the microcrystalline cellulose A is selected from microcrystalline cellulose PH14; in certain embodiments, the microcrystalline cellulose A is selected from microcrystalline cellulose 14. The microcrystalline cellulose B is selected from microcrystalline celluloses of PH102, PH105, PH103, PH301, PH101, PH112, PH302, and microcrystalline celluloses of 102, 105, 103, 301, 101, 112, 302. In certain embodiments, the microcrystalline cellulose B is selected from microcrystalline cellulose 102; in certain embodiments, the microcrystalline cellulose B is selected from microcrystalline cellulose PH102. 
     The filler in the composition according to the present disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein said microcrystalline cellulose comprises microcrystalline cellulose A and B, which are respectively selected from microcrystalline cellulose 102 and microcrystalline cellulose 12. 
     The filler in the composition according to the disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose comprises microcrystalline cellulose A and B, with a content of the microcrystalline cellulose A of 3% to 60% by weight. In certain embodiments, the content of the microcrystalline cellulose A is 3% to 59% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 3% to 58% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 3% to 10% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 3% to 8% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 15% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 12% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 10% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 9% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 8% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5% to 7.5% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5.5% to 7.5% by weight. 
     The filler in the composition according to the disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose comprises microcrystalline cellulose A and B, with a content of the microcrystalline cellulose B of 17% to 80% by weight. In certain embodiments, the content of the microcrystalline cellulose B is 17% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 40% to 80% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 40% to 70% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 40% to 75% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 41% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 42% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 50% to 80% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 50% to 75% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 50% to 70% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 55% to 80% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 55% to 75% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 56% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 56% to 61% by weight. 
     The filler in the composition according to the disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose comprises microcrystalline cellulose A and B, with a content of the microcrystalline cellulose A of 5% to 8% by weight. In certain embodiments, the content of the microcrystalline cellulose A is 5% to 7.5% by weight; in certain embodiments, the content of the microcrystalline cellulose A is 5.5% to 7.5% by weight, and a content of the microcrystalline cellulose B is 55% to 75% by weight. In certain embodiments, the content of the microcrystalline cellulose B is 56% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose B is 56% to 61% by weight. 
     The filler in the composition according to the disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose comprises microcrystalline cellulose 12 and microcrystalline cellulose 102, with a content of the microcrystalline cellulose 12 of 5% to 8% by weight. In certain embodiments, the content of the microcrystalline cellulose 12 is 5% to 7.5% by weight; in certain embodiments, the content of the microcrystalline cellulose 12 is 5.5% to 7.5% by weight, and a content of the microcrystalline cellulose 102 is 55% to 75% by weight. In certain embodiments, the content of the microcrystalline cellulose 102 is 56% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose 102 is 56% to 61% by weight. 
     The microcrystalline cellulose 12 has a particle size of D50 ranged from 130 μm to 230 μm, and a particle size of D90 ranged from 270 μm to 450 μm. The microcrystalline cellulose 102 has a particle size of D50 ranged from 90 μm to 150 μm, and a particle size of D90 ranged from 190 μm to 300 μm. 
     The filler in the composition according to the disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose comprises microcrystalline cellulose 12 and microcrystalline cellulose 102, with a content of the microcrystalline cellulose 12 of 5% to 8% by weight. In certain embodiments, the content of the microcrystalline cellulose 12 is 5% to 7.5% by weight; in certain embodiments, the content of the microcrystalline cellulose 12 is 5.5% to 7.5% by weight; and a content of the microcrystalline cellulose 102 of 55% to 75% by weight. In certain embodiments, the content of the microcrystalline cellulose 102 is 56% to 72% by weight; in certain embodiments, the content of the microcrystalline cellulose 102 is 56% to 61% by weight. The microcrystalline cellulose 12 has a particle size of D50 ranged from 130 μm to 230 μm, and a particle size of D90 ranged from 270 μm to 450 μm. The microcrystalline cellulose 102 has a particle size of D50 ranged from 90 μm to 150 μm, and a particle size of D90 ranged from 190 μm to 300 μm. 
     The filler in the composition according to the present disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the content, by weight percent, of the filler in the composition is the sum of that of the microcrystalline cellulose comprising microcrystalline cellulose A, B and that of mannitol, sum of which and that of other ingredients is 100%. 
     The filler in the composition according to the present disclosure is selected from a combination of mannitol and microcrystalline cellulose, wherein the microcrystalline cellulose has a particle size D50 ranged from 90 μm to 230 μm. When the microcrystalline cellulose has a particle size D50 less than 90 μm, a binder has to be added in the composition. 
     The lubricating agent in the composition according to the present disclosure is one or more selected from stearic acid, magnesium stearate, sodium stearyl fumarate and glyceryl behenate. In certain embodiments it is selected from magnesium stearate or stearic acid; in certain embodiments, it is magnesium stearate. 
     The lubricating agent is included in the composition according to the present disclosure in amount of 0.5% to 6% by weight, or in an amount of 0.5% to 5.5% by weight in some embodiments, or in an amount of 0.5% to 5.3% by weight in some embodiments, or in an amount of 0.5% to 2% by weight in some embodiments, or in an amount of 0.5% to 1.5% by weight in some embodiments, or in an amount of 0.5% to 1% by weight in some embodiments, or in an amount of 0.5% to 0.9% by weight in some embodiments, or in an amount of 0.5% to 0.8% by weight in some embodiments, or in an amount of 0.5% to 0.7% by weight in some embodiments, or in an amount of 0.5% to 0.6% by weight in some embodiments, or in an amount of 0.55% to 0.6% by weight in some embodiments, or in an amount of 0.51% to 0.55% by weight in some embodiments. 
     The composition according to the present disclosure may further include, optionally, one or more binders, if necessary. 
     The binder may be selected from hydroxypropyl cellulose or povidone. 
     The binder is included in an amount of 1% to 10% by weight, or in an amount of 1% to 6% in some embodiments, or in an amount of 1% to 5% in some embodiments, or in an amount of 1% to 4% in some embodiments, or in an amount of 1% to 3% in some embodiments, or in an amount of 4% in some embodiments, or in an amount of 3% in some embodiments. 
     The composition according to the present disclosure may further include, optionally, one or more disintegrating agents, if necessary. 
     The disintegrating agent may be selected from croscarmellose sodium and sodium carboxymethyl starch. 
     The disintegrating agent is included in an amount of 1% to 10% by weight, or in an amount of 1% to 5% in some embodiments, or in an amount of 1% to 4% in some embodiments, or in an amount of 3% to 4% in some embodiments, or in an amount of 4% in some embodiments. 
     The composition according to the present disclosure may further include, optionally, one or more glidants, if necessary. 
     The glidant is selected from silica or talc. 
     The glidant is included in an amount of 1% to 10% by weight, or in an amount of 1% to 6% in some embodiments, or in an amount of 1% to 5% in some embodiments, or in an amount of 1% to 4% in some embodiments, or in an amount of 1% to 3% in some embodiments, or in an amount of 4% in some embodiments, or in an amount of 3% in some embodiments. 
     The above percentages are based on the total weight of the composition (100%), while the defined percentage ranges of any individual component may be arbitrarily combined with that of the other component(s), provided the total percentage thereof is 100%. 
     The composition according to the present disclosure is a capsule formulation comprising:
         (i) a pharmaceutically acceptable salt of the compound of formula (I), as an active material, which is included in an amount of 1% to 45% by weight, or in an amount of 1% to 40% by weight in some embodiments, or in an amount of 1% to 35% by weight in some embodiments, or in an amount of 1% to 30% by weight in some embodiments, or in an amount of 1% to 25% by weight in some embodiments, or in an amount of 5% to 45% by weight in some embodiments, or in an amount of 5% to 40% by weight in some embodiments, or in an amount of 5% to 35% by weight in some embodiments, or in an amount of 5% to 30% by weight in some embodiments, or in an amount of 5% to 25% by weight in some embodiments, or in an amount of 5% to 21% by weight in some embodiments, or in an amount of 5.5% to 21% by weight in some embodiments, or in an amount of 5.5% to 20.5% by weight in some embodiments, or in an amount of 5.5% to 20% by weight in some embodiment;   (ii) a filler comprising mannitol, microcrystalline cellulose A and microcrystalline cellulose B, wherein mannitol is included in an amount of 9% to 40% by weight, or in an amount of 9% to 35% by weight in some embodiments, or in an amount of 10% to 28% by weight in some embodiments, or in an amount of 9% to 25% by weight in some embodiments, or in an amount of 9% to 20% by weight in some embodiments, or in an amount of 15% to 35% by weight in some embodiments, or in an amount of 15% to 30% by weight in some embodiments, or in an amount of 15% to 28% by weight in some embodiments, or in an amount of 15% to 25% by weight in some embodiments, or in an amount of 15% to 20% by weight in some embodiment; the microcrystalline cellulose A is included in an amount of 3% to 60% by weight, or in an amount of 3% to 59% by weight in some embodiments, or in an amount of 3% to 58% by weight in some embodiments, or in an amount of 3% to 10% by weight in some embodiments, or in an amount of 3% to 8% by weight in some embodiments, or in an amount of 5% to 15% by weight in some embodiments, or in an amount of 5% to 12% by weight in some embodiments, or in an amount of 5% to 10% by weight in some embodiments, or in an amount of 5% to 9% by weight in some embodiments, or in an amount of 5% to 8% by weight in some embodiments, or in an amount of 5% to 7.5% by weight in some embodiments, or in an amount of 5.5% to 7.5% by weight in some embodiment; and the microcrystalline cellulose B is included in an amount of 17% to 80% by weight, or in an amount of 40% to 80% by weight in some embodiments, or in an amount of 40% to 70% by weight in some embodiments, or in an amount of 40% to 75% by weight in some embodiments, or in an amount of 41% to 72% by weight in some embodiments, or in an amount of 42% to 72% by weight in some embodiments, or in an amount of 50% to 80% by weight in some embodiments, or in an amount of 50% to 75% by weight in some embodiments, or in an amount of 50% to 70% by weight in some embodiments, or in an amount of 55% to 80% by weight in some embodiments, or in an amount of 55% to 75% by weight in some embodiments, or in an amount of 56% to 72% by weight in some embodiments, or in an amount of 56% to 61% by weight in some embodiment;   (iii) magnesium stearate, as a lubricating agent, which is included in an amount of 0.5% to 6% by weight, or in an amount of 0.5% to 5.5% by weight in some embodiments, or in an amount of 0.5% to 5.3% by weight in some embodiments, or in an amount of 0.5% to 2% by weight in some embodiments, or in an amount of 0.5% to 1.5% by weight in some embodiments, or in an amount of 0.5% to 1% by weight in some embodiments, or in an amount of 0.5% to 0.9% by weight in some embodiments, or in an amount of 0.5% to 0.8% by weight in some embodiments, or in an amount of 0.5% to 0.7% by weight in some embodiments, or in an amount of 0.5% to 0.6% by weight in some embodiments, or in an amount of 0.55% to 0.6% by weight in some embodiments, or in an amount of 0.51% to 0.55% by weight in some embodiments;   wherein the defined percentage ranges of any individual component may be arbitrarily combined with that of the other component(s), provided the total percentage of all components is 100%; and   wherein the pharmaceutically acceptable salt of the compound of formula (I) has a structure as follows:       

     
       
         
         
             
             
         
       
     
     The composition according to the present disclosure may further comprise a glidant, which is selected from silica and talc. In some embodiments, it is silica. 
     The compositions according to the present disclosure may further comprise a binder selected from hydroxypropyl cellulose or povidone. In certain embodiments, the binder is hydroxypropyl cellulose. In particular, when the composition only comprises one auxiliary material as the filler, the composition further comprises a binder. 
     The present disclosure also relates to a pharmaceutical composition in a form of tablets, comprising:
         (i) a pharmaceutically acceptable salt of the compound of formula (I), as an active material which is included in an amount of 4% to 35% by weight, or in an amount of 4% by weight in some embodiments, or in an amount of 11% by weight in some embodiments, or in an amount of 20% by weight in some embodiments, or in an amount of 34% by weight in some embodiments;   (ii) a filler comprising mannitol and microcrystalline cellulose B, wherein mannitol is included in an amount of 13% to 60% by weight, or in an amount of 13% to 40% by weight in some embodiments, or in an amount of 13% to 20% by weight in some embodiments; and the microcrystalline cellulose B is included in an amount of 10% to 60% by weight, or in an amount of 19% to 60% by weight in some embodiments, or in an amount of 19% to 50% by weight in some embodiments, or in an amount of 19% to 40% by weight in some embodiments, or in an amount of 40% to 60% by weight in some embodiments, or in an amount of 40% to 50% by weight in some embodiments, or in an amount of 50% to 60% by weight in some embodiments;   (iii) a binder, selected from hydroxypropyl methylcellulose, povidone or hydroxypropyl cellulose, in an amount of 4% to 10% by weight; selected from hydroxypropyl methylcellulose in some embodiments, in an amount of 4% to 7% in some embodiments, or in an amount of 5% to 7% in some embodiments, or in an amount of 5% in some embodiments, or in an amount of 6% in some embodiments, or in an amount of 7% in some embodiments;   (iv) a disintegrating agent selected from croscarmellose sodium, croscarmellose calcium, crospovidone or carboxymethyl starch sodium, in an amount of 2% to 10% by weight; selected from croscarmellose sodium in some embodiments, the amount being 6% to 10% by weight in some embodiments, or in an amount of 6% to 9% by weight in some embodiments, or in an amount of 6% by weight in some embodiments, or in an amount of 7% by weight in some embodiments, or in an amount of 8% by weight in some embodiments, or in an amount of 9% by weight in some embodiments, or in an amount of 10% by weight in some embodiments;   (v) a lubricating agent selected from magnesium stearate and sodium stearyl fumarate, in an amount of 0.5% to 1% by weight; selected from magnesium stearate in some embodiments, or in an amount of 0.6% to 1% by weight in some embodiments, or in an amount of 0.6% by weight in some embodiments, or in an amount of 0.7% by weight in some embodiments, or in an amount of 0.8% by weight in some embodiments, or in an amount of 0.9% by weight in some embodiments, or in an amount of 1% by weight in some embodiments;   wherein the defined percentage ranges of any individual component may be arbitrarily combined with that of the other component(s), provided the total percentage of the composition is 100%; and   wherein the pharmaceutically acceptable salt of the compound of formula (I) has a structure as follows:       

     
       
         
         
             
             
         
       
     
     In the composition according to the present disclosure, which is a tablet or capsule formulation, the active material is present, in terms of a free base thereof, in an amount of 1 to 100 mg, or in an amount of 2 to 80 mg in some embodiments, or in an amount of 2 to 60 mg in some embodiments, or in an amount of 2 to 50 mg in some embodiments, or in an amount of 5 to 50 mg in some embodiments, or in an amount of 5 to 40 mg in some embodiments, or in an amount of 5 to 30 mg in some embodiments, or in an amount of 5 to 20 mg in some embodiments, or in an amount of 5 to 10 mg in some embodiments, or in an amount of 10 to 80 mg in some embodiments, or in an amount of 10 to 60 mg in some embodiments, or in an amount of 10 to 50 mg in some embodiments, or in an amount of 20 to 80 mg in some embodiments, or in an amount of 20 to 60 mg in some embodiments, or in an amount of 20 to 50 mg in some embodiments, or in an amount of 30 to 50 mg in some embodiments. 
     In the composition according to the present disclosure, which is a tablet or capsule formulation, the active material is present, in terms of a free base thereof, in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, or in an amount of 5 mg, 10 mg or 20 mg in some embodiments, or in an amount of 5 mg or 20 mg in some embodiments. 
     According to the present disclosure, there is also provided a method for preparing the pharmaceutical composition, comprising:
         (i) subjecting the active materials to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (ii) adding the sieved active substance and filler into a multi-directional movement mixer to be uniformly mixed;   (iii) adding a lubricating agent in the multi-directional movement mixer for mixing with the mixture obtained in (ii);   Or alternatively, when a disintegrating agent or/and a glidant is included in the mixture, adding the lubricating agent, the disintegrating agent and the glidant in the multi-directional movement mixer for mixing with the mixture obtained in (ii); and   (iv) filling a capsule with the mixture obtained in (iii).       

     According to the present disclosure, there is further provided a method for preparing the pharmaceutical composition, comprising:
         (i) subjecting the active materials to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (ii) preparing a 40% aqueous ethanol solution as a solvent;   (iii) adding the sieved active substance and filler with a binder into a wet granulator, and adding the solvent prepared in (ii) for mixing by shearing to prepare a soft material;   (iv) subjecting the soft material to sieving to produce particles, and performing static drying or dynamic drying on fluidized bed;   (v) granulating the dried soft material, and then adding it with a glidant and a disintegrating agent in a multi-directional movement mixer for uniform mixing;   (vi) adding a lubricating agent in the multi-directional movement mixer for mixing; and   (vii) filling a capsule with the mixture obtained in (vi).       

     Or alternatively, the steps (ii) and (iii) may be replaced by:
         (ii-1) formulating a binder and a 40% aqueous ethanol solution into a binder solution;   (iii-1) adding the active material and filler into a wet granulator, and adding the binder solution prepared in (ii-1) for mixing by shearing to prepare a soft material.       

     According to the present disclosure, there is further provided a method for preparing a pharmaceutical composition in form of tablet, comprising:
         (i) subjecting the active materials to a 100-mesh sieve, and subjecting a filler and a disintegrating agent to a 60-mesh sieve;   (ii) adding the sieved active material, filler and disintegrating agent into a high-speed wet granulator for uniform mixing;   (iii) adding a binder solvent into the mixed powder as obtained in (ii) to prepare a soft material;   (iv) subjecting the soft material to a 20-mesh sieve for producing particles, then performing static drying or dynamic drying on fluidized bed to adjust the moisture content to be less than 2%;   (v) subjecting the dried particles to a 24-mesh sieve for granulating, adding the granules with a lubricating agent into a multi-directional movement mixer for uniform mixing;   (vi) press-molding the mixture as obtained in step (v) into tablets.       

     Or alternatively, the steps (iii) and (iv) may be replaced by:
         (iii-1) adding the mixed powder as obtained in step (ii) to a fluidized bed, pumping the binder solution into the fluidized bed with a peristaltic pump, and producing particles by top spray.       

     The present disclosure also relates to a method for the treating and/or preventing pain, comprising: administering an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active material, wherein the effective dose is 1 to 100 mg in terms of a free salt of the compound of formula (I) or the pharmaceutically acceptable salt thereof, or 5 to 20 mg in certain embodiments, or 5 mg or 20 mg in certain embodiments. The pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, lower back pain, sciatica, dental pain, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-associated neuralgia, AIDS-associated neuralgia, cancer-associated neuralgia or non-neuropathic pain, acute or chronic tension headache, postoperative pain or fibromyalgia; in certain embodiments, it includes postherpetic neuralgia, pain caused by diabetic neuropathy or fibromyalgia. 
     The administration route in the treatment method according to the present disclosure is oral administration. 
     The present disclosure also relates to the use of the pharmaceutical composition in the preparation of a medication for treating and/or preventing pain. The pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, lower back pain, sciatica, dental pain, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-associated neuralgia, AIDS-associated neuralgia, cancer-associated neuralgia or non-neuropathic pain, acute or chronic tension headache, postoperative pain or fibromyalgia; in certain embodiments, it includes postherpetic neuralgia, pain caused by diabetic neuropathy or fibromyalgia. 
     Unless stated to the contrary, the terms used in the specification and claims have the following meanings. 
     The term “an effective dose” refers to an amount of a compound that causes physiological or medical response as required in a tissue, system, or subject, including an amount of a compound which, when administered to a subject, is sufficient to prevent the occurrence of, or to reduce to some extent, one or more symptoms of a condition or disorder being treated. 
     In the absence of special instructions, the expression “weight percent” in the present disclosure means the mass percent of a component based on the total mass of the composition, and the weight percent of each component of the formulation, such as a tablet or capsule, refers to the mass percent of such component based on the total components in the formulation, such as a tablet or capsule filler (including active agents and auxiliary materials). 
     The term “active material” in the present disclosure refers to the compound as represented by formula (I) below: 
     
       
         
         
             
             
         
       
     
     or the compound as represented by formula (II) below: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt of the compound of formula (I) or (II), such as: 
     
       
         
         
             
             
         
       
     
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a graph showing the effect of the Compound 1 on the mechanical pain threshold value in L5-L6 spinal nerve ligation animal model; 
         FIG. 2  is graph showing the effect on the mechanical pain threshold value after single-dose of Compound 1 is administrated to CCI modeling rat (X±s, n=10); 
         FIG. 3  is graph showing the effect on the mechanical pain threshold value after single-dose of Pregabalin is administrated to CCI modeling rat (X±s, n=10); 
         FIG. 4  is graph showing the XRD of Compound 1; 
         FIG. 5  is graph showing the TGA/DSC of Compound 1; and 
         FIG. 6  is a diagram depicting the single-crystal diffraction spectrum of Compound 1. 
     
    
    
     DETAILED DESCRIPTION OF THE DISCLOSURE 
     The technical solution of the disclosure is described in detail below in conjunction with drawings and examples in the following, which is, however, merely included in the protection scope of the present disclosure includes without limitation. 
     The structure of a compound was determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The NMR shift (δ) was given in 10 −6  ppm. NMR was determined using a nuclear magnetic resonance instrument (Bruker Avance III 400 and Bruker Avance 300) with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD) as a solvent, and tetramethylsilane (TMS) as an internal standard. 
     The MS measurement was conducted by Agilent 6120 B (ESI) and Agilent 6120 B (APCI). 
     The HPLC measurement was conducted by Agilent 1260 DAD high-pressure liquid chromatograph (ZorbaxSB-C 18 100×4.6 mm). 
     The known starting materials in the present disclosure may be synthesized by using or according to methods known in the art, or may be commercially available from companies such as Titan Technologies, Anaji Chemistry, Shanghai Demer, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. The microcrystalline cellulose represents microcrystalline cellulose 102, if it is not otherwise specified. 
     Intermediate 1: The Preparation of Intermediate 1j 
     
       
         
         
             
             
         
       
     
     Step 1: (±) (1S, 5R, 7S)-7-(2-bromoethyl)bicyclic [3.2.0] Hept-2-ene-6-one (1b) 
     
       
         
         
             
             
         
       
     
     A starting material 1a (24 g, 0.36 mol) and 1100 mL of cyclohexane were added into a reaction flask protected with nitrogen, and triethylamine (25 g, 0.25 mol) was added thereinto, and heated to reflux. A solution of 4-bromobutanoyl chloride (46 g, 0.25 mol) in cyclohexane was added dropwise with a syringe pump (100 mL, 25 ml/h), thereafter a reflux reaction was carried out for 4 hours. The reaction solution was suction filtered, washed with cyclohexane (150 mL×3), and the filtrates were combined, washed with saturated ammonium chloride (1000 mL×2) and water (1000 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=80:1) to give a light yellow oily product 1b (9.6 g, yield 18%).  1 H NMR (400 MHz, CDCl 3 ) δ 5.97-5.85 (m, 1H), 5.80-5.70 (m, 1H), 3.91-3.79 (m, 1H), 3.67 (dd, J=9.7, 5.5 Hz, 2H), 3.47 (t, J=6.8 Hz, 2H), 2.68 (ddd, J=18.3, 15.2, 3.9 Hz, 1H), 2.47-2.31 (m, 1H), 2.13 (dq, J=21.0, 6.5 Hz, 1H), 1.93 (ddd, J=21.5, 12.2, 7.1 Hz, 1H) 
     Step 2: (±) (1S, 5R, 7S)-7-(2-bromoethyl) Spiro[bicyclic [3.2.0] Hept-[2]-ene-6, 2′-[1, 3] Dioxolane] (1c) 
     
       
         
         
             
             
         
       
     
     The compound 1b (23 g, 0.11 mol), p-toluenesulfonic acid monohydrate (1.0 g, 5.5 mmol), and ethylene glycol (27.3 g, 0.44 mol) were taken into a single-necked flask, added with 250 mL of toluene, and heated for refluxing and water separation for 6 h. Upon cooling, the reaction solution was poured into ice water, added with sodium bicarbonate to adjust the pH value to neutral, and extracted with ethyl acetate (300 mL×3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate:petroleum ether=1:30) to obtain a yellow oily product 1c (21.2 g, yield 75%).  1 H NMR (400 MHz, CDCl 3 ) δ 5.94-5.83 (m, 1H), 5.67-5.56 (m, 1H), 3.95-3.75 (m, 4H), 3.36-3.25 (m, 2H), 3.23-3.12 (m, 1H), 3.02 (ddd, J=22.9, 15.7, 8.0 Hz, 2H), 2.48-2.25 (m, 2H), 1.99-1.78 (m, 2H). 
     Step 3: (±) (1S, 5R, 7S)-7-(2-bromoethyl) Spiro[bicyclic [3.2.0] Hept-[2]-ene-6,2′-[1, 3] Dioxolane]-2-ol (1d) 
     
       
         
         
             
             
         
       
     
     The starting material 1c (15 g, 0.06 mol) was added into a reaction flask, added with tetrahydrofuran (250 ml) as a solvent, and added dropwise with a borane dimethyl sulfide solution (30 ml, 0.3 mol) in an ice-water bath. Then, the resultant was left stand at the temperature for 2 hours, added dropwise with a purified water (0.6 mol) in the ice-water bath, then added dropwise with a sodium hydroxide aqueous solution (3 mol/1,200 ml), then added dropwise with hydrogen peroxide (containing 0.6 mol of H 2 O 2 ). Then it is heated to room temperature to react for 3 hours. Thereafter, it is extracted with ethyl acetate (200 mL×3), and the organic phases were combined, washed with water (300 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow oily product 1d (16.5 g), which was used in the next step without purification. 
     Step 4: (±) (1S, 5R, 7S)-7-(2-bromoethyl) Spiro[bicyclic [3.2.0] Hept-[2]-ene-6, 2′-[1,3] Dioxolane]-2-one (1e) 
     
       
         
         
             
             
         
       
     
     The compound 1d (16.5 g, 0.06 mol) and dichloromethane (250 mL) were added to a reaction flask, and added with a Dess-Martin oxidant (38.2 g, 0.09 mol) in batch manner in an ice bath, and reacted at room temperature for 2 hours. A saturated sodium bicarbonate solution was added dropwise to the reaction solution until the pH was about 7. The resultant was subjected for liquid separation, and the aqueous phase was extracted with dichloromethane (200 mL×2), while the organic phases were combined, washed with water (500 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=8:1) to give a light yellow oily product 1e (9.7 g, yield 59%).  1 H NMR (400 MHz, CDCl 3 ) δ 4.02-3.81 (m, 4H), 3.40 (dd, J=10.3, 3.8 Hz, 2H), 3.15 (td, J=10.3, 4.9 Hz, 2H), 2.61 (ddd, J=20.6, 14.0, 8.1 Hz, 2H), 2.27 (ddt, J=18.9, 9.6, 1.8 Hz, 1H), 2.12-2.00 (m, 1H), 1.99-1.70 (m, 3H). 
     Step 5: (±) (1′R, 3&#39;S, 6&#39;S)-spiro[[1,3]dioxolane-2,2′-tricyclic[4.2.1.0 3,8 ] Nonane] -7′-one (1f) 
     
       
         
         
             
             
         
       
     
     Potassium tert-butoxide (16 g, 0.14 mol) and tetrahydrofuran (1 L) were added to a reaction flask under protection of nitrogen. The resultant was cooled to −0° C., added dropwise with the compound 1e in toluene (29 g, 0.11 mol), and then stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added dropwise in an ice bath until the pH was about 7, extracted with ethyl acetate (500 mL×2), washed with water (1000 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10:1) to give a pale yellow oily product 1f (9.5 g, yield 45%).  1 H NMR (400 MHz, CDCl 3 ) δ 4.04-3.86 (m, 4H), 3.20-3.07 (m, 1H), 2.99-2.86 (m, 1H), 2.53 (ddd, J=8.6, 5.6, 1.7 Hz, 1H), 2.41-2.24 (m, 2H), 2.24-2.01 (m, 2H), 1.95 (d, J=13.2 Hz, 1H), 1.61 (dddd, J=14.4, 7.6, 2.6, 0.7 Hz, 1H), 1.51-1.38 (m, 1H). 
     Step 6: (±) (1′R, 3&#39;S, 6&#39;S)-spiro[[1,3] Dioxolane-2,2′-tricyclic [4.2.1.0 3,8 ] Nonane] (1g) 
     
       
         
         
             
             
         
       
     
     The starting material 1f (9.0 g, 46.3 mmol) and diethylene glycol (150 mL) were added into a reaction flask, added with hydrazine hydrate (8.9 g, 278 mmol) and potassium hydroxide (15.6 g, 278 mmol). The resultant was reacted at 180° C. for 3 hours, followed by a rotary evaporation under reduced pressure for water removal at 70° C., then warmed to 220° C. and reacted for 2 hours, and cooled. The resulting reaction solution was added with water (200 mL), extracted with methyl tert-butyl ether (300 mL×3), washed with 1 mol/1 hydrochloric acid (400 mL×2), washed with water (400 mL×2), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=60:1) to give a colorless oily product 1g (3 g), which was used in the next step without purification. 
     Step 7: (±) (1R, 3S, 6R, 8R)-tricyclic [4.2.1.0 3,8 ] Nonane-2-one (1h) 
     
       
         
         
             
             
         
       
     
     The starting material 1g (3 g, 16.6 mmol) was added to a reaction flask, then added with tetrahydrofuran (36 ml) and water (12 ml) as solvents, and added dropwise with trifluoroacetic acid (8 ml) in an ice bath, and reacted at 45° C. for 3 hours. The resultant was added dropwise with a saturated sodium bicarbonate solution in an ice bath until the pH was about 7, then extracted with ethyl acetate (80 mL×3), washed with water (100 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=100:1) to give a white solid product 1h (2 g, yield 88%).  1 H NMR (400 MHz, CDCl 3 ) δ 3.47-3.33 (m, 1H), 3.19 (dd, J=3.3, 1.8 Hz, 1H), 2.84-2.69 (m, 1H), 2.47-2.32 (m, 1H), 2.12-1.97 (m, 1H), 1.93 (d, J=12.3 Hz, 1H), 1.82-1.69 (m, 1H), 1.56-1.35 (m, 4H), 1.27-1.10 (m, 1H). 
     Step 8: (±) Ethyl 2-((1R, 3S, 6R, 8R)-tricyclic [4.2.1.0 3,8 ] Non-2-ylidene) Acetate (1i) 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60%, 91.6 g, 3.82 mol) and tetrahydrofuran (5 L) were added to a reaction flask, cooled to 0° C., and added dropwise with ethyl diethoxyphosphono ethylacetate (856 g, 3.82 mol) in tetrahydrofuran (400 mL). Then, the resultant was left stand at the temperature for 15 minutes, and added dropwise with the compound 1h (400 g, 2.94 mol) in tetrahydrofuran (200 mL), and then heated to room temperature for reaction for 1 hour. The resultant was added with a saturated ammonium chloride dropwise to pH 7-8 in an ice water bath, extracted with ethyl acetate (500 mL×3), washed with saturated brine (500 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=30:1) to give a light yellow oily product 1i (310 g, 51% yield). 
     Step 9: (±) Ethyl 2-((1R, 3S, 6R, 8R)-2-(nitromethyl) Tricyclic [4.2.1.0 3,8 ] non-2-yl) Acetate (1j) 
     
       
         
         
             
             
         
       
     
     The starting material 1i (390 g, 1.89 mol), nitromethane (4 L) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (575.6 g, 3.78 mol) were added to a reaction flask and was heated to 80° C. for 9 hours. The reaction liquid was poured into ice water (3000 ml), extracted with DCM (2000 mL×3), washed with brine (3000 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=100:1) to give a colorless oily product 1j (360 g, yield 71%). 
     The Preparation of Compound 1: 
     
       
         
         
             
             
         
       
     
     (±) ethyl 2-((1R, 3S, 6R, 8R)-2-(nitromethyl) tricyclic [4.2.1.0 3 ′ 8 ] non-2-yl) acetate (intermediate 1j) (360 g) was used for resolution under the following condition: using Thar analytical SFC (SFC-A) as an instrument, chiralPak AD, 150×4.6 mm I.D. 3 m as a column, with mobile phases of A for CO 2  and B for Methanol, gradient of B as 5-40%, a flow velocity of 2.4 mL/min, and a column temperature of 35° C. Two optical isomers were obtained after separation: peak 1 (retention time: 3.8 minutes, 174 g) and peak 2 (retention time: 5.7 minutes, 160 g). Compound 1j: [α] 20D=0.00° (C=0.9, CH2Cl2); peak 2: [α] 20D=44° (C=0.103, CH3OH). Here, C refers to the weight (in g) of the substance to be tested per 100 mL of solution, and 20D refers to a test at 20° C., with a sodium light lamp as a light source, at a wavelength of 589 nm. 
     Step 1: (1&#39;S, 2&#39;S, 3′R, 6&#39;S, 8&#39;S)-spiro[pyrrolidine-3,2′-tricyclic [4.2.1.0 3,8 ] Nonane]-5-one (1k-1) 
     
       
         
         
             
             
         
       
     
     The starting material 1j-1 (peak 2, 270 g, 1.01 mol), ethanol (1 L) and water (1 L) were added to a reaction flask, then added with reduced iron powders (282 g, 5.05 mol) and ammonium chloride (162 g, 3.03 mol), and reacted under refluxing for 4 hours. The reaction solution was filtered, and the filtrate was concentrated to remove ethanol, thereafter the remaining solution was added with 500 mL of water, while the filter residue was washed with dichloromethane (200 mL×3). The filtrate was collected, and the organic phase was mixed with the aforesaid remaining solution, subjected to liquid separation, extracted with dichloromethane twice (500 mL×2). The organic phases were combined, washed with water (500 mL×2), dried with sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40: 1-10:1) to obtain a white solid product 1k-1 (160 g, yield 83%). 
     Step 2: 2-((1S, 2S, 3R, 6S, 8S)-2-(aminomethyl) Tricyclic[4.2.1.0 3,8 ]non-2-yl) Acetic Acid (1l-1) 
     
       
         
         
             
             
         
       
     
     The starting material 1k-1 (320 g, 1.673 mol) was added to a reaction flask, then added with 6N hydrochloric acid (1.6 L), and reacted under refluxing for 16h. The precipitated solid was filtered. The obtained solid was dissolved in 1 L of purified water, adjusted with concentrated ammonia water until the pH was about 7, subjected to suction filtration, washed with ice water, and dried to obtain a white solid. The filtrate was adjusted with 10N sodium hydroxide in an ice water bath until the pH was about 6, and further adjusted with concentrated ammonia water until the pH was about 7, and extracted with dichloromethane (1 L×3). The remaining aqueous phase was concentrated and dried, filtered, and washed with ice water to obtain a white solid. The resulting solid as obtained in the two portions was pulped with dichloromethane (1.5 L×3) to give a white solid compound 1l-1 (245 g, 70%). 
     The Preparation of Compound 1: 
     
       
         
         
             
             
         
       
     
     The compound 1l-1 (245 g, 1.17 mol) was added into a reaction flask, added with methanol (2.2 L), and added dropwise with benzenesulfonic acid monohydrate (268.0 g, 1.52 mol) in methanol, then stirred for 1 hour at room temperature. The precipitated solid was filtered by suction, and the filtrate was concentrated to obtain a solid. The resulting solid in the two portions was combined and pulped with dichloromethane (1.5 L×3), filtered, washed with ethyl acetate, and dried to obtain a pure compound 1 (398 g, yield 92.5%, HPLC: 9 9%, with a chemical formula of C 12 H 19 NO 2 .C 6 H 6 O 3 S).  1 H NMR (400 MHz, D 2 O) δ 7.85-7.70 (m, 2H), 7.54 (tt, J=14.3, 7.2 Hz, 3H), 3.33 (d, J=13.8 Hz, 2H), 2.81 (dd, J=13.2, 5.4 Hz, 1H), 2.57 (q, J=17.6 Hz, 2H), 2.47-2.37 (m, 1H), 2.27 (dd, J=12.0, 6.0 Hz, 1H), 2.17-2.06 (m, 1H), 1.96 (dd, J=21.6, 9.5 Hz, 1H), 1.79-1.66 (m, 1H), 1.66-1.40 (m, 4H), 1.33 (dd, J=14.3, 9.0 Hz, 1H), 1.26-1.15 (m, 1H). 
     The peak value of compound 1 in the X-ray powder-diffraction pattern (XRD) is shown in the table as below, and specifically shown in  FIG. 4 . 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Peak 
                   
                 Interplanar 
                 Relative peak 
               
               
                 2θ 
                 height 
                 FWHM 
                 spacing [Å] 
                 height [%] 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 9.7167 
                 4046.64 
                 0.1279 
                 9.10278 
                 33.05 
               
               
                 11.1352 
                 1612.11 
                 0.0384 
                 7.94615 
                 13.17 
               
               
                 11.2128 
                 1820.68 
                 0.1023 
                 7.89135 
                 14.87 
               
               
                 11.8322 
                 277.75 
                 0.1535 
                 7.47961 
                 2.27 
               
               
                 14.0077 
                 3132.13 
                 0.0512 
                 6.32246 
                 25.58 
               
               
                 14.0962 
                 2255.84 
                 0.064 
                 6.28296 
                 18.43 
               
               
                 15.1565 
                 3670.71 
                 0.064 
                 5.84573 
                 29.98 
               
               
                 15.3713 
                 1403.94 
                 0.0768 
                 5.76452 
                 11.47 
               
               
                 15.6037 
                 1165.35 
                 0.1279 
                 5.67918 
                 9.52 
               
               
                 15.9607 
                 443.05 
                 0.0512 
                 5.55295 
                 3.62 
               
               
                 16.3325 
                 12242.87 
                 0.1023 
                 5.42737 
                 100 
               
               
                 18.2092 
                 900.66 
                 0.1151 
                 4.87203 
                 7.36 
               
               
                 18.87 
                 1903.14 
                 0.064 
                 4.70287 
                 15.54 
               
               
                 19.0176 
                 2554.83 
                 0.0384 
                 4.66672 
                 20.87 
               
               
                 19.3165 
                 5667.72 
                 0.1279 
                 4.59518 
                 46.29 
               
               
                 19.8771 
                 4571.39 
                 0.0895 
                 4.46681 
                 37.34 
               
               
                 20.3279 
                 1930.15 
                 0.0384 
                 4.36878 
                 15.77 
               
               
                 20.4622 
                 3513.85 
                 0.0768 
                 4.3404 
                 28.7 
               
               
                 21.1053 
                 859.6 
                 0.0768 
                 4.20958 
                 7.02 
               
               
                 21.2599 
                 1641.19 
                 0.0512 
                 4.17932 
                 13.41 
               
               
                 21.5253 
                 3785.86 
                 0.0384 
                 4.12837 
                 30.92 
               
               
                 21.6885 
                 7208.47 
                 0.1151 
                 4.09769 
                 58.88 
               
               
                 22.3935 
                 724.03 
                 0.1535 
                 3.97025 
                 5.91 
               
               
                 22.7865 
                 262.87 
                 0.0384 
                 3.90265 
                 2.15 
               
               
                 23.4692 
                 1810.44 
                 0.0895 
                 3.79065 
                 14.79 
               
               
                 24.1631 
                 54.8 
                 0.1535 
                 3.68334 
                 0.45 
               
               
                 25.3274 
                 1659.16 
                 0.0624 
                 3.51369 
                 13.55 
               
               
                 25.4027 
                 1478.13 
                 0.0512 
                 3.50635 
                 12.07 
               
               
                 25.6773 
                 1433.37 
                 0.0512 
                 3.46946 
                 11.71 
               
               
                 25.9344 
                 1421.23 
                 0.0468 
                 3.4328 
                 11.61 
               
               
                 25.999 
                 1046.47 
                 0.0468 
                 3.43294 
                 8.55 
               
               
                 26.9314 
                 950.92 
                 0.1404 
                 3.30794 
                 7.77 
               
               
                 27.3414 
                 296.52 
                 0.1248 
                 3.25927 
                 2.42 
               
               
                 27.9554 
                 2439.22 
                 0.0468 
                 3.18906 
                 19.92 
               
               
                 28.0286 
                 2418.82 
                 0.0624 
                 3.1809 
                 19.76 
               
               
                 28.5766 
                 1038.14 
                 0.078 
                 3.12113 
                 8.48 
               
               
                 29.1738 
                 996.82 
                 0.0468 
                 3.05858 
                 8.14 
               
               
                 29.8174 
                 1938.81 
                 0.1248 
                 2.99402 
                 15.84 
               
               
                 30.6914 
                 348.82 
                 0.0468 
                 2.91071 
                 2.85 
               
               
                 31.3063 
                 653.82 
                 0.1248 
                 2.85493 
                 5.34 
               
               
                 31.5601 
                 212.27 
                 0.0936 
                 2.83255 
                 1.73 
               
               
                 32.3291 
                 96.39 
                 0.1872 
                 2.76691 
                 0.79 
               
               
                 33.0473 
                 214.64 
                 0.1872 
                 2.7084 
                 1.75 
               
               
                 34.2421 
                 109.66 
                 0.1248 
                 2.61658 
                 0.9 
               
               
                 35.264 
                 437.3 
                 0.078 
                 2.54306 
                 3.57 
               
               
                 35.5326 
                 412.09 
                 0.0468 
                 2.52445 
                 3.37 
               
               
                 36.1622 
                 418.43 
                 0.156 
                 2.48193 
                 3.42 
               
               
                 36.6015 
                 376.67 
                 0.1872 
                 2.45315 
                 3.08 
               
               
                 37.239 
                 295.68 
                 0.156 
                 2.4126 
                 2.42 
               
               
                 37.714 
                 195.04 
                 0.1092 
                 2.3833 
                 1.59 
               
               
                 35.5326 
                 412.09 
                 0.0468 
                 2.52445 
                 3.37 
               
               
                   
               
            
           
         
       
     
     The spectra of TGA/DSC of Compound 1 is shown in  FIG. 5 , and the single-crystal diffraction spectrum thereof is shown in  FIG. 6 . 
     Example 1: Compatibility of Auxiliary Material and Compound 1 
     The mixture of active material compound 1 and various types of filler was prepared according to table 1, and placed uncovered under a condition of a moisture and heat of 75% RH and 40° C., then was measured for its impurity content, respectively. The testing results for impurity are shown in Table 2. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Mixtures of Compound 1 with various types of fillers 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Scheme 
                 Scheme 
                 Scheme 
                 Scheme 
                 Scheme 
                 Scheme 
                 Scheme 
                 Scheme 
               
               
                 Materials 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
               
               
                   
               
               
                 Compound 1 
                 1 part     
                 1 part     
                 1 part     
                 1 part     
                 1 part     
                 1 part     
                 1 part     
                 1 part     
               
               
                 Mannitol 
                 5 parts 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 Lactose 
                 0 
                 5 parts 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 Starch 
                 0 
                 0 
                 5 parts 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 Pregelatinized 
                 0 
                 0 
                 0 
                 5 parts 
                 0 
                 0 
                 0 
                 0 
               
               
                 starch 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Sorbitol 
                 0 
                 0 
                 0 
                 0 
                 5 parts 
                 0 
                 0 
                 0 
               
               
                 Saccharose 
                 0 
                 0 
                 0 
                 0 
                 0 
                 5 parts 
                 0 
                 0 
               
               
                 Low-substituted 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 5 parts 
                 0 
               
               
                 hydroxypropyl 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 cellulose 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Microcrystalline 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 5 parts 
               
               
                 cellulose 
               
               
                   
               
            
           
         
       
     
     The preparation of the mixture of Compound 1 and various types of fillers was as follows:
         (1) subjecting Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) mixing Compound 1 and the filler uniformly to obtain a mixed powder;   (3) placing a sample uncovered under a condition of a moisture and heat of 75% RH and 40° C.       

     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 the variations in the impurity content in the 
               
               
                 mixture of Compound 1 and various fillers 
               
            
           
           
               
               
               
            
               
                   
                 Total impurity/% 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 No. 
                 Day 0 
                 Day 7 
                 Day 14 
                 Day 30 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Scheme 1 
                 0.054 
                 0.056 
                 0.064 
                 0.173 
               
               
                   
                 Scheme 2 
                 0.061 
                 0.068 
                 0.166 
                 0.297 
               
               
                   
                 Scheme 3 
                 0.054 
                 0.068 
                 0.123 
                 0.282 
               
               
                   
                 Scheme 4 
                 0.059 
                 0.139 
                 0.272 
                 0.381 
               
               
                   
                 Scheme 5 
                 0.064 
                 0.078 
                 0.148 
                 0.298 
               
               
                   
                 Scheme 6 
                 0.062 
                 0.185 
                 0.312 
                 0.425 
               
               
                   
                 Scheme 7 
                 0.068 
                 0.098 
                 0.112 
                 0.188 
               
               
                   
                 Scheme 8 
                 0.042 
                 0.056 
                 0.057 
                 0.063 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: the mannitol, low-substituted hydroxypropyl cellulose and microcrystalline cellulose have good compatibility with Compound 1. 
     Example 2: The Effect of Various Types of Fillers on the Mixing Uniformity of the Capsule Formulation 
     The capsules of Compound 1 are prepared according to Table 3, by a preparation method as follows:
         (1) subjecting Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) adding the sieved Compound 1 and the filler in a multi-directional movement mixer for uniform mixing;   (3) adding a binder, a disintegrating agent and a glidant into the multi-directional movement mixer for uniform mixing with the mixture in (2);   (4) adding a lubricating agent in the multi-directional movement mixer for a final mixing with the mixture in (3);   (5) selecting an appropriate type of capsule and filling the capsule with the final mixture obtained in (4).       

     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 the capsules with various fillers formulation 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 composition of 
                   
               
               
                   
                   
                   
                 a single dosage, 
               
               
                 No. 
                 Raw materials 
                 Amount 
                 by weight percent 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 1 
                 Compound 1 (in terms of 
                 1 
                 part 
                 4.08 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 20 
                 parts 
                 81.63  
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 4.08 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 4.08 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 4.08 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 2.04 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 2 
                 Compound 1 (in terms of 
                 1 
                 part 
                 4.08 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Low-substituted hydroxypropyl 
                 20 
                 parts 
                 81.63  
                 Filler 
               
               
                   
                 cellulose 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 4.08 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 4.08 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 4.08 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 2.04 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 3 
                 Compound 1 (in terms of 
                 1 
                 part 
                 4.08 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 12 
                 20 
                 parts 
                 81.63  
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 4.08 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 4.08 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 4.08 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 2.04 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
               
            
               
                   
                 No. 
                 Value of A + 2.2S 
                 RSD % 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Formulation 1 
                 10.75 
                 6.56 
               
               
                   
                 Formulation 2 
                 12.64 
                 7.42 
               
               
                   
                 Formulation 3 
                 8.42 
                 4.38 
               
               
                   
                   
               
            
           
         
       
     
     Example 3: The Effect of the Combination of Various Types of Fillers on Formulation Stability and Content Uniformity 
     The capsules of Compound 1 were prepared according to the ratios in Table 5, by the preparation method as shown in Example 2, and the content uniformity and stability thereof were measured. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 The raw materials for the capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 The composition of 
                   
               
               
                   
                   
                   
                 a single dosage, 
               
               
                 No. 
                 Raw materials 
                 Amount 
                 by weight percent 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 4 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Low-substituted hydroxypropyl cellulose 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 5 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 0 
                 part 
                 0.00 
                 Filler 
               
               
                   
                 Low-substituted hydroxypropyl cellulose 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 14 
                 parts 
                 54.90 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 6 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Low-substituted hydroxypropyl cellulose 
                 0 
                 part 
                 0.00 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 14 
                 parts 
                 54.90 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 7 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Low-substituted hydroxypropyl cellulose 
                 14 
                 parts 
                 54.90 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 0 
                 part 
                 0.00 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 8 
                 Compound 1 (in terms of 
                 1 
                 part 
                 9.52 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 3 
                 parts 
                 28.57 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 3 
                 parts 
                 28.57 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 9.52 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 9.52 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 9.52 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 4.76 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 9 
                 Compound 1 (in terms of 
                 1 
                 part 
                 1.55 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 30 
                 parts 
                 46.51 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 30 
                 parts 
                 46.51 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 1.55 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 1.55 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 1.55 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 0.78 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared in Example 3 were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
               
            
               
                   
                 No. 
                 Value of A + 2.2S 
                 RSD % 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Formulation 4 
                 6.25 
                 2.53 
               
               
                   
                 Formulation 5 
                 6.34 
                 2.18 
               
               
                   
                 Formulation 6 
                 4.11 
                 1.52 
               
               
                   
                 Formulation 7 
                 5.48 
                 2.45 
               
               
                   
                 Formulation 8 
                 10.25 
                 4.13 
               
               
                   
                 Formulation 9 
                 12.34 
                 4.28 
               
               
                   
                   
               
            
           
         
       
     
     The impurity detection was carried out by placing the samples uncovered under a condition of a moisture and heat of 75% RH and 40° C. to measure its impurity content. The detection results are shown in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 The stability of capsules of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 Total impurity/% 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 No. 
                 Day 0 
                 Day 7 
                 Day 14 
                 Day 30 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 4 
                 0.054 
                 0.153 
                 0.284 
                 0.573 
               
               
                   
                 Formulation 5 
                 0.061 
                 0.098 
                 0.256 
                 0.547 
               
               
                   
                 Formulation 6 
                 0.057 
                 0.061 
                 0.201 
                 0.372 
               
               
                   
                 Formulation 7 
                 0.059 
                 0.139 
                 0.372 
                 0.781 
               
               
                   
                   
               
            
           
         
       
     
     The results show that the impurity levels of Formulations 4-7 were high after 30 days. 
     Example 4: The Wet Preparation of Capsules of Compound 1 
     The capsules of Compound 1 were prepared according to the formulations in Table 8 by a preparation method as follows:
         (1) subjecting Compound 1 to a 60-mesh sieve, and subjecting mannitol and microcrystalline cellulose to a 40-mesh sieve for use;   (2) formulating a hydroxypropyl cellulose into a 40% aqueous ethanol solution as a binder;   (3) adding Compound 1, mannitol and microcrystalline cellulose into a wet granulator, and adding the binder in (2) thereinto for mixing by shearing to prepare a soft material;   (4) subjecting the soft material to a sieve for producing particles, and then performing static drying;   (5) subjecting the dried soft materials to granulation, and then adding it with croscarmellose sodium and silica in a multi-directional movement mixer for uniform mixing;   (6) adding magnesium stearate in the multi-directional movement mixer for a final mixing;   (7) selecting an appropriate type of capsule and filling the capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 the raw materials for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 10 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 14 
                 parts 
                 54.90 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 9. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
               
            
               
                   
                 No. 
                 Value of A + 2.2S 
                 RSD % 
               
               
                   
                   
               
               
                   
                 Formulation 10 
                 5.42 
                 2.54 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: the composition as prepared has a value of A+2.2S equal to or less than 15, satisfying the requirement as described in Chinese Pharmacopoeia, 2015 edition for the content uniformity. 
     The capsule of Compound 1 as prepared was subjected to a dissolution test using high performance liquid chromatography, and the results are shown in Table 10. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 the dissolution of the capsule of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 No. 
                 Dissolution rate after 15 mins (%) 
               
               
                   
                   
               
               
                   
                 Formulation 10 
                 92.5 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: the composition as prepared can be rapidly dissolved out. 
     Example 5: The Wet Preparation of Capsules of Compound 1 
     The capsules of Compound 1 were prepared according to the formulations in Table 11 by a preparation method as follows:
         (1) subjecting Compound 1 to a 60-mesh sieve, and subjecting mannitol and microcrystalline cellulose to a 40-mesh sieve for use;   (2) formulating a 40% aqueous ethanol solution as a solvent;   (3) adding Compound 1, hydroxypropyl methyl cellulose, mannitol and microcrystalline cellulose into a wet granulator, and adding the solvent in (2) therein for mixing by shearing to prepare a soft material;   (4) subjecting the soft material to a sieve for producing particles, and then performing dynamic drying on a fluidized bed;   (5) subjecting the dried soft materials to granulation, and then adding it with croscarmellose sodium and silica in a multi-directional movement mixer for uniform mixing;   (6) adding magnesium stearate in the multi-directional movement mixer for a final mixing;   (7) selecting an appropriate type of capsule and filling the capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 the raw materials for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 11 
                 Compound 1 (in terms of 
                 1 
                 part 
                 3.92 
                 Active 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Mannitol 
                 7 
                 parts 
                 27.45 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 14 
                 parts 
                 54.90 
                 Filler 
               
               
                   
                 Hydroxypropyl Cellulose 
                 1 
                 part 
                 3.92 
                 Binder 
               
               
                   
                 Silica 
                 1 
                 part 
                 3.92 
                 Glidant 
               
               
                   
                 Croscarmellose sodium 
                 1 
                 part 
                 3.92 
                 Disintegrating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 part 
                 1.96 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 12. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
               
            
               
                   
                 No. 
                 Value of A + 2.2S 
                 RSD % 
               
               
                   
                   
               
               
                   
                 Formulation 11 
                 6.41 
                 1.78 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: the composition as prepared has a value of A+2.2S equal to or less than 15, satisfying the requirement as described in Chinese Pharmacopoeia, 2015 edition for the content uniformity. 
     The capsule of Compound 1 as prepared was subjected to a dissolution test using high performance liquid chromatography, and the results are shown in Table 13. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 the dissolution of the capsule of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 No. 
                 Dissolution rate after 15 mins (%) 
               
               
                   
                   
               
               
                   
                 Formulation 11 
                 92.4 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: the composition as prepared can be rapidly dissolved out. 
     The capsules of Compound 1 were prepared according to Table 14 by the method as described in Example 5. The capsules as prepared had a content uniformity satisfying the requirement in Chinese Pharmacopoeia, 2015 edition. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 the raw materials and compositions for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                   
                   
                 Capsule 
               
               
                 No. 
                 Actives 
                 Filler 1 
                 Filler 2 
                 Binder 
                 Glidant 
                 Disintegrant 
                 Lubricant 
                 shell 
               
               
                   
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS1 part 
                 Magnesium 
                 One 
               
               
                 12 
                   
                 30 parts 
                 30 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 13 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMSS 1 part 
                 Magnesium 
                 One 
               
               
                 14 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 15 
                   
                 7 parts 
                 14 parts 
                 0.1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 16 
                   
                 7 parts 
                 14 parts 
                 3 parts 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPMC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 17 
                   
                 7 parts 
                 14 parts 
                 0.1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPMC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 18 
                   
                 7 parts 
                 14 parts 
                 3 parts 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 Povidone 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 19 
                   
                 7 parts 
                 14 parts 
                 0.1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 Povidone 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 20 
                   
                 7 parts 
                 14 parts 
                 5 parts 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 21 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 5 parts 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Talc 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 22 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Talc 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 23 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 5 parts 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 24 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 2    
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One 
               
               
                 25 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.1 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Stearic acid 
                 One 
               
               
                 26 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 2 parts 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Stearic acid 
                 One 
               
               
                 27 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 0.1 part 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 SSF 
                 One 
               
               
                 28 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 2 parts 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 SSF 
                 One 
               
               
                 29 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 0.1 part 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Glyceryl 
                 One 
               
               
                 30 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 Behenate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 2 parts 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Glyceryl 
                 One 
               
               
                 31 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 Behenate 
                 Gelatin 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.1 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One blank 
               
               
                 32 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 HPS 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
                 capsule 
               
               
                 Formulation 
                 1 part 
                 Mannitol 
                 MCC 
                 HPC 
                 Silica 
                 CMS 1 part 
                 Magnesium 
                 One HPMC 
               
               
                 33 
                   
                 7 parts 
                 14 parts 
                 1 part 
                 1 part 
                   
                 stearate 
                 capsule 
               
               
                   
                   
                   
                   
                   
                   
                   
                 0.5 part 
               
               
                   
               
            
           
         
       
     
     The abbreviations in the above table: 
     MCC: Microcrystalline cellulose 
     HPC: Hydroxypropyl cellulose 
     HPMC: Hydroxypropyl methyl cellulose 
     CMS: Croscarmellose sodium 
     HPS: Hydroxypropyl starch 
     Example 6: Capsules of Compound 1 
     The capsules of Compound 1 were prepared according to the formulations in Table 15 by a preparation method as follows:
         (1) subjecting a bulk drug of Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) adding the Compound 1 and the filler in a multi-directional movement mixer for uniform mixing;   (3) adding a lubricating agent and other additives in the multi-directional movement mixer for a final mixing with the mixture in (2);   (4) filling a capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 the raw materials and compositions for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 34 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.52 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 17 
                 parts 
                 93.92  
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.55 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 35 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.52 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Microcrystalline cellulose 102 
                 17 
                 parts 
                 93.92  
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.55 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 36 
                 Compound 1 (in terms of 
                 1 
                 part 
                 6.06 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 30.30  
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 10 
                 parts 
                 62.11  
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.62 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 16. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 Value of A + 2.2S 
                   
               
               
                 No. 
                 of Capsules 
                 RSD % of mixed powders 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Formulation 34 
                 18.9 
                 9.64 
               
               
                 Formulation 35 
                 21.4 
                 12.5 
               
               
                 Formulation 36 
                 15.4 
                 6.24 
               
               
                   
               
            
           
         
       
     
     Conclusion: the formulations 34, 35 and 36 have a value of A+2.2S larger than 15, which does not satisfy the requirement as described in Chinese Pharmacopoeia, 2015 edition for the content uniformity. 
     Example 7: Capsules of Compound 1 
     The capsules of Compound 1 were prepared according to the formulations in Table 17 by a preparation method as follows:
         (1) subjecting a bulk drug of Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) adding the Compound 1 and the filler in a multi-directional movement mixer for uniform mixing;   (3) adding a lubricating agent and other additives in the multi-directional movement mixer for a final mixing with the mixture in (2);   (4) filling a capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 the raw materials and compositions for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 37 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.85 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 29.24 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 10 
                 parts 
                 58.48 
                 Filler 
               
               
                   
                 Hydroxypropyl cellulose 
                 1 
                 part 
                 5.85 
                 Binder 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.58 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 38 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.85 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 29.24 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 5 
                 parts 
                 29.24 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 101 
                 5 
                 parts 
                 29.24 
                 Filler 
               
               
                   
                 Hydroxypropyl cellulose 
                 1 
                 part 
                 5.85 
                 Binder 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.58 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     Impurity test: the sample was placed under a condition of a moisture of 75% RH and 40° C. (uncovered) for its impurity test. The variations of a total impurity content are shown in Table 18. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Variations of a total impurity content in capsules of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 Total impurity/% 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Sample No. 
                 Day 0 
                 Day 7 
                 Day 14 
                 Day 30 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 37 
                 0.051 
                 0.065 
                 0.148 
                 0.342 
               
               
                   
                 Formulation 38 
                 0.054 
                 0.066 
                 0.164 
                 0.387 
               
               
                   
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 19. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 Value of A + 2.2S 
                   
               
               
                 No. 
                 of Capsules 
                 RSD % of mixed powders 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Formulation 37 
                 10.5 
                 5.44 
               
               
                 Formulation 38 
                 8.42 
                 4.29 
               
               
                   
               
            
           
         
       
     
     It can be seen from the above results that the compatibility of the active material and excipients was improved. 
     Example 8: Capsules of Compound 1 
     The capsules of Compound 1 were prepared according to the formulations in Table 20 by a preparation method as follows:
         (1) subjecting a bulk drug of Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) adding the Compound 1 and the filler in a multi-directional movement mixer for uniform mixing;   (3) adding a lubricating agent and other additives in the multi-directional movement mixer for a final mixing with the mixture in (2);   (4) filling a capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 the raw materials and compositions for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 39 
                 Compound 1 (in terms of 
                 1 
                 part 
                 6.21 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 103 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.62 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 40 
                 Compound 1 (in terms of 
                 1 
                 part 
                 6.21 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 5 
                 part 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 112 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.62 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 41 
                 Compound 1 (in terms of 
                 1 
                 part 
                 6.21 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 14 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.62 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 42 
                 Compound 1 (in terms of 
                 1 
                 part 
                 6.21 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 102 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 5 
                 parts 
                 31.06 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.62 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 43 
                 Compound 1 (in terms of 
                 8 
                 parts 
                 44.2 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Microcrystalline cellulose 102 
                 7.6 
                 parts 
                 41.99 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 0.6 
                 part 
                 3.31 
                 Filler 
               
               
                   
                 Mannitol 
                 1.8 
                 parts 
                 9.94 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.55 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                   
                 — 
               
               
                 Formulation 44 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.85 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Microcrystalline cellulose 102 
                 3 
                 parts 
                 17.54 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 10 
                 parts 
                 58.48 
                 Filler 
               
               
                   
                 Mannitol 
                 3 
                 parts 
                 17.54 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.58 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                   
                 — 
               
               
                 Formulation 45 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.26 
                 — 
               
               
                   
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Microcrystalline cellulose 102 
                 13 
                 parts 
                 68.42 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 1 
                 part 
                 5.26 
                 Filler 
               
               
                   
                 Mannitol 
                 3 
                 part 
                 15.79 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 1 
                 part 
                 5.26 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                   
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 21. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
            
               
                   
                 Value of A + 2.2S 
                   
               
               
                 No. 
                 of Capsules 
                 RSD % of mixed powders 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Formulation 39 
                 15.3 
                 8.47 
               
               
                 Formulation 40 
                 11.4 
                 7.58 
               
               
                 Formulation 41 
                 10.7 
                 7.4 
               
               
                 Formulation 42 
                 8.5 
                 5.18 
               
               
                 Formulation 43 
                 4.67 
                 1.21 
               
               
                 Formulation 44 
                 6.27 
                 2.87 
               
               
                 Formulation 45 
                 7.24 
                 0.97 
               
               
                   
               
            
           
         
       
     
     Conclusion: the formulation 39 has a value of A+2.2S larger than 15, which does not satisfy the requirement as described in Chinese Pharmacopoeia, 2015 edition for the content uniformity. The formulations 42, 43, 44 and 45 were improved in the content uniformity. 
     Example 9: The Preparation of Capsule Formulations of Specification of 5 mg and 20 mg of an Active Material (in Terms of Free Base of Compound 1) 
     The capsules of Compound 1 were prepared according to the formulations in Table 22 by a preparation method as follows:
         (1) subjecting a bulk drug of Compound 1 to a 60-mesh sieve, and subjecting the filler to a 40-mesh sieve for use;   (2) adding the Compound 1 and the filler in a multi-directional movement mixer for uniform mixing;   (3) adding a lubricating agent in the multi-directional movement mixer for a final mixing with the mixture in (2);   (4) filling a capsule with the mixed powders.       

     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 the compositions for capsules of Compound 1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Weight 
                   
               
               
                 No. 
                 Raw materials 
                 Amount 
                 percentage (%) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 46 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.52 
                 Active 
               
               
                 (5 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 13 
                 parts 
                 71.82 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 1 
                 part 
                 5.52 
                 Filler 
               
               
                   
                 Mannitol 
                 3 
                 parts 
                 16.57 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.55 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 47 
                 Compound 1 (in terms of 
                 1 
                 part 
                 5.52 
                 Active 
               
               
                 (5 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 11 
                 parts 
                 60.77 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 1 
                 part 
                 5.52 
                 Filler 
               
               
                   
                 Mannitol 
                 5 
                 parts 
                 27.62 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.55 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                 Formulation 48 
                 Compound 1 (in terms of 
                 4 
                 parts 
                 20.41 
                 Active 
               
               
                 (20 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                   
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 11 
                 parts 
                 56.12 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 1.5 
                 parts 
                 7.65 
                 Filler 
               
               
                   
                 Mannitol 
                 3 
                 parts 
                 15.31 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.1 
                 part 
                 0.51 
                 Lubricating 
               
               
                   
                   
                   
                   
                   
                 agent 
               
               
                   
                 Gelatin blank capsule 
                 1 
                 capsule 
                 1 capsule 
                 — 
               
               
                   
               
            
           
         
       
     
     The capsules of Compound 1 as prepared were assayed by high-performance liquid chromatography, according to General Rule 0941 “a test method for content uniformity” in Chinese Pharmacopoeia, 2015 edition. The results are shown in Table 23. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Content uniformity of the capsules of Compound 1 
               
            
           
           
               
               
               
               
            
               
                   
                 No. 
                 Value of A + 2.2S 
                 RSD % 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Formulation 46 
                 3.52 
                 1.09 
               
               
                   
                 Formulation 47 
                 3.21 
                 0.86 
               
               
                   
                 Formulation 48 
                 3.18 
                 0.94 
               
               
                   
                   
               
            
           
         
       
     
     It can be seen from the test results that the formulations 46 to 48 were improved in the content uniformity. 
     The capsules of Compound 1 as prepared were also subjected to a dissolution test by high performance liquid chromatography, and the test results are shown in Table 24. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Dissolution of capsules of Compound 1 
               
            
           
           
               
               
            
               
                   
                 Dissolution rate % 
               
               
                   
                 Month 0 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No. 
                 3 mins 
                 5 mins 
                 10 mins 
                 15 mins 
                 20 mins 
                 30 mins 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Formulation 
                 66.24 
                 91.21 
                 99.81 
                 100.03 
                 101.08 
                 101.15 
               
               
                 46 
                   
                   
                   
                   
                   
                   
               
               
                 Formulation 
                 64.69 
                 90.69 
                 99.65 
                 101.21 
                 102.17 
                 102.89 
               
               
                 47 
                   
                   
                   
                   
                   
                   
               
               
                 Formulation 
                 71.30 
                 90.29 
                 96.46 
                 98.30 
                 98.98 
                 99.06 
               
               
                 48 
               
               
                   
               
            
           
         
       
     
     It can be seen from the test results that the compositions as prepared can all dissolved out rapidly. 
     Example 10: Study on Stability 
     Objectives: to perform study on the stability for formulations 47 and 48. 
     Method: the capsules of formulations 47 and 48 were packed by aluminium foil and a solid composite plate of polyvinyl chloride/polyethylene/polyvinylidene chloride for medicine, placed uncovered under the conditions of 75% RH and 40° C. for 1 month, and then measured for its impurity content, active material content (equal to a ratio of the active material content as tested to the active material content as marked, by using a mark content as reference) and dissolution speed. The result is shown in Tables 25-27. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Variations in total impurity content 
               
            
           
           
               
               
            
               
                   
                 Total impurity content(%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 No. 
                 1 month 
                 3 months 
                 6 months 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Formulation 47 
                 0.121 
                 0.153 
                 0.237 
               
               
                   
                 Formulation 48 
                 0.117 
                 0.136 
                 0.197 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Variations in the content 
               
            
           
           
               
               
               
            
               
                   
                 Content, % (compared to the mark content) 
                   
               
            
           
           
               
               
               
               
            
               
                 No. 
                 1 month 
                 3 months 
                 6 months 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Formulation 47 
                 100.57 
                 100.16 
                 99.98 
               
               
                 Formulation 48 
                 100.86 
                 100.06 
                 100.05 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 Dissolution 
               
            
           
           
               
               
            
               
                   
                 Dissolution rate after 15 mins (%) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 No. 
                 1 month 
                 3 months 
                 6 months 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Formulation 47 
                 99.74 
                 99.12 
                 98.31 
               
               
                   
                 Formulation 48 
                 98.28 
                 98.21 
                 98.09 
               
               
                   
                   
               
            
           
         
       
     
     Example 11: Tablets of Compound 1 with Various Specification 
     The tablets of Compound 1 with various specification (in terms of free base of Compound 1) are prepared according to the composition in Table 28. 
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 the composition of tablets of Compound 1 
               
            
           
           
               
               
               
               
            
               
                 No. 
                 Raw materials 
                 Amount (mg) 
                 Functions 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Formulation 49 
                 Compound 1 (in terms of 
                 26.34 
                 — 
               
               
                 (15 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 42.31 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 
                 126.91 
                 Filler 
               
               
                   
                 Hydroxypropyl methyl cellulose 
                 15.00 
                 Binder 
               
               
                   
                 Croscarmellose sodium 
                 20.00 
                 Disintegrating 
               
               
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 2.00 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                 Formulation 50 
                 Compound 1 (in terms of 
                 52.68 
                 — 
               
               
                 (30 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 42.31 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 
                 126.91 
                 Filler 
               
               
                   
                 Hydroxypropyl methyl cellulose 
                 15.00 
                 Binder 
               
               
                   
                 Croscarmellose sodium 
                 20.00 
                 Disintegrating 
               
               
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 2.00 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                 Formulation 51 
                 Compound 1 (in terms of 
                 105.36 
                 — 
               
               
                 (60 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
               
               
                   
                 Mannitol 
                 42.31 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 
                 126.91 
                 Filler 
               
               
                   
                 Hydroxypropyl methyl cellulose 
                 15.00 
                 Binder 
               
               
                   
                 Croscarmellose sodium 
                 20.00 
                 Disintegrating 
               
               
                   
                   
                   
                 agent 
               
               
                   
                 Magnesium stearate 
                 2.00 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                 Formulation 52 
                 Compound 1 (in terms of 
                 8.78 
                 Active 
               
               
                 (5 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 114.14 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 8.78 
                 Filler 
               
               
                   
                 Mannitol 
                 26.34 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.88 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                 Formulation 53 
                 Compound 1 (in terms of 
                 8.78 
                 Active 
               
               
                 (5 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 96.58 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 8.78 
                 Filler 
               
               
                   
                 Mannitol 
                 43.9 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.88 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                 Formulation 54 
                 Compound 1 (in terms of 
                 35.12 
                 Active 
               
               
                 (20 mg) 
                 C 12 H 19 NO 2 •C 6 H 6 O 3 S) 
                   
                 material 
               
               
                   
                 Microcrystalline cellulose 102 
                 96.58 
                 Filler 
               
               
                   
                 Microcrystalline cellulose 12 
                 13.17 
                 Filler 
               
               
                   
                 Mannitol 
                 26.34 
                 Filler 
               
               
                   
                 Magnesium stearate 
                 0.88 
                 Lubricating 
               
               
                   
                   
                   
                 agent 
               
               
                   
               
            
           
         
       
     
     The preparation method is as follows:
         (1) subjecting an active drug of Compound 1 to a 100-mesh sieve, and subjecting the filler and disintegrating agent to a 60-mesh sieve for use;   (2) adding the active drug of Compound 1, the filler and the disintegrating agent into a high-speed wet granulator for uniform mixing;   (3) adding a prescribed amount of a solution of hydroxypropyl methyl cellulose as a binder to prepare a soft material;   (4) subjecting the soft material to a 20-mesh sieve for producing particles;   (5) subjecting the particles as produced to dynamic drying on a fluidized bed to adjust the moisture content to be less than 2%;   (6) subjecting the dried particles to a 24-mesh sieve for granulating;   (7) adding the granules with a prescribed amount of magnesium stearate into a multi-directional movement mixer for uniform mixing; and   (8) press-molding the final mixed powders with a mould having a proper size into tablets.       

     Example 12: The Stability Test 
     The tablets in formulations 49 to 54 were placed uncovered under the conditions of a temperature of 40° C.±2° C., and a relative humidity of 75%±5%, respectively. Then, they were tested on day 7, day 14 and day 30 for the relevant materials. The test results are shown in Table 29. 
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 test results of relevant materials 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Examples 
                 Day 0 
                 Day 7 
                 Day 14 
                 Day 30 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Numbers of impurities 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 49 
                 4 
                 5 
                 5 
                 8 
               
               
                   
                 Formulation 50 
                 5 
                 5 
                 5 
                 8 
               
               
                   
                 Formulation 51 
                 5 
                 5 
                 5 
                 8 
               
               
                   
                 Formulation 52 
                 3 
                 4 
                 4 
                 5 
               
               
                   
                 Formulation 53 
                 3 
                 4 
                 4 
                 4 
               
               
                   
                 Formulation 54 
                 3 
                 4 
                 5 
                 6 
               
            
           
           
               
               
               
            
               
                   
                 Total impurity content (%) 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 49 
                 0.037 
                 0.056 
                 0.060 
                 0.085 
               
               
                   
                 Formulation 50 
                 0.061 
                 0.066 
                 0.097 
                 0.120 
               
               
                   
                 Formulation 51 
                 0.054 
                 0.055 
                 0.064 
                 0.173 
               
               
                   
                 Formulation 52 
                 0.039 
                 0.048 
                 0.051 
                 0.073 
               
               
                   
                 Formulation 53 
                 0.036 
                 0.048 
                 0.054 
                 0.087 
               
               
                   
                 Formulation 54 
                 0.040 
                 0.052 
                 0.060 
                 0.085 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: it can be seen from the test results that impurities increase of formulations 49-54 are not significant and the formulations are relatively stable. 
     Example 13: The Preparation of Tablets by One-Step Method 
     The formulations 49-2, 50-2 and 51-2 were respectively produced by using a top spray process on a fluidized bed, according to the compositions of formulations 49, 50 and 51. 
     The method for preparing tablets by one-step method is as follows:
         (1) subjecting an active drug of Compound 1 to a 100-mesh sieve, and subjecting the filler and disintegrating agent to a 60-mesh sieve for use;   (2) adding the active drug of Compound 1, the filler and the disintegrating agent into a multi-directional movement mixer for uniform mixing;   (3) adding the mixed powder to a fluidized bed, pumping a solution of hydroxypropyl methyl cellulose into the fluidized bed with a peristaltic pump, and producing particles by top spray, wherein the inlet temperature is set to 60° C. to 65° C., the material temperature is controlled to 30° C. to 35° C., the air feeding rate is set to 140 m 3 /h to 180 m 3 /h, and the peristaltic pump is controlled to 20 rpm to 80 rpm;   (4) subjecting the dried particles to a 24-mesh sieve for granulating;   (5) adding the granules with magnesium stearate into a multi-directional movement mixer for uniform mixing; and   (6) press-molding the final mixed powders with a mould having a proper size into tablets.       

     The tablets in formulations 49-2, 50-2 and 51-2 were placed uncovered under the conditions of a temperature of 40° C.±2° C., and a relative humidity of 75%±5%, respectively. Then, they were tested on day 7, day 14 and day 30 for the relevant materials. The test results are shown in Table 30. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 test results of relevant materials 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 No. 
                 Day 0 
                 Day 7 
                 Day 14 
                 Day 30 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Numbers of impurities 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 49-2 
                 4 
                 5 
                 5 
                 8 
               
               
                   
                 Formulation 50-2 
                 5 
                 5 
                 5 
                 8 
               
               
                   
                 Formulation 51-2 
                 5 
                 5 
                 5 
                 8 
               
            
           
           
               
               
               
            
               
                   
                 Total impurity content (%) 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Formulation 49-2 
                 0.036 
                 0.055 
                 0.060 
                 0.084 
               
               
                   
                 Formulation 50-2 
                 0.060 
                 0.064 
                 0.095 
                 0.120 
               
               
                   
                 Formulation 51-2 
                 0.053 
                 0.054 
                 0.064 
                 0.172 
               
               
                   
                   
               
            
           
         
       
     
     Conclusion: it can be seen from the test results that impurities increase of formulations 54-2, 56-2 and 62-2 are not significant and the tablets are relatively stable. Meanwhile, compared with tablets obtained by a high-efficiency wet granulation process, the impurity content has no obvious difference. 
     Example 14: Bioassay 
     1. Test on the Competitive Binding Ability of Compounds to the Calcium-Ion Channel Protein Cavα2δ 
     A rat cerebral cortex tissue was placed in an ice-cold 0.32M sucrose/5 mM Tris-acetic acid (pH 7.4) having a 10-folded volume, and subjected to a sucrose density gradient centrifugation to prepare synaptic plasma membrane, which was stored in a Tris-acetic acid (pH 7.4) buffer, and re-suspended in a 10 mM HEPES (pH 7.4) buffer prior to use. The test compound was dissolved in 1% DMSO and diluted to a gradient concentration (1 nM-1000 nM), added to the suspension of synaptic plasma membrane (having about 0.05-0.1 mg protein in total) with 20 nM [3H]gabapentin and incubated at 25° C. for 30 mins. At the end of the reaction, the system was vacuum filtered into Whatman GFB membranes, which were washed three times with 5 mL of 100 mM ice-cold sodium chloride. The radioactivity of the membranes were measured by a liquid scintillation counter. Non-specific binding was closed with 100 mM gabapentin. The inhibition rate of the compound on the binding of radiolabeled gabapentin to the synaptic plasma membrane was calculated and the IC50 of the compound was also calculated. IC50 for Compound 1 is 3.96 nM. Compound 1 has a good competitive binding capacity to the calcium-ion channel protein Cavα2δ. 
     2. Animal Models of L5-L6 Spinal Nerve Ligation (SNL) 
     Six- to seven-week-old SD male rats (from Charles River) were anesthetized with 5% isoflurane in an animal surgical setting. The anesthetized animals were placed in prone position, incised at the 5th lumbar vertebra. The skin was opened to expose the left paravertebral muscles, and the L5 and L6 spinal nerves were exposed by laceration layer by layer. 4-0 surgical wires were used to ligate the distal ends of the L5 and L6 dorsal root ganglia. The muscles and skin were sutured layer by layer, and the animals were left recovered for one week. 
     After recovery, the model animals were tested for contact pain using a Von Frey wire (DanMic Global, USA). The “up-down” method was used to measure the strength of the animal having 50% leg retraction response (g; 50% PWT). First, animals were grouped with a 50% PWT of 1-5 g. Before administration, animals were tested for base value, followed by oral administration of different compounds (formulated with 5% sodium carboxymethyl cellulose). The animals were tested for pain responses at different timing for the test range of 1.0 g to 15 g. The test results are shown in  FIG. 1 . Conclusion: The compounds according to the present disclosure can significantly inhibit the mechanical pain hypersensitivity caused by spinal nerve ligation in rats. 
     3. Rat CCI-Induced Nociception Sensitization Model 
     SD rats of 160-180 g were purchased from Charles River (Beijing) with a license number of sCXK (Beijing)-2012-001 and a qualification number of 11400700254251. The surgery was performed to establish the CCI model as follows: the animals ware first anesthetized, then the left posterior sciatic nerve was exposed. A 2 mm long PE-90 catheter was applied to the middle site of the sciatic nerve. Finally the muscle and skin were sutured. Adaptation of the animal&#39;s left hind limb at 15 g was carried out from day 10 after the surgery, three times a week. 
     The baseline testing was performed 17 days after surgery (starting from 2 g at the time of testing, with an upper limit of 8 g and a lower limit of 1 g which is the −24h point), with a pain threshold of 1-4 g as a grouping criterion. Grouping was done according to baseline test results, with 10 animals per group. The animals in the group were fasted but given water overnight. On the second day, mechanical pain values were tested at 2 h, 4 h and 6 h after oral/intragastric administration. The test started at 8 g, with an upper limit of 15 g and a lower limit of 1 g. 
     The data were processed according to equation (1) to calculate the PWT 50% value, where Xf is the log value of the final test fibers used in the test, k is a table value (Chaplan et al., 1994), and δ is the mean difference (here 0.224). 
       PWT 50% (g)=(10[ Xf+k δ])/10000  [equation (1)]
 
     The data were expressed in a form of mean±standard deviation (X±s) and were statistically analyzed using one-way ANOVA and Dunnett&#39;s t test (Graphpad prism 6.01). 
     The experimental results are shown in  FIGS. 2 and 3 , which show that the mechanical pain threshold of CCI molded SD rats was significantly increased after single oral administration of Compound 1 and pregabalin. Compound 1 has an effective dose of 3 mg/kg, which is superior to pregabalin having an effective dose of 10 mg/kg. 
     Although specific embodiments of the disclosure have been described, those skilled in the art should recognize that a variety of changes and modifications can be made to the disclosure without departing from the scope or spirit of the disclosure. Thus, the present disclosure is intended to cover all such alterations and modifications that fall within the scope defined in the appended claims and their equivalents.