Patent Description:
Opioid drugs have been used to treat pains for thousands of years and play a physiological role primarily by binding to three known classic opioid receptors, i.e., mu, delta and kappa opioid receptors. These three receptors are all members of the G protein-coupled receptor family, are mainly distributed in the central nervous system, and also exist in many peripheral tissues. One of the most classic drugs is morphine, which exerts an analgesic effect mainly through the action of µ opioid receptors.

<CIT> discloses a class of synthetic peptide amide ligands of kappa opioid receptors, which have the effects of treating pains, inflammation, itching, edema, hyponatraemia, hypokalaemia, intestinal obstruction, cough and glaucoma and comprise a compound having the structure below and a development code of CR845:
<CHM>.

<CIT> discloses a class of peptide amide compounds having analgesic effects, kappa opioid receptors, and a compound comprising the structure below, which is referred to as compound II:
<CHM>.

Preclinical studies of the compound show that the compound has potent and long-acting effects on analgesia and itching treatment, and while exerting peripheral analgesic and anti-pruritic efficacies, the compound can reduce side effects associated with opioid drugs on the central nervous system.

There are currently no kappa opioid receptor peptide amide compounds on the market and no disclosure of compositions and related preparations thereof.

The present invention aims to provide a pharmaceutical composition with stability, high efficacy, low dosage, reliable safety, good compliance and low cost. The composition of the present invention can be a small-volume solution for injection.

The composition of the present invention can realize large-scale production, and the obtained product is stable and excellent in safety and can be used as medicines for the treatment of acute and chronic pain, pruritus, etc..

The present invention relates to a pharmaceutical composition comprising a compound of formula (II) below or a pharmaceutically acceptable salt thereof and a pH regulator, wherein the composition has a pH value of <NUM>-<NUM>,
<CHM>.

The pH value of the composition of the present invention is adjusted by a pH regulator, wherein the pH regulator is as defined in claim <NUM> and can be any pharmaceutically acceptable inorganic acid or organic acid buffer, wherein the inorganic acid includes sulfuric acid, hydrochloric acid, phosphoric acid, etc., and the organic acid includes acetic acid, benzoic acid, tartaric acid, lactic acid, methanesulfonic acid, citric acid, maleic acid, etc. The pH regulator is a buffer consisting of acids and salts and having a pH value in the range of <NUM>-<NUM>, and the buffer is a buffer system consisting of an acid and a corresponding salt thereof, such as an acetic acid-acetate buffer system, a tartaric acid-tartrate buffer system, and a benzoic acid-benzoate buffer system.

The pH regulator of the composition of the present invention is a buffer, which is selected from an acetic acid-acetate buffer, a phosphoric acid-phosphate buffer, a tartaric acid-tartrate buffer or a benzoic acid-benzoate buffer; in certain embodiments, the buffer is selected from an acetic acid-sodium acetate buffer, a phosphoric acid-phosphate (a sodium salt) buffer, and a tartaric acid-tartrate (a sodium salt) buffer; and in certain embodiments, the buffer is selected from an acetic acid-sodium acetate buffer.

The pH regulator of the present invention is a buffer. The concentration of the buffer can be <NUM> mmol/L-<NUM> mmol/L; in certain embodiments, the concentration is <NUM> mmol/L-<NUM> mmol/L; in certain embodiments, the concentration is <NUM> mmol/L-<NUM> mmol/L; in certain embodiments, the concentration is <NUM> mmol/L-<NUM> mmol/L; and in certain embodiments, the concentration is <NUM> mmol/L-<NUM> mmol/L.

It should be noted that the concentration of the pH regulator is the sum of the concentration of a weak acid and all corresponding salts thereof. With regard to a weak monoacid buffer system, such as an acetic acid-sodium acetate buffer, the concentration of the pH regulator is the sum of the concentration of HAc (acetic acid) and Ac- (an acetate ion); and with regard to a weak polyacid buffer system, such as a phosphoric acid-phosphate buffer, the concentration of the pH regulator is the sum of the concentration of H<NUM>PO<NUM>, H<NUM>PO<NUM>-, HPO<NUM><NUM>- and PO<NUM><NUM>- present in a solution.

In the composition of the present invention, the weight/volume ratio, w/v, of the compound of formula (I) is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; and in certain embodiments, the w/v is <NUM>%-<NUM>%. The concentration of the above-mentioned lyophilized preparation refers to the concentration of active ingredients in an aqueous solution formulated before being placed in a lyophilizer.

The composition of the present invention as prepared by the present method(s) is a solution for injection.

With regard to the composition of the present invention, a single-dose active substance content is <NUM>-<NUM>.

In addition to an active substance, i.e., a compound of formula (I), and a pH regulator, the composition of the present invention may further contain a stabilizer. The stabilizer can be selected from polyhydroxy compounds, such as sugar, sugar alcohol and polyol; the sugar includes but is not limited to monosaccharide or disaccharide, such as glucose, trehalose, raffinose or sucrose; the sugar alcohol includes but is not limited to mannitol, sorbitol or inositol; and the polyol includes but is not limited to glycerol or propylene glycol or a mixture thereof.

Where the composition is made from a sterile lyophilized powder for injection, the stabilizer thereof can also be one or any combination of the following polymers, such as HES (isethionic acid), PVP (polyvinylpyrrolidone), PEG (polyethylene glycol), glucan and albumin; the stabilizer can also be selected from a surfactant, such as Tween-<NUM> and Tween-<NUM>, or amino acids, such as L-serine, sodium glutamate, alanine and glycine; and the stabilizer can further be selected from a non-aqueous solvent, such as glycerol, dimethyl sulfoxide and tert-butanol.

In certain embodiments, the polyhydroxy compounds are selected from mannitol or propylene glycol.

The concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution; and in certain embodiments, the concentration of the stabilizer accounts for <NUM>%-<NUM>% (w/v) of the total solution.

In addition to an active substance, i.e., a compound of formula (II), and a pH regulator, the composition can further contain an isotonic regulator, and the isotonic regulator can be selected from glycerol, sodium chloride, sugars, sugar alcohol; the sugars are selected from but not limited to glucose, fructose, maltose, etc.; the sugar alcohol is selected from but not limited to sorbitol, xylitol, mannitol, etc.; in certain embodiments, the isotonic regulator is selected from mannitol, glucose, trehalose or sodium chloride; and in certain embodiments, the isotonic regulator is selected from mannitol.

The weight/volume (w/v) of the isotonic regulator is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; in certain embodiments, the w/v is <NUM>%-<NUM>%; and in certain embodiments, the w/v is <NUM>%-<NUM>%.

In addition to an active substance, i.e., a compound of formula (II), and a pH regulator, the composition of the present invention can further contain an antioxidant, and the antioxidant can be selected from sodium pyrosulfite (which can also be used as an antibacterial agent), sodium sulfite, sodium hydrogen sulfite, potassium metabisulfite, sodium thiosulphate, edetate disodium (which can also be used as an antibacterial agent), calcium disodium edetate (which can also be used as an antibacterial agent), etc..

The weight/volume (w/v) of the antioxidant is <NUM>-<NUM>%; in certain embodiments, the weight/volume (w/v) of the antioxidant is <NUM>%-<NUM>%; in certain embodiments, the weight/volume (w/v) of the antioxidant is <NUM>%-<NUM>%; in certain embodiments, the weight/volume (w/v) of the antioxidant is <NUM>%-<NUM>%; and in certain embodiments, the weight/volume (w/v) of the antioxidant is <NUM>%-<NUM>%.

In addition to an active substance, i.e., a compound of formula (II), and a pH regulator, the composition of the present invention may further contain an antibacterial agent, and the antibacterial agent can be selected from sodium pyrosulfite (which can also be used as an antioxidant), edetate disodium (which can also be used as an antioxidant), calcium disodium edetate (which can also be used as an antioxidant), methyl benzoate, sodium octanoate, cresol, benzyl alcohol, phenol, sodium benzoate, phenethyl alcohol, chlorobutanol, phenylethanol, methyl hydroxybenzoate, propyl hydroxybenzoate, etc.; and in certain embodiments, the antibacterial agent is selected from edetate disodium.

The weight/volume (w/v) of the antibacterial agent is <NUM>-<NUM>%; in certain embodiments, the weight/volume (w/v) of the antibacterial agent is <NUM>%-<NUM>%; in certain embodiments, the weight/volume (w/v) of the antibacterial agent is <NUM>%-<NUM>%; and in certain embodiments, the weight/volume (w/v) of the antibacterial agent is <NUM>%-<NUM>%.

In addition to an active substance, i.e., a compound of formula (II), and a pH regulator, the composition of the present invention may contain all of or one or more of an isotonic regulator, an antioxidant, a stabilizer and an antibacterial agent, or none of them are present in the composition of the present invention. In addition to these, the composition may also contain other excipients suitable for aqueous solution preparations.

Where the composition made from a sterile lyophilized powder for injection, in addition to an active substance, i.e., a compound of formula (II), and a pH regulator, the composition of the present invention may further contain a filler. The filler can be selected from one or any combination of trehalose, lactose, sucrose, glucose, mannitol, glucan, sodium dihydrogen phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactobionate, dextran, polyvinylpyrrolidone, cyclodextrin derivatives (such as hydroxypropyl-β-cyclodextrin). In certain embodiments, the filler is selected from one or any combination of trehalose, mannitol and glucose. In certain embodiments, the filler is selected from trehalose.

The weight/volume (w/v) of the filler is <NUM>%-<NUM>%; in certain embodiments, the weight/volume (w/v) of the filler is <NUM>%-<NUM>%; in certain embodiments, the weight/volume (w/v) of the filler is <NUM>%-<NUM>%; and in certain embodiments, the weight/volume percentage (w/v) of the filler is <NUM>%-<NUM>%.

The composition of the present invention is an aqueous solution preparation for injection - as prepared by the present method(s) - and is administered by intravenous injection or infusion. The pH value of the solution is <NUM>-<NUM>. The composition contains <NUM>% w/v-<NUM>% w/v of an active substance, i.e., a compound of formula (I), an appropriate amount of a pH regulator, <NUM>% w/v-<NUM>% w/v of a stabilizer, <NUM>% w/v-<NUM>% w/v of an isotonic regulator, <NUM>-<NUM>% w/v of an antioxidant, <NUM>-<NUM>% w/v of an antibacterial agent, and <NUM>% w/v-<NUM>% w/v of a filler. In certain embodiments, the composition contains <NUM>% w/v-<NUM>% w/v of an active substance, i.e., a compound of formula (I), an appropriate amount of a pH regulator, <NUM>% w/v-<NUM>% w/v of a stabilizer, <NUM>% w/v-<NUM>% w/v of an isotonic regulator, <NUM>% w/v-<NUM>% w/v of an antioxidant, <NUM>% w/v-<NUM>% w/v of an antibacterial agent, and <NUM>% w/v-<NUM>% w/v of a filler. In certain embodiments, the composition contains <NUM>% w/v-<NUM>% w/v of an active substance, i.e., a compound of formula (I), an appropriate amount of a pH regulator, <NUM>% w/v-<NUM>% w/v of a stabilizer, <NUM>% w/v-<NUM>% w/v of an isotonic regulator, <NUM>% w/v-<NUM>% w/v of an antioxidant, <NUM>-<NUM>% w/v of an antibacterial agent, and <NUM>% w/v-<NUM>% w/v of a filler. In certain embodiments, the composition contains <NUM>% w/v-<NUM>% w/v of an active substance, i.e., a compound of formula (I) and an appropriate amount of a pH regulator. In certain embodiments, the composition contains <NUM>% w/v-<NUM>% w/v of an active substance, i.e., a compound of formula (I) and an appropriate amount of a pH regulator.

The "w/v" content of each component in the present invention refers to the weight/volume percentage content, i.e., "weight of each component (g)/volume of the solution prior to dispensing (ml)".

The present invention further provides a method for preparing the composition, the method comprising the following steps:.

A solution preparation is prepared, and an injection can be obtained by filling and sealing; alternatively, the solution preparation can also be further lyophilized and prepared into a sterile lyophilized powder for injection.

The composition of the present invention can also be prepared according to the following preparation method, which comprises the following steps:.

The solution preparation can be filled and sealed in pyrogen-free vials, such as penicillin vials and ampoule vials. The volume of pyrogen-free vials can be <NUM>-<NUM>, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>.

Where the composition of the present invention is further lyophilized to a sterile lyophilized powder for injection, and on the basis of a solution preparation, a lyophilizing step is further comprised.

In certain embodiments, the lyophilizing step comprises:.

The preparation method of the sterile lyophilized powder for injection is simple and easy to implement, facilitates long-term storage and convenient transportation, and is beneficial to large-scale production.

The present invention also relates to a method for treating or preventing a disease or condition associated with kappa opioid receptors in a mammal, wherein the method comprises administering the composition of the present invention.

In certain embodiments, the disease or condition associated with kappa opioid receptors is selected from the group consisting of pain, inflammation, itching, edema, hyponatraemia, hypokalaemia, intestinal obstruction, cough and glaucoma.

In certain embodiments, the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain; in particular, neuropathic pain.

The present invention also relates to the use of the composition thereof in the preparation of a medicine for a disease or condition associated with kappa opioid receptors.

In certain embodiments, the disease or condition associated with kappa opioid receptors is selected from pain, inflammation, itching, edema, hyponatraemia, hypokalaemia, intestinal obstruction, cough and glaucoma.

The preparation method of the composition of the present invention, especially the aqueous solution injection as prepared by the present method, is simple and involves no excipients or only a few types and a small amount of excipients, leading to a reduced cost; and the storage stability and safety thereof comply with national standards for drugs, are comparable to commercially available preparations, and are suitable for clinical applications.

Unless stated to the contrary, the terms used in the description and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all comprises their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention is optionally further substituted with one or more of their corresponding isotopes, wherein the isotopes of carbon comprise <NUM>C, <NUM>C and <NUM>C, the isotopes of hydrogen comprise protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), the isotopes of oxygen comprise <NUM>O, <NUM>O and <NUM>O, the isotopes of sulfur comprise <NUM>S, <NUM>S, <NUM>S and <NUM>S, the isotopes of nitrogen comprise <NUM>N and <NUM>N, the isotopes of fluorine comprise <NUM>F, the isotopes of chlorine comprise <NUM>Cl and <NUM>Cl, and the isotopes of bromine comprise <NUM>Br and <NUM>Br.

On the premise of no contradiction, the above embodiments can be combined with each other arbitrarily.

The technical solutions of the present invention will be described in detail below in conjunction with the drawings and examples, but the protection scope of the present invention includes but is not limited thereto.

Unless otherwise specified, tartaric acid is from Merck, Germany.

<NUM> of water for injection was measured and taken; nitrogen was charged beneath the surface of the liquid for about <NUM>; and the water temperature was controlled to be <NUM> or less. <NUM> of compound II was weighed, added to the above-mentioned water for injection and stirred to dissolution and clarification to obtain solution (<NUM>). Solution (<NUM>) was adjusted with glacial acetic acid (source: Chengdu Kelong Chemical Co. ) and tartaric acid to different pH values, respectively, and aqueous solutions containing compound II at different pH values were obtained. The aqueous solutions were placed under the conditions of <NUM> ± <NUM> for <NUM> days, and the performance of related substances in the solutions at different pH values was examined (including the solution at a pH value not being adjusted), with data shown in Table <NUM>.

Curves of pH versus total impurity, which are plotted with the data of the pH values and total impurity of compound II solution (at a pH value adjusted with glacial acetic acid) and compound II solution (at a pH value adjusted with tartaric acid) in Table <NUM> respectively, are shown in <FIG>. It can be seen from Table <NUM> and <FIG> that the compound II aqueous solutions prepared thereby have the best stability at a pH value of about <NUM>; and related substances in the compound II solutions at a pH value adjusted with glacial acetic acid and tartaric acid show substantially the same trend of changes.

Considering the operability of industrial production, we examined the stability of solutions at a pH range of <NUM>-<NUM>. <NUM> of water for injection was measured and taken; nitrogen was charged beneath the surface of the liquid for about <NUM>; and the water temperature was controlled to be <NUM> or less. <NUM> of compound II was weighed, added to the above-mentioned water for injection and stirred to dissolution and clarification to obtain solution (<NUM>). Solution (<NUM>) was adjusted with glacial acetic acid (source: Chengdu Kelong Chemical Co. ) to different pH values, and aqueous solutions containing compound II at different pH values were obtained. The aqueous solutions were placed under the conditions of <NUM> ± <NUM> for <NUM> days, and the performance of related substances in the solutions at different pH values was examined, with data shown in Table <NUM>.

A curve of pH versus total impurity, which is plotted with the data of the pH values and total impurity of compound II solution in Table <NUM>, is shown in <FIG>. It can be seen from Table <NUM> and <FIG> that this product is stable at a pH range of <NUM>-<NUM>.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co. ) and sodium acetate (source: Chengdu Jinshan Chemical Test Co. ) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing, and formulation <NUM> solution for injection was obtained.

The sample of Formulation <NUM> solution for injection was placed under the conditions of <NUM> ± <NUM> for <NUM> days; compound II raw material (stored under refrigerated conditions of <NUM>-<NUM>) was used as a control; and changes of related substances in the sample were examined, with data shown in Table <NUM>.

After the sample prepared according to Example <NUM> was placed at <NUM> ± <NUM> for high temperature acceleration for <NUM> days, the total impurity level was not significantly different from that of the raw material at day <NUM>, indicating that formulation <NUM> has a good stability.

Formulation <NUM> solution for injection was placed under the conditions of <NUM> ± <NUM> for <NUM> days; compound II raw material (stored under refrigerated conditions of <NUM>-<NUM>) was used as a control; and changes of related substances in the sample were examined, with data shown in Table <NUM>.

After the sample of formulation <NUM> solution for injection was placed at <NUM> ± <NUM> for high temperature acceleration for <NUM> days, the total impurity level was not significantly different from that of the raw material at day <NUM>, indicating that formulation <NUM> solution for injection has a good stability.

After formulation <NUM> solution for injection was placed at <NUM> ± <NUM> for high temperature acceleration for <NUM> days, the total impurity level was not significantly different from that of the raw material at day <NUM>, indicating that formulation <NUM> solution for injection has a good stability.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co. ) and sodium acetate (source: Chengdu Jinshan Chemical Test Co. ) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (<NUM>). Mannitol (source: Merck, Germany) was weighed, added to solution (<NUM>) and stirred to clarification to afford solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing, and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co. ) and sodium acetate (source: Chengdu Jinshan Chemical Test Co. ) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred to clarification to afford solution (<NUM>). Mannitol (source: Qingdao Bright Moon Seaweed Group Co. ) was weighed, added to solution (<NUM>) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing, and formulation <NUM> solution for injection was obtained.

Formulation <NUM> solution for injection was placed under the conditions of <NUM>-<NUM> and <NUM> ± <NUM>, respectively, and changes of pH values and related substances of each sample were examined, with data shown in Table <NUM>.

Conclusion: Under storage conditions of different temperatures, the pH values and total impurity levels were substantially the same, and the content of the total impurity was low, indicating that formulation <NUM> has a good stability.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Chengdu Kelong Chemical Co. ) and sodium acetate (source: Chengdu Jinshan Chemical Test Co. ) were added to the above-mentioned water for injection under stirring and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred to clarification to afford solution (<NUM>). Glucose (source: Weifang Shengtai Medicine Co. ) was weighed, added to solution (<NUM>) and stirred to clarification, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing, and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Duksan Pure Chemicals Co. of Republic of Korea) and sodium acetate trihydrate (source: Duksan Pure Chemicals Co. of Republic of Korea) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and after passing the detection, formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ) and sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and after passing the detection, formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ) and sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Formulation <NUM> solution for injection obtained in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%, and <NUM>-<NUM>; the quality indicators of the preparation were measured <NUM> months later; and the results are shown in Table <NUM>.

Conclusion: Compared with the sample under the conditions of <NUM>-<NUM> for <NUM> months, the sample under the conditions of <NUM> for <NUM> months showed no significant difference in various quality indicators, indicating that the stability of formulation <NUM> solution for injection was good within <NUM> months.

Formulation <NUM> solution for injection obtained in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%; the quality indicators of the preparation were measured <NUM> months later; and the results are shown in Table <NUM>.

Conclusion: Compared with the sample at month <NUM>, the sample at month <NUM> showed no significant change in various quality indicators, indicating that formulation <NUM> solution for injection has a good stability.

Formulation <NUM> solution for injection prepared in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%; the quality indicators of the preparation were measured <NUM> months later; and the results are shown in Table <NUM>.

Conclusion: Compared with the sample at month <NUM>, the sample at month <NUM> showed no significant change in various quality indicators, indicating that the sample obtained in the present invention has a good stability.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Mannitol (source: Qingdao Bright Moon Seaweed Group Co. ), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ), sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ), sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ), sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) and edetate disodium (source: Hunan Er-kang Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Trehalose (source: Ron Pharm), glacial acetic acid (source: Taishan Xinning Pharmaceutical Co. ) and sodium acetate (source: Taishan Xinning Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Sodium chloride (source: Tianjin Haiguang Pharmaceutical Co. ) and sodium phosphate (source: Sichuan Xilong Chemical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification and adjusted with phosphoric acid (source: Chengdu Kelong Chemical Co. ) to a pH value of <NUM>-<NUM> to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Sodium benzoate (source: Chengdu Huayi Pharmaceutical Excipient Manufacturing Co. ) and sodium chloride (source: Tianjin Haiguang Pharmaceutical Co. ) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification to obtain solution (<NUM>). Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution. An appropriate amount of tartaric acid was added to adjust the pH to <NUM>-<NUM>, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) were weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification; an appropriate amount of sodium hydroxide (Sichuan Xilong Chemical Co. ) was added to adjust the pH to <NUM>-<NUM>; and solution (<NUM>) was obtained. Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Formulation <NUM> solution for injection obtained in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%; the quality indicators of the preparation were measured <NUM> month later; and the results are shown in Table <NUM>.

Formulation <NUM> solution for injection obtained in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%; the quality indicators of the preparation were measured <NUM> d later; and the results are shown in Table <NUM>.

Conclusion: Compared with the sample at month <NUM>, the sample under the conditions of <NUM> for <NUM> d showed no significant change in various quality indicators, indicating that formulation <NUM> solution for injection has a good stability.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken; nitrogen was charged beneath the surface of the liquid for <NUM> or longer; and the water temperature was controlled to be <NUM> or less. Tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) was weighed, added to the above-mentioned water for injection under stirring, and then stirred to dissolution and clarification; an appropriate amount of sodium hydroxide (source: Chengdu Kelong Chemical Co. ) was added to adjust the pH to <NUM>-<NUM>; and solution (<NUM>) was obtained. Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water. The resulting solution was subjected to sterilizing filtration through a <NUM> filter and then subjected to filling and sealing; a leak detection was carried out; and formulation <NUM> solution for injection was obtained.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Chengdu Kelong Chemical Reagent Factory) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Chengdu Kelong Chemical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Compound II was weighed, added to solution (<NUM>) and stirred until complete dissolution, and a constant volume was achieved by adding water.

Following sterilizing filtration through a <NUM> filter, filling and sealing were carried out, wherein the resulting solution was filled into <NUM> penicillin vials in a loading amount of <NUM>/vial, and the vials were partially stoppered and placed in a lyophilizer for pre-freezing.

Partition boards were cooled to -<NUM> or lower which was maintained for <NUM>-<NUM>; then a chamber was cooled to -<NUM> or lower and vacuumed to <NUM> Pa or lower; a limited leakage valve was opened and the temperature was raised to -<NUM> over <NUM> which was maintained for another <NUM>; the temperature was raised to <NUM> over <NUM> which was maintained until the temperature of the preparation reached <NUM> or higher; the temperature was risen to <NUM> over <NUM> which was maintained until the temperature of the preparation reached <NUM> or higher; and then the limited leakage valve was closed, and the temperature was maintained for <NUM>.

Vacuuming or charging nitrogen was performed, and the vials were completely stoppered, taken out from the chamber and capped.

Formulation <NUM> lyophilized sample prepared in Example <NUM> was placed under the conditions of <NUM> ± <NUM> and RH <NUM>% ± <NUM>%; the quality indicators of the preparation were measured <NUM> months later; and the results are shown in Table <NUM>.

Conclusion: Compared with the sample at month <NUM>, the sample within <NUM> months showed no significant change in various quality indicators, indicating that the sample obtained in the present invention has a good stability.

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Trehalose (source: Ron Pharm) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co. ) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Lactose (source: MEGGLE GmbH & Co. KG, Germany) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co. ) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Sucrose (source: Merck, Germany) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co. ) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Hydroxypropyl-β-cyclodextrin (source: Roquette, France) and tartaric acid (source: Hunan Er-kang Pharmaceutical Co. ) were weighed and added to the above-mentioned water for injection under stirring; sodium hydroxide (source: Hunan Er-kang Pharmaceutical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Water for injection in a volume of <NUM>% of the constant volume was measured and taken, and the water temperature was controlled to be <NUM> or less. Trehalose (source: Ron Pharm) and sodium phosphate (source: Sichuan Xilong Chemical Co. ) were weighed and added to the above-mentioned water for injection under stirring; phosphoric acid (source: Chengdu Kelong Chemical Co. ) was used to adjust the pH value to <NUM>-<NUM>; and the mixture was stirred to dissolution and clarification to obtain solution (<NUM>).

Claim 1:
A pharmaceutical composition comprising a compound of formula (II) below or a pharmaceutically acceptable salt thereof and a pH regulator, wherein the composition has a pH value of <NUM>-<NUM>, wherein the composition is a solution for injection;
wherein the pH regulator is a buffer consisting of acids and salts and having a pH value in the range of <NUM>-<NUM>,
<CHM>