Patent Description:
Polypeptide drugs can be used for treating various diseases due to its wide indications, high safety, remarkable selectivity and effectiveness. With the development of biotechnology, a large number of peptide drugs have entered the market. Currently, the commercially available peptide preparations are mainly in the form of injections and nasal sprays, which bring great inconvenience to patients. For patients, the oral administration is simpler and does not directly damage the skin or mucous membranes, thereby reducing patients' pain and improving patient compliance. However, the oral administration of polypeptide drugs is limited by a series of barriers, specifically, the polypeptide drugs are easily degraded and destroyed by proteolytic enzymes in the digestive tract, and are difficult to pass through the epithelial cell layer of the inner wall of the small intestine due to the large molecular weight, resulting in low oral bioavailability and limiting the clinical use thereof. For example, the absolute bioavailability of the listed semaglutide tablets is only <NUM>%-<NUM>%. In order to achieve the blood concentration required for the onset of action, the oral dose is relatively high, and it is difficult to achieve oral administration of some polypeptide drugs with a high cost or a narrow therapeutic window. Therefore, improving the oral bioavailability of polypeptide drugs is the key to achieving the oral administration of polypeptide drugs.

Most polypeptide drugs are susceptible to degradation by a protease activated by gastric acid, resulting in a decrease in the activity thereof. Enteric coating technology is usually used to protect polypeptides, which, however, requires complicated process and is of high cost.

<CIT> discloses a class of peptide amide compounds with novel structure and good analgesic effect, and the general formula thereof is as follows:
<CHM>
Such compounds have a significant agonizing effect on human κ-opioid receptors. Specifically, compound A is disclosed therein:
<CHM>
with a chemical name of <NUM>-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-<NUM>-acetyl-<NUM>,<NUM>-diazaspiro[<NUM>]nonane.

The present invention provides an oral polypeptide pharmaceutical composition, which is prepared by combining a polypeptide drug with a specific absorption enhancer and other non-active ingredients, thereby promoting the permeability of the polypeptide drug in the gastrointestinal tract, improving the oral bioavailability of the polypeptide drug, and achieving the oral administration so as to improve patient compliance.

The present invention provides a simple intragastric administration technology, which greatly simplifies the technological process and can greatly improve the oral bioavailability of the polypeptide compound A.

One object of the present invention is to provide an oral pharmaceutical composition of compound A:
<CHM>.

The present invention significantly improves the oral bioavailability of compound A, and is more favorable to develop a drug with the compound A.

Another object of the present invention is to provide a method for preparing the oral pharmaceutical composition.

Another object of the present invention is to provide the use of the oral pharmaceutical composition.

The present invention provides an oral pharmaceutical composition comprising:.

In some embodiments of the present invention, the oral pharmaceutical composition comprises:.

In some embodiments of the present invention, the weight ratio of compound A to N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is <NUM> : <NUM>-<NUM> : <NUM>, preferably <NUM> : <NUM>-<NUM> : <NUM>, further preferably <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is <NUM> : <NUM>.

In some embodiments of the present invention, the absorption enhancer is N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]sodium caprylate.

In some embodiments of the present invention, the absorption enhancer is N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]potassium caprylate.

In some embodiments of the present invention, the absorption enhancer is N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]calcium caprylate.

In some embodiments of the present invention, the weight ratio of compound A to <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is <NUM> : <NUM>-<NUM> : <NUM>, preferably <NUM> : <NUM>-<NUM> : <NUM>, further preferably <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is <NUM> : <NUM>.

In some embodiments of the present invention, the absorption enhancer is <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]sodium butyrate.

In some embodiments of the present invention, the absorption enhancer is <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]potassium butyrate.

In some embodiments of the present invention, the absorption enhancer is <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]calcium butyrate.

In some embodiments of the present invention, the lubricant is magnesium stearate.

In some embodiments of the present invention, the filler is microcrystalline cellulose and/or anhydrous calcium hydrogenphosphate.

In some embodiments of the present invention, the binder is povidone.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the lubricant is <NUM> : (<NUM>-<NUM>) : (<NUM>-<NUM>).

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the lubricant is <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : magnesium stearate is <NUM> : (<NUM>-<NUM>) : (<NUM>-<NUM>).

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : magnesium stearate is <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the filler : the binder is <NUM> : (<NUM>-<NUM>) : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the filler : the binder is <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : microcrystalline cellulose : povidone is <NUM> : (<NUM>-<NUM>) : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : microcrystalline cellulose : povidone is <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the filler : the binder : the lubricant is <NUM> : (<NUM>-<NUM>) : <NUM> : <NUM> : (<NUM>-<NUM>).

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the filler : the binder : the lubricant is <NUM> : <NUM> : <NUM> : <NUM> : (<NUM>-<NUM>), for example <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the filler : the binder : the lubricant is <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : microcrystalline cellulose : povidone : magnesium stearate is (<NUM>-<NUM>) : (<NUM>-<NUM>) : <NUM> : <NUM> : (<NUM>-<NUM>).

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : microcrystalline cellulose : povidone : magnesium stearate is <NUM> : <NUM> : <NUM> : <NUM> : (<NUM>-<NUM>), for example <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : microcrystalline cellulose : povidone : magnesium stearate is <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : povidone : anhydrous calcium hydrogenphosphate : magnesium stearate is (<NUM>-<NUM>) : (<NUM>-<NUM>) : <NUM> : <NUM> : (<NUM>-<NUM>).

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : povidone : anhydrous calcium hydrogenphosphate : magnesium stearate is <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : the surfactant : the filler : the lubricant is (<NUM>-<NUM>) : (<NUM>-<NUM>) : (<NUM>-<NUM>) : <NUM> : (<NUM>-<NUM>), for example <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof : propylene glycol monolaurate : polyethylene glycol <NUM> : anhydrous calcium hydrogenphosphate : magnesium stearate is (<NUM>-<NUM>) : (<NUM>-<NUM>) : (<NUM>-<NUM>) : (<NUM>-<NUM>) : <NUM> : (<NUM>-<NUM>), for example <NUM> : <NUM> : <NUM> : <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine or a hydrochloride thereof is <NUM> : <NUM>-<NUM> : <NUM>, for example <NUM> : <NUM>, <NUM> : <NUM>, <NUM> : <NUM>, <NUM> : <NUM>, <NUM> : <NUM>, <NUM> : <NUM>, <NUM> : <NUM> or <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is <NUM> : <NUM>-<NUM> : <NUM>, preferably <NUM> : <NUM>-<NUM> : <NUM>, further preferably <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is <NUM> : <NUM>-<NUM> : <NUM>, preferably lauroyl-L-carnitine hydrochloride is used in an amount of <NUM>-<NUM>, further preferably lauroyl-L-carnitine hydrochloride is used in an amount of <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is <NUM> : <NUM>.

In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition does not comprise enteric coated excipients.

In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition is not in the form of an enteric coated tablet or an enteric coated capsule.

In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition is in the form of a gastric coated capsule, gastric coated tablet or gastric coated granule.

In some embodiments of the present invention, the weight ratio of compound A : lauroyl-L-carnitine : the pH regulator is <NUM> : (<NUM>-<NUM>) : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : lauroyl-L-carnitine : citric acid is <NUM> : (<NUM>-<NUM>) : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : lauroyl-L-carnitine : citric acid is <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is <NUM> : <NUM>-<NUM> : <NUM>, preferably <NUM> : <NUM>-<NUM> : <NUM>, most preferably <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : sodium caprate : povidone is <NUM> : (<NUM>-<NUM>) : <NUM>, for example <NUM> : <NUM> : <NUM>, <NUM> : <NUM> : <NUM> or <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is <NUM> : <NUM>-<NUM> : <NUM>, preferably <NUM> : <NUM>-<NUM> : <NUM>, most preferably <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is <NUM> : <NUM>.

In some embodiments of the present invention, the weight ratio of compound A : caprylocaproyl macrogolglyceride : capric acid is <NUM> : (<NUM>-<NUM>) : (<NUM>-<NUM>), for example <NUM> : <NUM> : (<NUM>-<NUM>) or <NUM> : (<NUM>-<NUM>) : <NUM>, for example <NUM> : <NUM> : <NUM>, <NUM> : <NUM> : <NUM>, <NUM> : <NUM> : <NUM>, <NUM> : <NUM> : <NUM> or <NUM> : <NUM> : <NUM>.

In some embodiments of the present invention, the oral pharmaceutical composition is in the form of a solution, a suspension, a granule, a powder, a capsule, a tablet or other oral dosage forms.

In some embodiments of the present invention, the oral pharmaceutical composition is in the form of a gastric coated capsule, a gastric coated tablet or a gastric coated granule.

In some embodiments of the present invention, compound (A) is present in the oral pharmaceutical composition at a therapeutically effective amount or unit dose. In some embodiments of the present invention, compound (A) is present in the oral pharmaceutical composition at a does of less than <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or more than <NUM>.

In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and other non-active ingredients are mixed directly, and then filled into capsules or compressed into tablets.

In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and other non-active ingredients are wet granulated and then filled into capsules or compressed into tablets.

In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and the hydrophilic non-active ingredients are wet granulated, then dispersed in a hydrophobic medium, and filled into capsules.

In the present invention, the oral pharmaceutical composition can also be prepared as a solution, a suspension, a granule, a powder or other oral dosage forms using a conventional preparation process.

In the present invention, the capsule may be a hard capsule or a soft capsule.

The present invention also provides the use of the oral pharmaceutical composition in preparing a drug for treating diseases or conditions related to the κ-opioid receptor.

The present invention also provides a method for treating diseases or conditions related to the x-opioid receptor in a subject, comprising administering the oral pharmaceutical composition of any one of the foregoing embodiments to the subject.

In some embodiments of the present invention, the diseases or conditions related to the κ-opioid receptor are selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.

In some embodiments of the present invention, the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain.

In some embodiments of the present invention, the diseases or conditions are selected from arthritis pain, kidney stone pain, hysterotrismus, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, pain after medical treatment, ocular pain, otitis pain, breakthrough cancer pain, and pain associated with GI disorders (gastrointestinal disorders).

In one embodiment of the present invention, the oral pharmaceutical composition can be used for treating acute and chronic pain and itching.

In certain embodiments, the oral pharmaceutical composition is administered to the subject <NUM>, <NUM>, or <NUM> times daily.

In certain embodiments, the subject is a mammal, such as a bovine, an equine, a porcine, a canine, a feline, a rodent, a primate animal, wherein, particularly preferred subjects are humans.

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

The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present invention.

The raw materials/reagents used in the examples are commercially available or self-prepared, and the formulations in the examples are all at single preparation dosage.

Unless otherwise specified, "<NUM># capsule" in the following examples refers to the shell that can be used to prepare gastric coated hard capsules with the specification of <NUM>#.

Compound A was prepared with reference to the method disclosed in <CIT>.

<NUM> of compound A was dissolved in physiological saline to prepare <NUM>/ml physiological saline solution.

<NUM> of compound A and <NUM> of SNAC were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of lauroyl-L-carnitine and <NUM> of citric acid were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A and <NUM> of <NUM>-CNAB were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of <NUM>-CNAB and <NUM> of magnesium stearate were mixed uniformly and then compressed into tablets.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of microcrystalline cellulose, and <NUM> of povidone were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of microcrystalline cellulose, <NUM> of povidone, and <NUM> of magnesium stearate were mixed uniformly and then compressed into tablets.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of microcrystalline cellulose, and <NUM> of povidone were weighed; compound A and <NUM>-CNAB were dissolved in water, subjected to rotary evaporation, dried, ground and pulverized; and same were mixed with the other non-active ingredients uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of microcrystalline cellulose, <NUM> of povidone, and <NUM> of magnesium stearate were weighed; compound A and <NUM>-CNAB were dissolved in water, subjected to rotary evaporation, dried, ground and pulverized; and same were mixed with the other non-active ingredients and then compressed into tablets.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of povidone, <NUM> of microcrystalline cellulose, and <NUM> of magnesium stearate were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of <NUM>-CNAB, <NUM> of povidone, <NUM> of anhydrous calcium hydrogenphosphate, and <NUM> of magnesium stearate were mixed uniformly and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of povidone K12 and <NUM> of sodium caprate were completely dissolved in <NUM> of purified water, then freeze-dried and passed through a <NUM>-mesh sieve and then filled into <NUM># capsules.

<NUM> of compound A and <NUM> of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a <NUM> solution.

<NUM> of compound A and <NUM> of caprylocaproyl macrogolglyceride were mixed and suspended uniformly by ultrasonic dispersion, and then filled into <NUM># capsules.

<NUM> of compound A, <NUM> of caprylocaproyl macrogolglyceride and <NUM> of sodium caprate were completely dissolved in purified water to obtain a <NUM> solution.

<NUM> of compound A, <NUM> of caprylocaproyl macrogolglyceride and <NUM> of mgcapric acid were completely dissolved in purified water to obtain a <NUM> solution.

<NUM> of compound A and <NUM> of lauroyl-L-carnitine were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of lauroyl-L-carnitine were filled into <NUM># enteric coated capsules.

<NUM> of compound A and <NUM> of lauroyl-L-carnitine hydrochloride were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of sodium caproate were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of sodium caprylate were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of sodium laurate were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of sodium myristate were filled into <NUM># capsules.

<NUM> of compound A and <NUM> of sodium palmitate were filled into <NUM># capsules.

The physiological saline solution of compound A obtained in Example <NUM> was orally administered at a single dose to male Beagle dogs (<NUM> for each preparation), venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

After a single oral administration of the capsules obtained in Example <NUM> to male Beagle dogs (<NUM> for each preparation) with <NUM> tablets of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

By means of adding <NUM> of SNAC to the formulations, the bioavailability is significantly improved, and the absolute bioavailability is up to <NUM>%.

After a single oral administration of the capsules obtained in Examples <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation) with <NUM> tablet of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

In the case of the weight ratio of compound A to SNAC being in the range of <NUM> : <NUM>-<NUM> : <NUM>, the bioavailability of compound A can be significantly improved, and the absolute bioavailability is better when the weight ratio thereof is <NUM> : <NUM>.

After a single oral administration of the capsules obtained in Example <NUM> to male Beagle dogs (<NUM> for each preparation) with <NUM> tablets of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

Adding <NUM> of lauroyl-L-carnitine and <NUM> of citric acid to the formulations provides a good absorption promoting effect, and the absolute bioavailability of compound A is up to <NUM>%.

In the case of the weight ratio of compound A to <NUM>-CNAB being in the range of <NUM> : <NUM>-<NUM> : <NUM>, the bioavailability of compound A can be significantly improved, and the absolute bioavailability is better when the weight ratio thereof is <NUM> : <NUM>.

After a single oral administration of the preparation samples prepared in Examples <NUM>-<NUM> by different processes to male Beagle dogs (<NUM> for each preparation) with <NUM> tablet of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

By means of adding <NUM>-CNAB to the formulations, the absolute bioavailability of samples at different dosage forms and prepared by different preparation processes is increased significantly.

After a single oral administration of the preparation samples obtained in Examples <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation) with <NUM> tablet of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

In the formulations, the bioavailability of compound A is improved by sodium caprate in a dose-response manner. When the weight ratio of compound A to sodium caprate is <NUM> : <NUM>, the bioavailability does not change significantly, while the weight ratio of compound A to sodium caprate is <NUM> : <NUM> and <NUM> : <NUM>, the bioavailability is increased significantly.

After a single oral administration of the preparation samples obtained in Examples <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation) with <NUM> of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

In the formulations, the bioavailability is significantly improved when the weight ratio of compound A to caprylocaproyl macrogolglyceride is <NUM> : <NUM>-<NUM> : <NUM>, and the absolute bioavailability is better when the weight ratio is <NUM> : <NUM>.

After a single oral administration of the preparation samples obtained in Examples <NUM>, <NUM> and <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation), venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

Both solutions and capsules obtained by adding caprylocaproyl macrogolglyceride to the formulations can significantly improve the bioavailability of compound A, and the improvement levels of the bioavailability of compound A are similar at the specification of <NUM> and <NUM>.

In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A : caprylocaproyl macrogolglyceride : sodium caprate is <NUM> : <NUM> : <NUM>-<NUM>, and the bioavailability is better when the weight ratio is <NUM> : <NUM> : <NUM>.

In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A : caprylocaproyl macrogolglyceride : capric acid is <NUM> : (<NUM>-<NUM>) : <NUM>, and the bioavailability is better when the weight ratio is <NUM> : <NUM> : <NUM>.

In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A to lauroyl-L-carnitine is <NUM> : <NUM>-<NUM> : <NUM>, and the bioavailability is better when the weight ratio is <NUM> : <NUM>.

When the weight ratio of compound A to lauroyl-L-carnitine is <NUM> : <NUM>, the bioavailability of the gastric coated capsule preparation is <NUM> times that of the enteric coated capsule preparation.

After a single oral administration of the preparation samples obtained in Examples <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation) <NUM> tablet of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

The bioavailability of compound A is significantly improved when the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is <NUM> : <NUM>-<NUM> : <NUM>, and the bioavailability is better when the weight ratio is <NUM> : <NUM> and <NUM> : <NUM>.

After a single oral administration of the preparation samples obtained in Examples <NUM> and <NUM>-<NUM> to male Beagle dogs (<NUM> for each preparation) <NUM> tablet of the samples for each dog, venous blood was taken at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, and the absolute bioavailability (F%) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.

Claim 1:
An oral pharmaceutical composition, comprising:
a) compound A:
<CHM>
and
b) an absorption enhancer;
wherein the absorption enhancer is selected from one or more of N-[<NUM>-(<NUM>-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof, <NUM>-[(<NUM>-chloro-<NUM>-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof, lauroyl-L-carnitine or a hydrochloride thereof, sodium caprylate, sodium caprate, capric acid, caprylocaproyl macrogolglyceride; preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt or calcium salt.