CN112587651B

CN112587651B - Oral pharmaceutical composition of Bremelanotide and application thereof

Info

Publication number: CN112587651B
Application number: CN202011595795.7A
Authority: CN
Inventors: 吴涛; 卢骏; 冯岩; 胡建平; 姜艳; 崔宏亮
Original assignee: Beijing Huicheng Ruixiang Pharmaceutical Biotechnology Co ltd
Current assignee: Beijing Huicheng Ruixiang Pharmaceutical Biotechnology Co ltd
Priority date: 2020-12-29
Filing date: 2020-12-29
Publication date: 2022-05-13
Anticipated expiration: 2040-12-29
Also published as: CN112587651A

Abstract

The invention relates to the field of polypeptide drug oral pharmaceutical compositions, in particular to a brameracil oral pharmaceutical composition and an application field thereof. The invention provides an oral pharmaceutical composition and application thereof, wherein the pharmaceutical composition at least comprises brameran and 8- (2-hydroxybenzamido) sodium caprylate, wherein the weight ratio of the brameran to the 8- (2-hydroxybenzamido) sodium caprylate counted by basic groups is 3.2-12: 12-18. Compared with the subcutaneous injection on the market, the oral pharmaceutical composition has simple preparation process, avoids potential risks in the aspects of microorganisms and bacterial endotoxin of the injection, solves the problem of poor compliance of many patients to the injection, and can obviously improve the in vivo absorption and utilization of the oral Bremelanotide.

Description

Oral pharmaceutical composition of Bremelanotide and application thereof

Technical Field

The invention relates to the field of polypeptide drug oral pharmaceutical compositions, in particular to a brameracil oral pharmaceutical composition and an application field thereof.

Background

Polypeptide and protein drugs are mostly administered clinically by intramuscular injection, intravenous injection or subcutaneous injection, and pharmaceutical scientists have been devoted to the study of oral formulations of such drugs. The existing researches believe that the digestion products of proteins or polypeptides in the gastrointestinal tract are mainly polypeptides such as dipeptide and tripeptide. For polypeptides consisting of 12 or less amino acids, oral administration is more likely to be achieved, whereas for proteins, it is difficult to predict. The mechanisms and pathways for oral absorption of currently known polypeptide and protein drugs include: 1) carrier transport, which is mainly used for transporting small molecule drugs; 2) pinocytosis and M cell pathway; 3) the paracellular pathway.

Factors that affect oral absorption of polypeptide and protein drugs include: 1) relative molecular mass; 2) a spatial structure; 3) physical and chemical properties; 4) acid barriers, enzyme barriers, and membrane barriers. Most of polypeptides and proteins are not acid-resistant, the pH value of gastric acid is 1-3, when polypeptide drugs pass through the stomach, a part of the drugs are hydrolyzed to lose biological activity, the pH environment of the whole intestinal tract is complex and changeable, and some polypeptides are easy to undergo pH-dependent hydrolysis, so that the polypeptide drugs become a first barrier for oral absorption. Meanwhile, the gastrointestinal tract contains a plurality of digestive enzymes, which mainly comprise enzymes secreted by the lumen, such as pepsin, trypsin, chymotrypsin and the like; ② enzymes secreted from brush border, such as carboxypeptidase, aminopeptidase, endopeptidase and exonuclease, etc., the enzyme digestion is the main cause for degrading polypeptide drugs. In addition, epithelial cells of the small intestine are attached with a layer of hydrated gel called a non-flowing water layer, and a phospholipid surface active layer is arranged below the hydrated gel, so that the hydrophobic property is strong, and the diffusion of hydrophilic molecules such as polypeptide drugs and the like to the epithelial cells is hindered. Secondly, the phospholipid bilayer of the small intestine epithelial cell membrane has the property of a semipermeable membrane, which allows passive transport of fat-soluble drugs, while macromolecules and hydrophilic drugs need to be transported actively to enter cells through the membrane. Finally, the major barrier to oral absorption is the dense intestinal epithelial cell membrane, since the small intestinal intercellular space is only 5nm, and only small molecular weight drugs can pass through without the addition of any absorption enhancers.

The strategies reported in the literature for improving the oral absorption of polypeptide and protein drugs comprise preparation means such as chemical modification, use of absorption promoters, use of enzyme inhibitors, preparation of nanoparticle preparation carriers, liposomes, microemulsions and the like.

Blarimellan (Bremelanotide) is a melanocortin receptor agonist marketed under the trade name: VYLE ESI, a subcutaneous injection formulation, 1.75mg in size. The bremer langdan is an artificially synthesized cyclic heptapeptide, the carboxyl terminal is free acid, and the amino terminal forms acetylation.

Chinese patent application CN104755094 discloses subcutaneous injection of 1.25mg-1.75mg for treating female hyposexuality. Meanwhile, as is known from the reports of published research documents of the applicant, in early clinical trials, the company has been clinically developed by using a nasal administration form, and the dose is 20mg (in base).

The Bremelanotide is already marketed in the United states as an injection for female hyposexuality and is administered by a subcutaneous injection route. The main side effects of the drug are nausea, elevated blood pressure and reduced heart rate as reported in the specification. The polypeptide chain part of the molecular structure is in a ring shape, so that certain stability is improved.

The product on the market of the Bremelanotide is an injection, and compared with an oral preparation, the Bremelanotide is not convenient enough to use and has poor compliance. Researchers have been working on developing compositions and pharmaceutical preparations of the more convenient to take bremer langdan.

The U.S. patent application No. 20180185440A1 discloses an oral capsule containing the bremeracil and the SNAC, the preparation process is complex, the condition of stomach absorption in experimental animals is not described, the influence of in vitro dissolution rate on the peak time of blood concentration in animals is not described, the influence of the particle size of the raw material medicine of the bremeracil and various auxiliary materials on the dissolution rate of the medicine and the time curve of the medicine is not described, and the proportioning relation and the preparation composition of the bremeracil and the SNAC with the in vivo pharmacokinetic characteristics equivalent to that of a subcutaneous injection preparation are not described.

Disclosure of Invention

In order to solve the defects of the prior art and meet the requirement of patients on medication, the invention aims to provide the oral pharmaceutical composition of the Bremelanotide.

The invention combines the bremer wave pill and the absorption enhancer, and improves the absorption and utilization in vivo after the oral administration of the bremer wave pill. Bremelanotide (PT-141), also known as pramipeptide, bumetanide and bumetanide, is an artificially synthesized cyclic heptapeptide, the carboxyl end of which is free acid and the amino end of which is acetylated. U.S. Pat. Nos. 6579968 and 6794489 disclose Bremelanotan, which has a structural formula of Ac-Nle-cyclo- (Asp-His-D-Phe-Arg-Trp-Lys) -OH, is developed from Melanotan-II (Ac-Nle-cyclo- (Asp-His-D-Phe-Arg-Trp-Lys) -NH2), and has a stronger pharmacological activity than Melanotan-II.

The structural formula of the acetate form of the bremer langdan is as follows: Ac-Nle-cyclo- (Asp-His-D-Phe-Arg-Trp-Lys-OH) xCH3 COOH; molecular formula C₅₀H68N14O10 xCH3COOH (1. ltoreq. x.ltoreq.2), molecular weight 1025.2 (calculated as free base).

The medicine of the invention, namely the Braimeidan, can be in a free base form, can also be in an acetate form, can be an anhydrate, can also be an aquosity or a solvate. Preferably, the bremer langdan in the invention is acetate of the bremer langdan in the form of acetate.

The absorption enhancers include SNAC (8- (2-Hydroxybenzamido) octanoid acid sodium),5-CNAC (N- (5-chlorosalicyloyl) -8-aminocaprylic acid),4-CNAB (4- [ (4-chloro-2-hydroxy-benzoyl) amino ] butanoic acid), SNAD (N- (10- [ 2-hydroxyphenyl ] -amino) decanoic acid),5-CNAB (monosodium N- (4-chlorosalicyloyl) -4-aminobenzoylate) and 4-MOAC (N- [8- (2-hydroxy-4-methoxy) benzoyl ] amino acid), preferably SNAC.

SNAC (sodium N- [8- (2-hydroxybenzoyl) amino ] propionate, Salcapronate sodium) with chemical name of sodium 8- (2-hydroxybenzamido) caprylate (CAS number: 203787-91-1), abbreviated in the present invention as follows: SNAC. SNAC in the present invention can be amorphous, can be one of a plurality of crystalline forms or a mixture thereof, or can be amorphous mixed with one or more specific crystalline forms.

The oral pharmaceutical composition comprises the bremer langdan and the absorption enhancer, and one or more of a binder, an excipient and a lubricant.

Preferably, the absorption enhancer is sodium 8- (2-hydroxybenzamido) caprylate; the weight ratio of the bremer langdan to the sodium 8- (2-hydroxybenzamido) caprylate is 3.2-12: 12-18; the weight of the bremerrand is calculated as free base.

Preferably, the weight ratio of the Braimei red to the SNAC is 4.8-12: 12-18;

preferably, the weight ratio of the bremerang to the sodium 8- (2-hydroxybenzamido) caprylate is 8-12: 12-18;

more preferably, the weight ratio of the Braimeidan to the sodium 8- (2-hydroxybenzamido) caprylate is 8-12: 15.

Most preferably, the weight ratio of the bremer langdan to the SNAC is 10: 15.

The above-mentioned bremerrand is a therapeutically effective amount of bremerrand.

"therapeutically effective amount" means an amount effective to treat, prevent, alleviate or ameliorate the symptoms or physiological functions of a disease with the composition of the present invention. Preferably, the amount of the bremer langdan in the unit preparation containing the pharmaceutical composition of the invention is 5mg-200 mg; further preferably 20mg to 120 mg.

Preferably, the particle size of the Braimer wave lead material is less than 180 μm, and the particle size of the sodium 8- (2-hydroxybenzamido) caprylate is less than 124 μm;

more preferably, the particle size of the Braomelania material is D90 < 56 μm, and the particle size of the sodium 8- (2-hydroxybenzamido) caprylate is D90 < 8.6 μm.

Preferably, the composition further comprises one or more of a binder, an excipient, and a lubricant;

preferably, wherein the binder is selected from povidone or hydroxypropylmethylcellulose;

more preferably, the binder is one or both of povidone K30 and povidone K90;

more preferably, the binder is povidone K30.

Preferably, the excipient is selected from one or more of microcrystalline cellulose, starch, lactose, dextrin and calcium hydrogen phosphate;

preferably, the excipient is microcrystalline cellulose.

Preferably, the lubricant is selected from one or two of magnesium stearate and sodium stearyl fumarate;

preferably, the lubricant is magnesium stearate.

Preferably, the adhesive is 0.1 to 10 percent of the total weight of the Braimersan and the sodium 8- (2-hydroxybenzamido) caprylate; the weight of the bremerrand is calculated as free base.

Preferably, the binder is 0.5 to 5 percent of the total weight of the Braimer wave lead and the sodium 8- (2-hydroxybenzamido) caprylate, and more preferably 0.5 to 2.5 percent;

preferably, the excipient is 0.2-200% of the total weight of the brameracil and the sodium 8- (2-hydroxybenzamido) caprylate, and the weight of the brameracil is calculated in a free base form; preferably 1% to 150%, more preferably 2% to 100%.

Preferably, the lubricant is 0.1-10% of the total weight of the bramer wave red and the sodium 8- (2-hydroxybenzamido) caprylate, and the weight of the bramer wave red is calculated by a free base form.

Preferably 0.2% to 5%, more preferably 0.5% to 2.0%.

Preferably, the composition comprises 32-120 mg of bremerdan and 120-180mg of sodium 8- (2-hydroxybenzamido) caprylate in a single dose or multiple doses;

preferably, the composition comprises 80-120 mg of bremerdan and 150mg of 8- (2-hydroxybenzamido) caprylic acid in a single dose or multiple doses.

The pharmaceutical composition of the present invention may further comprise one or more of a sweetener and an essence.

When the pharmaceutical composition contains the sweetener, the sweetener is 0.1-15%, preferably 0.2-10%, and more preferably 0.5-5% of the total weight of the bremerdane and the SNAC.

Preferably, the sweetener comprises sucralose, steviol glycosides, aspartame, etc., preferably sucralose.

When the pharmaceutical composition contains essence, the essence is 0.1-2% of the total weight of the bremer langdan and the SNAC, and the weight of the bremer langdan is calculated in a free alkali form. Preferably 0.1% to 1%, more preferably 0.1% to 0.5%.

Preferably, the essence comprises banana essence, raspberry essence, beef tallow essence, vanillin and the like, and vanillin is preferred.

In a specific embodiment of the pharmaceutical composition, the pharmaceutical composition contains the bremer langerhans, the SNAC, the adhesive, the excipient and the lubricant, wherein the weight ratio of the bremer langerhans to the SNAC is 3.2-12: 12-18, the adhesive is 0.1-10% of the total weight of the bremer langerhans and the SNAC, the excipient is 0.2-200% of the total weight of the bremer langerhans and the SNAC, and the lubricant is 0.1-10% of the total weight of the bremer langerhans and the SNAC.

In a specific embodiment of the pharmaceutical composition, the pharmaceutical composition contains the bremer langerhans, the SNAC, the adhesive, the excipient and the lubricant, wherein the weight ratio of the bremer langerhans to the SNAC is 8-10: 12-18, the adhesive is 0.1-5% of the total weight of the bremer langerhans and the SNAC, the excipient is 1-150% of the total weight of the bremer langerhans and the SNAC, and the lubricant is 0.1-10% of the total weight of the bremer langerhans and the SNAC.

In a specific embodiment of the pharmaceutical composition, the pharmaceutical composition contains the bremer langerhans, the SNAC, the binder, the excipient and the lubricant, wherein the weight ratio of the bremer langerhans to the SNAC is 8-10: 12-18, the binder is 0.1-10% of the total weight of the bremer langerhans and the SNAC, the excipient is 0.2-200% of the total weight of the bremer langerhans and the SNAC, the lubricant is 0.1-10% of the total weight of the bremer langerhans and the SNAC, the binder is povidone K30 or povidone K90, the excipient is microcrystalline cellulose, and the lubricant is magnesium stearate or sodium stearyl fumarate.

In a specific embodiment of the pharmaceutical composition, the pharmaceutical composition contains the bremer langerhans, the SNAC and the adhesive, the weight ratio of the bremer langerhans to the SNAC is 8-10: 12-18, the adhesive is 0.1-10% of the total weight of the bremer langerhans and the SNAC, and the pharmaceutical composition does not contain an excipient and a lubricant.

In a specific embodiment of the pharmaceutical composition, the pharmaceutical composition contains the bremer langerhans, the SNAC, the adhesive and the lubricant, wherein the weight ratio of the bremer langerhans to the SNAC is 8-10: 12-18, the adhesive is 0.1-10% of the total weight of the bremer langerhans and the SNAC, the lubricant is 0.1-10% of the total weight of the bremer langerhans and the SNAC, and the pharmaceutical composition does not contain an excipient.

The invention also aims to provide a oral preparation of the Bremelanotide, which comprises the oral pharmaceutical composition.

The oral preparation of the Bremelanotide can be any dosage form suitable for oral administration.

Preferably, the oral preparation of the invention is a tablet, a capsule, a granule or an oral solution;

more preferably capsules or granules.

The oral preparation of the bremer lang comprises effective dose of the bremer lang and SNAC, and selectively comprises one or more of a binding agent, an excipient and a lubricant, wherein the weight ratio of the bremer lang to the SNAC is 3.2-12: 12-18.

The oral preparation of the Bremelanotide can be any dosage form suitable for oral administration. Preferably, the oral preparation of the present invention is a tablet, capsule, granule or oral solution, more preferably capsule or granule.

When the oral preparation of the invention contains the adhesive, the adhesive is 0.1-10 percent of the total weight of the oral preparation of the invention, preferably 0.5-5 percent of the total weight of the oral preparation of the invention and the SNAC, and more preferably 0.5-2.5 percent of the total weight of the oral preparation of the invention. The binder comprises polyvidone, hydroxypropyl methylcellulose, etc., preferably one or more of polyvidone, more preferably polyvidone K-30.

When the oral preparation of the invention contains the excipient, the excipient is 0.2-200 percent of the total weight of the bremer langdan and the SNAC, preferably 0.2-150 percent, and more preferably 0.2-100 percent. The excipient comprises microcrystalline cellulose, starch, lactose, dextrin, calcium hydrogen phosphate, etc., preferably microcrystalline cellulose.

When the oral preparation of the bremelanotide contains the lubricant, the lubricant is 0.1-10 percent of the total weight of the bremelanotide and the SNAC, preferably 0.2-5 percent, and more preferably 0.5-2 percent. The lubricant comprises magnesium stearate and sodium stearyl fumarate, and preferably magnesium stearate is used as lubricant.

In the oral preparation of the invention, preferably, the bremer langdan is sieved, the particle size of the bremer langdan material is observed by a microscope, the long diameter of the particles is less than 180 microns, and the particle size D is more preferably selected₉₀Less than 56 microns.

In the oral preparation of the bremer langdan, preferably, the SNAC is subjected to screening treatment, the particle size of the SNAC is observed by a microscope to observe the long diameter of the particles, the particle size is less than 124 microns, and the particle size D is more preferably selected₉₀Less than 8.6 microns.

The oral preparation of the Bremelanotide can also contain one or more of a sweetening agent and an essence.

When the oral preparation of the bremer langdan contains the sweetening agent, the sweetening agent accounts for 0.1-15 percent of the total weight of the bremer langdan and the SNAC, preferably 0.2-10 percent, and more preferably 0.5-5 percent. The sweetener includes sucralose, stevioside, aspartame, etc., preferably sucralose.

When the oral preparation of the invention contains the essence, the essence is 0.1-2 percent of the total weight of the oral preparation of the invention, preferably 0.1-1 percent, and more preferably 0.1-0.5 percent of the total weight of the oral preparation of the invention. The essence comprises banana essence, raspberry essence, beef tallow essence, vanillin, etc., preferably vanillin.

The oral preparation of the bremer wave pill preferably contains effective dose of the bremer wave pill, SNAC and an adhesive, wherein the weight ratio of the bremer wave pill to the SNAC is 3.2-12: 12-18, and the adhesive is 0.1-10% of the total weight of the bremer wave pill and the SNAC.

More preferably, the oral preparation of the bremer lang contains effective dose of the bremer lang, the SNAC, the adhesive and the lubricant, wherein the weight ratio of the bremer lang to the SNAC is 8-10: 12-18, the adhesive is 0.1-10% of the total weight of the bremer lang and the SN AC, and the lubricant is 0.1-10% of the total weight of the bremer lang and the SNAC.

Further preferably, the oral preparation of the bremer lang contains effective dose of the bremer lang, the SNAC, the adhesive, the excipient and the lubricant, wherein the weight ratio of the bremer lang to the SNAC is 8-10: 12-18, the adhesive is 0.1-10% of the total weight of the bremer lang and the SNAC, the excipient is 0.2-200% of the total weight of the bremer lang and the SNAC, and the lubricant is 0.1-10% of the total weight of the bremer lang and the SNAC.

Further preferably, the oral preparation of the bremer lang contains effective dose of the bremer lang, the SNAC, the adhesive, the excipient and the lubricant, wherein the weight ratio of the bremer lang to the SNAC is 8-10: 15, the adhesive is 0.1-10% of the total weight of the bremer lang and the SNAC, the excipient is 0.2-200% of the total weight of the bremer lang and the SNAC, and the lubricant is 0.1-10% of the total weight of the bremer lang and the SNAC.

The oral preparation of the bremer lang preferably contains 32-120 mg of the bremer lang and 120-180mg of the SNAC in single dose or multiple doses, further preferably contains 80-120 mg of the bremer lang and 120-180mg of the SNAC in single dose or multiple doses, and more preferably contains 80-120 mg of the bremer lang and 150mg of the SNAC in single dose or multiple doses.

Preferably, the weight of the aforementioned bremer langdan is in the form of the free base.

A single dose refers to the smallest unit of formulation available for administration, for example, one tablet or scored half of a tablet; one capsule of the capsule; a minimum package or minimum administrable amount of the granule; oral solution refers to the amount taken per time, or a measurable portion thereof. "Single dose" in the context of the present invention may have the same meaning as "unit dose" and may also refer to the dosage specification of a pharmaceutical product.

Multiple doses refers to multiple single doses.

The oral pharmaceutical composition of the present invention can be prepared by the techniques commonly used in the art, for example, by mixing the components of the pharmaceutical composition according to the corresponding ratio and dosage.

The oral preparation of the Bremelanotide can be prepared by adopting a common method. For example, tablets may be compressed or capsules may be filled using powder direct mixing techniques as understood by those skilled in the art of pharmacy; the dry granulation technology can be adopted to compress tablets or fill capsules, or the granules can be used; the wet granulation technology can be adopted to compress tablets, or prepare capsules, or prepare granules; the composition of the present invention can be used as an oral solution by adding water.

The oral preparation of the Bremelanotide can be prepared by adopting the oral pharmaceutical composition.

It is generally believed that polypeptide drugs are unstable and easily degraded by the gastric acid and the environment in which pepsin is present. The researchers of the invention find that the combination of the bremer langdan and the SNAC is relatively stable in rat gastric juice and artificial gastric juice through research. The oral pharmaceutical composition formed by combining the bremer wave pill and the absorption enhancer can obviously improve the in-vivo absorption and utilization of the oral bremer wave pill, and the SNAC has a good effect of improving the in-vivo absorption of the bremer wave pill when being used as the absorption enhancer. In a rat in-vivo absorption test, the SNAC is proved to promote the absorption of the Braimersan in the stomach and small intestine.

The researchers of the invention find that the SNAC effectively improves the absorption degree of the bremer-wave in small intestine perfusion of rats, and the concentration of the bremer-wave in blood is greatly improved (compared with the result without the SNAC). Surprisingly, the amount of absorbed Brahman from 0.5mmol to 1.0mmol in rats tended to decrease with increasing SNAC concentration, and did not increase with increasing SNAC. The mechanism of SNAC to promote macromolecular absorption is not completely clear, and it is reported in the literature that at a concentration of 10mM, the mechanism reversibly increases intercellular permeability, so that molecules with a molecular weight of less than 10K daltons increase the amount of permeation.

According to the invention, the researchers find that the SNAC effectively improves the absorption degree of the Bramerella is absorbed in the gastric perfusion of the rat, and the result shows that the Bramerella has higher blood concentration level in the blood (compared with the result of not using the SNAC). It was confirmed that in the presence of SNAC, the absorption degree of the bremelanotide is better in the stomach of the rat, and that the absorption degree of the bremelanotide is better when the SNAC concentration is 1.0mmol than when the SNAC concentration is 0.5 mmol.

The researchers of the invention surprisingly found that the higher the dosage of the SNAC in the composition containing the bremer langerhans and the SNAC, the better the in vivo absorption effect of the bremer langerhans is promoted. Meanwhile, the smaller the dosage of the SNAC, the more beneficial the oral pharmaceutical composition to be prepared into an oral preparation, and the better the safety after taking the medicine. When the bremer wave is in an effective treatment amount, the in-vivo absorption effect of the ideal bremer wave can be obtained when the weight ratio of the bremer wave to the SNAC is 3.2-12: 12-18; more preferably, the weight ratio of the bremer wave red to the SNAC is 8-12: 12-18, and further preferably, the weight ratio of the bremer wave red to the SNAC is 8-12: 15.

In the embodiment of the invention, the relative absorption degree of the bremer langdan 20mg is not as high as 80mg and 120mg under the same dosage of SNAC. It can be seen that in the composition of bremer langdan and SNAC, the higher the relative amount of SNAC, the better the absorption.

Compared with the marketed subcutaneous injection, the preparation process of the oral drug composition of the Bremelanotide is simple, the use of an injector drug delivery device is avoided, potential risks in the aspects of microorganism and bacterial endotoxin of the injection are avoided, and the problem of poor compliance of many patients to the injection is solved.

After the oral administration of Beagle dogs, the absolute bioavailability of the oral pharmaceutical composition of the invention can be more than 1.0 percent compared with the subcutaneous injection dosage form, and the data is superior to the absolute bioavailability data of the previous related researches. From the perspective of drug effectiveness, the pharmaceutical composition of the invention, which is orally administered with 20-200mg of bremelanotide, is possible to replace the injection of 1.75mg of bremelanotide injection.

In one embodiment of the invention, the oral pharmaceutical composition of the invention comprising 100mg of brimordant is administered orally to beagle dogs, C_maxAbout 424.79ng/ml, AUC_0-last _T686.80h ng/ml.

In the inventionIn one embodiment, the dissolution rate of the preparation prepared by the oral pharmaceutical composition of the present invention in an in vitro dissolution test (refer to the first method or the second method device for determining dissolution rate and release rate in the general rule 931 of the four parts of the 2020 edition of Chinese pharmacopoeia, 50rpm, 0.1M hydrochloric acid as release medium) for 15 minutes is not less than 85% of the labeled amount, and the relative standard deviation between each determined preparation unit is less than 10% (RSD)<10%). The dissolution rate of the common oral preparation is more than 85% in 15 minutes, and the similarity of dissolution rate curves of different preparation batches can be judged, which is widely accepted and expressed in numerous drug development regulations and literatures. The pharmaceutical composition and the oral preparation of the invention use the disintegrant, the adhesive and the lubricant, and control the particle size of the Bramerlian red and the SNAC, which is beneficial to improving the dissolution behavior of the medicine. The dissolution behavior of the drug in vitro can greatly influence the absorption speed and degree of the drug in vivo, that is, the fast-dissolving preparation has a fast drug release speed in vivo, is reflected in pharmacokinetic parameters and shows a small time to peak T_maxHigher blood concentration C_max. The uniformity of dissolution rate of the preparation in vitro also influences the uniformity of release of the preparation in vivo.

In a specific embodiment of the oral preparation of the present invention, when the first method of the dissolution testing device specified in the 2020 edition of chinese pharmacopoeia or the second method of the dissolution testing device is selected as the in vitro dissolution testing experiment, the rotation speed of the stirring paddle or the blue turning device is 50RPM, 900ml of 0.1M hydrochloric acid solution is selected as the medium for dissolution testing, samples are taken at 5, 10, 15, 30, 45 and 60 minutes, and the dissolution of the preparation is tested. The dissolution rate of the oral preparation is more than 85 percent within 15 minutes. The degree of dissolution uniformity of each formulation unit of the oral formulation of the invention is such that the relative standard deviation of the dissolution values for 6 formulation units is less than 10% (RSD < 10%) at 15 minutes or 30 minutes or 45 minutes or 60 minutes.

In the specific embodiment of the oral preparation, the absorption degree of the oral preparation in Beagle dogs is compared with that of the Braimer wave injection (subcutaneous injection, 1.75mg/0.3ml), and the absolute bioavailability of the oral preparation is more than 1.0%.

The invention also aims to provide application of the oral pharmaceutical composition or an oral preparation prepared from the oral pharmaceutical composition in a product for treating female hyposexuality.

The invention has the beneficial effects that:

(1) the SNAC effectively improves the absorption degree of the Braimeer's wave in the small intestine perfusion of the rat, and effectively improves the absorption degree of the Braimeer's wave in the stomach perfusion of the rat;

(2) the higher the dosage of SNAC in the composition containing the bremer langdan and the SNAC, the better the in vivo absorption effect of the bremer langdan is promoted. Meanwhile, the smaller the dosage of the SNAC, the more beneficial the oral pharmaceutical composition to be prepared into an oral preparation, and the better the safety after taking the medicine. When the bremer langdan is in an effective treatment amount, the in-vivo absorption effect of the ideal bremer langdan can be obtained when the weight ratio of the bremer langdan (counted by base) to the SNAC is 3.2-12: 12-18; more preferably, the weight ratio of the Bramerella ramoso (counted by base) to the SNAC is 8-12: 12-18, and further preferably, the weight ratio of the Bramerella ramoso (counted by base) to the S NAC is 8-12: 15.

(3) Compared with the marketed subcutaneous injection, the preparation process of the oral drug composition of the Bremelanotide is simple, the use of an injector drug delivery device is avoided, potential risks in the aspects of microorganism and bacterial endotoxin of the injection are avoided, and the problem of poor compliance of many patients to the injection is solved.

(4) Compared with a subcutaneous injection, the absolute bioavailability of the oral drug composition of the Bremelanotide is more than 1.0%. From the perspective of drug effectiveness, the proportion relation and the preparation composition of the in-vivo pharmacokinetic characteristic of the loratadine and the SNAC which are equivalent to the subcutaneous injection preparation are explained, and the pharmaceutical composition of the invention with 20-200mg oral loratadine is possible to replace and inject the 1.75mg of loratadine injection.

(5) The pharmaceutical composition and the oral preparation of the invention use the disintegrant, the adhesive and the lubricant, and control the particle size of the Bramerlian red and the SNAC, thus effectively improving the dissolution behavior of the drug, and the oral preparation of the invention has dissolution rate of more than 85 percent in 15 minutes and uniform dissolution among batches.

Drawings

FIG. 1 is a comparison of plasma levels of Braimersan in rats at different SNAC levels (absorption in the small intestine of rats);

FIG. 2 is a comparison of plasma levels of Braimersan in rats at different SNAC levels (absorption in the stomach of the rat);

figure 3 is a plot of plasma concentration versus time in vivo following administration of beagle dogs of examples 20, 21, 22.

Detailed Description

The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The experimental procedures in the following examples are conventional unless otherwise specified. The pharmaceutical raw materials, auxiliary materials, reagent materials and the like used in the following examples are all commercially available products unless otherwise specified.

The Bremelanotide uses acetate, and is used after converting base.

In the study of oral compositions, the stability of bremer-wave in artificial gastric juice and artificial intestinal juice (example 3) and the degree of absorption of the composition of bremer-wave and SNAC in different relative amounts in rat small intestine perfusion and rat stomach (examples 1 and 2) were studied. The method comprises the following specific steps:

example 1

Rats were fasted for 16 hours prior to dosing, but had free access to water. After intraperitoneal injection, rats are placed under a heating lamp to keep the body temperature at about 37 ℃, and the abdominal median incision exposes the intestinal tract. After ligation of the bile duct, the intestine was flushed with phosphate buffer (pH 7.4) and the remaining buffer was removed with air. The small intestine was cannulated at both ends with polyethylene tubing. The preparation method comprises filling 200ml of drug solution containing absorption enhancer or drug-only solution, and weighing NaCl 7.8g, KCl 0.35g, and CaCl₂ 0.37g，NaHCO3 1.37g，NaH₂PO₄ 0.32g，MgCl₂0.02g, grapeSugar 1.4g, dissolved in a small amount of water, with CaCl₂Dissolving separately, adding dropwise, adding glucose until use, dissolving, and adding purified water to constant volume of 1L.

The perfusion solution was maintained at 37 ℃, introduced directly into the intestine through the hollow opening in the proximal part of the small intestine, and the dosing solution was circulated with incubation. The jugular vein was exposed and a 0.3ml blood sample was taken by direct puncture of a heparin syringe at 20, 40, 60, 90, 120 minutes into the drug-containing solution cycle. Plasma was obtained immediately by centrifugation at 12000 rpm for 5 minutes and stored frozen for further analysis. Adding the bremer langdan or the bremer langdan and the SNAC into the perfusion solution. Two concentration levels of absorption enhancer were chosen for experimental design. For each experiment, 3 rat experiments were used, and additionally the absorption of the perfusate of the bremer langdan without the absorption enhancer was determined. The formulation is shown in Table 1, and the test results are shown in FIG. 1.

TABLE 1 amount of the composition of Bremelanotide and SNAC

According to the test results, the SNAC effectively improves the absorption degree of the bremer langdan in rat small intestine perfusion under the concentration of 0.5mmol/200ml and 1.0mmol/200ml of perfusion liquid, and the concentration of the bremer langdan in blood is greatly improved (compared with the result without the SNAC). Surprisingly, there was a tendency to decrease the amount of absorbed bremer langdan in rats from 0.5mmol to 1.0mmol as the SNAC concentration increased. The mechanism by which SNAC promotes macromolecular absorption is not completely understood, and it is reported in the literature that at a concentration of 10mM, the mechanism reversibly increases intercellular permeability, so that molecules with a molecular weight of less than 10 kdaltons increase the amount of permeation.

Example 2

Rats were fasted for 16 hours prior to dosing, but had free access to water. After anesthesia by intraperitoneal injection, the rats were placed under a heating lamp, the body temperature was kept at about 37 ℃, and the stomach was exposed through the median incision in the abdomen. Incision is made at both ends of stomach, polyethylene tube is inserted into the two ends of stomach, phosphate buffer (pH 7.4) is used to flush the stomach, and the rest buffer is removed with air. A solution containing the absorption enhancer or a solution containing only the drug in a volume of 200ml was poured in Krebs-Ringer solution, and the preparation method was the same as in example 1. The perfusion solution was maintained at 37 ℃ and the solution administered through the catheter was circulated with incubation. The jugular vein was exposed and a 0.3ml blood sample was taken by direct puncture of a heparin syringe at 20, 40, 60, 90, 120 minutes after the drug-containing circulation was started. Plasma was obtained immediately by centrifugation at 12000 rpm for 5 minutes and stored frozen for further analysis. Adding the bremer langdan or the bremer langdan and the SNAC into the perfusion solution.

Two concentration levels of SNAC were selected for experimental design. Each experiment was performed using 3 rats and additionally the absorption of the perfusate of the bremer langdan without SNAC was determined. The formulation is shown in Table 2.

TABLE 2 Blameria de la and SNAC combination addition

The drug concentration in the blood of the drug solution of the Braimersondan without the absorption enhancer is not measured within 120 minutes. The test results are shown in FIG. 2.

In the stomach, the polypeptide drug is generally considered to be sensitive to pepsin and hydrochloric acid, and is easy to degrade and influence absorption. As can be seen from example 2, without addition of an absorption enhancer, the Bremelanotide was not substantially absorbed in the stomach of the body rat, and the drug could not be detected in the blood.

Under the concentration of 0.5mmol/200ml and 1.0mmol/200ml perfusion liquid, the SNAC effectively improves the absorption degree of the Braimeldian in the stomach perfusion of rats, which is reflected in that the Braimeldian in the blood has higher blood concentration level (compared with the result without using the absorption enhancer). The better absorption degree of the Bremelanotide in the stomach of the rat is proved under the condition that the absorption enhancer exists.

Example 3

Preparing artificial gastric juice (reference American medicine)Typical preparation method) and artificial intestinal juice (see the preparation method of phosphate buffer solution containing pancreatin and having a pH of 6.8 recorded in the 2020 edition of chinese pharmacopoeia). Weighing appropriate amount of Bremelanotide, dissolving into 0.1mg/ml solution with artificial gastric juice and artificial intestinal juice, respectively, and placing in water bath at 37 deg.C. Detecting the content of the Bremelanotide in the artificial gastric juice and the artificial intestinal juice by adopting a high performance liquid chromatography. The detection method comprises the following steps: high performance liquid chromatography, C₁₈A column with a detection wavelength of 215 nm; the column temperature is 30 ℃; the flow rate is 1.0 ml/min; sample introduction volume: 20 ul; the sample concentration is 0.1 mg/ml; the mobile phase A contains acetonitrile solution of 1 percent trifluoroacetic acid, and the mobile phase B contains aqueous solution of 1 percent trifluoroacetic acid; the gradient elution procedure is shown in table 3:

TABLE 3 procedure table for gradient elution of mobile phase

Time	Mobile phase A	Mobile phase B
			0 minute	25％	75％
25 minutes	50％	50％
			30 minutes	100％	0％
35 minutes	25％	75％
			40 minutes	25％	75％

From the change of the peak area of the main peak of the bremerrand in the measurement result, the chromatographic peak area of the bremerrand in the artificial gastric juice is not changed basically within 4 hours, and the relative standard deviation RSD of the chromatographic peak area at 5 time points of 0, 1, 2, 3 and 4 hours is 1.59 percent. It has surprisingly been found that the drug is stable to artificial gastric fluid. In the artificial intestinal juice, the chromatographic peak area of the bremerrand is reduced by 5% within 4 hours, and the relative standard deviation of the chromatographic peak area is 3% at 5 time points of 0, 1, 2, 3 and 4 hours. It is believed that bremer langdan is more unstable in artificial intestinal fluid than in artificial gastric fluid. In order to make the oral onset of action of the drug as consistent as possible with the effect of subcutaneous injection, the oral formulation is required to rapidly release the bremer-wave pellet in the stomach.

Examples 4 to 6

The formulation compositions of examples 4-6 are shown in Table 4 below, expressed as mass of material in a unit formulation.

TABLE 4 prescription compositions for examples 4-6

Example 4: commercially available Bremelanotide and SNAC are taken, the materials are weighed according to the prescription composition without being crushed, mixed for 5 minutes and filled into No. 0 capsules, and each capsule is filled with about 160 mg.

Example 5: commercially available Bremelanotide and SNAC are taken, the materials are weighed according to the prescription composition without being crushed, mixed for 5 minutes and filled into No. 0 capsules, and each capsule is filled with about 230 mg.

Example 6: pulverizing the bremer langdan and the SNAC, sieving the bremer langdan with a 80-mesh sieve, sieving the SNAC with a 100-mesh sieve, weighing according to the prescription composition, mixing for 5 minutes, and filling into No. 0 capsules, wherein each capsule is filled with about 230 mg.

The dissolution rate determination method comprises the following steps: a first method of a dissolution rate measuring device specified in the 2020 edition of Chinese pharmacopoeia is selected, the rotating speed of a blue rotating device is 50RPM, 900ml of 0.1M hydrochloric acid solution is used as a medium for dissolution rate measurement, samples are taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes, and the dissolution rate is measured. The determination method employed was high performance liquid chromatography as described in example 3. The test results are shown in Table 5:

table 5 dissolution test results of examples 4 to 6 (mean and relative standard deviation RSD, n ═ 6)

Both examples 4 and 5 did not address the material particle size. At 15 minutes, the dissolution rates were all less than 85%, and the dissolution rate differences among the capsules were large, the material of example 6 was subjected to pulverization, the D of the drug and SNAC₉₀And when the dissolution rate is less than 56 and 8.6 microns, the dissolution rate is slightly increased at 5 minutes, and the dissolution rate is lower than 85% at 15 minutes.

From the powder characteristics of the materials, the materials of examples 4 and 5 are not crushed, have good fluidity, but have large size difference of particles, and have the risk of nonuniform mixing during large-scale production. Moreover, the particle size is not controlled, and the variation among product batches is easy to be large.

Examples 7 to 10

The wet granulation process is a common process for improving the flowability of powder aiming at substances with stable humidity and temperature, and achieves the aim of improving the flowability by adding a binder for granulation and adding a lubricant for flow aid. The common adhesive is hydroxypropyl methylcellulose with low viscosity and polyvidone compounds. Commonly used lubricants include magnesium stearate, sodium stearyl fumarate, and the like.

The formulation compositions of examples 7-10 are given in Table 5 below, expressed in units of material added for a single formulation: and (5) mg.

TABLE 5 examples 7-10 recipe compositions

The preparation method comprises the following steps: comminution of Rameran and SNAC, medicaments and SNAC D₉₀Less than 56, 8.6 microns. Taking the two materials, respectively adding polyvidone K-30 or K-90 according to the prescription design, adding water for granulation, sieving with a 18-mesh sieve for granulation, drying at 40-60 ℃, finishing with a 20-mesh sieve, adding magnesium stearate or sodium stearyl fumarate, and mixing for 2 minutes. And (4) encapsulating. The dissolution was measured.

The dissolution rate determination method comprises the following steps: selecting a first method of a dissolution rate measuring device specified in the 2020 edition of Chinese pharmacopoeia, rotating speed of a blue turning device at 50RPM, selecting 900ml of 0.1M hydrochloric acid solution as a medium for dissolution rate measurement, sampling at 5, 10, 15, 30 and 45 minutes, and measuring dissolution rate. The determination was carried out by high performance liquid chromatography as described in example 3. Test results table 6:

table 6 dissolution test results of examples 7 to 10 (mean/relative standard deviation, n ═ 6)

The test result shows that the particle size of the material of the Braimeidan has influence on the dissolution rate. In order to improve the flowability of the material, suitable for filling capsules, the material was wet granulated with povidone K-90 as binder (example 10) and dissolution significantly slower than povidone K-30 as binder (example 8). After granulation, the dissolution of the drug needs to be achieved after disintegration of the granules, and it is expected that the value of the dissolution rate of the granulated capsule will be smaller than that of the non-granulated and filled capsule at the same time point,

but the actual result is unexpected, the dissolution rate of the granulated and filled capsule adopting the povidone K-30 as the adhesive is higher than that of the capsule directly filled with the materials at the same time point.

While sodium stearyl fumarate, as a hydrophilic lubricant, acted similarly to magnesium stearate in terms of material flow, in the above test, it showed a faster dissolution of the drug in 5 minutes, the end result was unexpected, as example 7, where magnesium stearate was used as a lubricant, was more effective than sodium stearyl fumarate (examples 8, 9).

Through the use of povidone K-30 for granulation and the addition of magnesium stearate for glidant, the dissolution rate of the capsule is greatly improved by adopting a wet granulation process, and the dissolution rate is more than 85 percent within 15 minutes.

Examples 11 to 19

Pulverizing the bremer-wave-red and SNAC, and mixing the medicine with SNAC₉₀Less than 56, 8.6 microns. The formulations of examples 11-19 are shown in the following table, expressed as the material added to the individual formulations, in units: and (5) mg.

TABLE 7 compositions of formulations of examples 11-19

The preparation method comprises the following steps: examples 11-19 the composition is prepared by weighing the composition in accordance with the formula, mixing the components for 5 minutes, adding an appropriate amount of water, granulating, and sieving with a 18 mesh sieve. After drying at 40-60 ℃, magnesium stearate is added, mixed for 2 minutes, and loaded into a No. 00 capsule shell, (example 15, 18 two No. 0 capsules) to obtain a capsule preparation.

The dissolution rate determination method comprises the following steps: a first method of a dissolution rate measuring device specified in the 2020 edition of Chinese pharmacopoeia is selected, the rotating speed of a blue rotating device is 50RPM, 900ml of 0.1M hydrochloric acid solution is selected as a medium for dissolution rate measurement, samples are taken at 15 and 30 minutes, and the dissolution rate is measured. The determination was carried out by high performance liquid chromatography as described in example 3. The test results are shown in Table 8:

TABLE 8 dissolution test results of examples 11 to 19

Beagle dogs were dosed orally with the capsules of examples 11-19, and all animals were fasted for 12 hours without water deprivation prior to dosing. Drinking water is forbidden from 1h before administration to 1h after administration, and drinking water can be provided as required at other times. Collecting blood of 2mL from forelimb vein before administration (0min), 5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, and 8h, respectively, placing in a container containing EDTA-K₂The tubes were mixed by gentle inversion and centrifuged for 1h, and the plasma samples were separated after centrifugation at 4 ℃ for 10min (1700g) at 2-8 ℃. All post-centrifugation plasma samples approximately 1mL of plasma was placed in polypropylene cryovials. After centrifugation, the plasma sample can be kept in a refrigerator at minus 20 ℃ (-10 to minus 30 ℃) for temporary storage within 2 hours, and is transferred to an ultra-low temperature refrigerator at minus 80 ℃ (-60 to minus 90 ℃) for storage within 24 hours, or can be directly stored in the ultra-low temperature refrigerator at minus 80 ℃. The concentration of bremeranle red in Beagle dog plasma samples was determined by hplc tandem mass spectrometry and analyzed by software analyst1.6.3(AB Sciex). Peak time T of blood concentration_maxPeak concentration C_maxAnd area under the curve of drug time AUC_0-∝The results are given in Table 9 below:

TABLE 9 results of pharmacokinetic indices in examples 11-19

The observed data show that the peak time T of the blood concentration of 9 examples_maxAll within 0.5-1.0 hour, and the Bremer

The amount of langdan and SNAC varied and had no effect on the time to peak. The reason for this is probably that the dissolution rate of all 9 preparations is more than 85% in 15 minutes, and the preparation belongs to the rapid dissolution behavior in hydrochloric acid medium, so the peak reaching time in vivo is close.

Under the condition that the enteric protective auxiliary materials are not used, the dissolution rate of the preparation is more than 85% within 15 minutes, and the SNAC can promote the absorption of the Braimer's disease pill under the condition that the preparation is quickly dissolved in the stomach. Examples 11-19, the formulation of Braimersan in beagl e dogsTo reach C_max40.2-415.2 ng/ml; AUC can reach 71.5-989.0h ng/ml.

The relative absorption effect of 20mg of the bremer langdan is not as good as 80mg and 120mg under the same dosage of the SNAC. The higher the dose of SNAC, the higher the Cmax and AUC, the better the absorption, which is not necessarily the case with higher SNAC doses given with the same dose of bremer langerhans.

Under the condition of realizing the expected effect, the absorption enhancer SNAC with lower dosage has the advantages of safety, is beneficial to preparing preparations and is beneficial to patients to take the medicines as less as possible.

Examples 20 to 22

The formulation of examples 20-22 is shown in Table 10 below.

TABLE 10 prescription compositions for examples 20-22

Example 20: pulverizing the Bremelanotide to obtain powder with particle diameter D₉₀56 μm, sodium 8- (2-hydroxybenzoylamino) caprylate, particle size D₉₀8.6 μm. Weighing the bremer langdan, the sodium 8- (2-hydroxybenzoylamino) caprylate, the microcrystalline cellulose, the povidone k-30 and the sucralose according to the prescription amount, mixing for 3 minutes, adding a proper amount of water for granulation, sieving with a 18-mesh sieve, drying at 40-60 ℃ until the drying weight loss is less than 3%, sieving with a 20-mesh sieve for granulation, adding the vanillin, mixing for 2 minutes, and filling into a packaging bag to obtain granules, wherein the filling amount is 500mg per bag.

Example 21: pulverizing the Bremelanotide to obtain powder with particle diameter D₉₀56 μm, sodium 8- (2-hydroxybenzoylamino) caprylate, particle size D₉₀8.6 μm. Weighing the bremer rambutan, the sodium 8- (2-hydroxybenzoylamino) caprylate, the microcrystalline cellulose and the povidone k-30 according to the prescription amount, mixing for 3 minutes, adding a proper amount of water, granulating by using a 18-mesh sieve, drying at 40-60 ℃ until the drying weight loss is less than 3%, sieving by using a 20-mesh sieve, granulating, adding the magnesium stearate, mixing for 2 minutes, and filling into a No. 0 capsule shell to obtain the capsule.

Example 22: and cleaning and drying the penicillin bottle, the rubber plug and the aluminum cover. Weighing the prescribed dose of the bremer langdan and the glycerol, adding the bremer langdan and the glycerol into a small beaker, adding water, stirring for dissolving, and homogenizing. The pH was measured. If necessary, the pH is adjusted to between 4.0 and 6.0 with hydrochloric acid or sodium hydroxide solution (0.5M). Subpackaging into penicillin bottles, pressing plugs and pressing aluminum caps. And sterilizing at 121 ℃ for 15 minutes. And (6) cooling. Obtaining the injection. The concentration was 1.75mg (calculated as the bases of Braimersan) per 0.3 ml.

The pharmacokinetic profile of examples 20-22 was determined in Beagle dogs using 6 dogs in a randomized, open, three formulation, three cycle, three crossover test design with a wash period of at least 5 days between doses. Example 22 is an injection, 1.75mg/0.3mL of subcutaneous injection; example 20 is an oral granule, with the following specifications: 80mg/0.5g, 0.5g for oral administration (10mL warm water is taken after being mixed with water, 30mL warm water is taken for 3 times, and the bottle wall is washed to ensure that the medicine is taken completely). Example 21 is a capsule, specification: 100 mg/capsule, 1 capsule is taken orally (about 2mL water per capsule). Dogs were male and female, and all animals were fasted for 12 hours before dosing without water deprivation. Drinking water is prohibited from 1 hour before administration to 1 hour after administration, and drinking water can be given at other times as required. Collecting blood of 2mL from forelimb vein before administration (0min), 5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, and 8h, respectively, placing in a container containing EDTA-K₂The tubes were mixed by gentle inversion and centrifuged for 1h, and the plasma samples were separated after centrifugation at 4 ℃ for 10min (1700g) at 2-8 ℃. All post-centrifugation plasma samples approximately 1mL of plasma was placed in polypropylene cryovials. After centrifugation, the plasma sample can be kept in a refrigerator at minus 20 ℃ (-10 to minus 30 ℃) for temporary storage within 2 hours, and is transferred to an ultra-low temperature refrigerator at minus 80 ℃ (-60 to minus 90 ℃) for storage within 24 hours, or can be directly stored in the ultra-low temperature refrigerator at minus 80 ℃. The concentration of bremeranle red in Beagle dog plasma samples was determined by hplc tandem mass spectrometry and analyzed by software analyst1.6.3(AB Sciex). Peak time T of blood concentration_maxPeak concentration C_maxArea under the time curve AUC_0-∝。

The results are shown in Table 11, in vivo plasma concentrations at various time points in ng/ml.

TABLE 11 examples 20-22 plasma drug concentrations in vivo at various time points

The test result shows that the peak reaching time T_maxIn one aspect, example 20 is a granule, which is dissolved in water prior to administration, gavage a canine, and has a rapid absorption rate with a peak time of about 0.25 hours, a subcutaneous peak time of 0.5 hours, and an oral capsule peak time of 0.75 hours. Dissolution control was verified, an assumption that Tmax was guaranteed to reach the expected interval. In examples 20 and 21, the dissolution rates measured by the bluing method at 50rpm were 92% and 90%, respectively, and the RSD was less than 10% at 15 minutes. C of example 22_max429.83ng/ml, 100mg oral capsule, C_maxAbout 424.79ng/ml, corresponding to subcutaneous injection levels. The concentration is higher than that of granules (80 mg for oral administration). In terms of AUC, AUC of oral capsule_0-T686.80 hng/ml; the granules in example 20 were 548.20hng/ml, and the subcutaneous injection in example 22 was 662.42 hng/ml. The absolute bioavailability of the oral formulation after conversion to orally administered doses is greater than 1.0%.

Examples 23 to 28

TABLE 12 compositions and proportions of the formulations 23-24 of examples

TABLE 13 compositions and proportions of the formulations in examples 25-26

TABLE 14 examples 27-28 recipe compositions and ratios

Pulverizing the Bremelanotide to obtain powder with particle diameter D₉₀56 μm sodium 8- (2-hydroxybenzoylamino) caprylate (SNAC for short) and has a particle diameter D₉₀8.6 μm. According to the test report, after the acetate content is converted by the bremer langdan, the corresponding base content is 80mg, 100mg and 120mg, and the actual feeding amount is 85mg, 106mg and 127.5mg respectively. Weighing the bremer rambutan, the sodium 8- (2-hydroxybenzoylamino) caprylate, the microcrystalline cellulose and the povidone k-30 according to the prescription amount, mixing for 3 minutes, adding a proper amount of water for granulation, sieving by a 18-mesh sieve for granulation, drying at 40-60 ℃ until the drying weight loss is less than 3%, sieving by a 20-mesh sieve for granulation, adding the magnesium stearate, mixing for 2 minutes, and filling into a No. 0 capsule shell to obtain the capsule. Examples 23-28 the apparatus for the first method of dissolution determination in the 2020 edition of chinese pharmacopoeia was used to determine that the dissolution rate in 0.1MHCl medium in 900ml at 50rpm for 15 minutes was more than 85% of the marked amount.

Referring to example 21, Beagle dog oral capsules were administered, and about 2mL of each of the blood was collected from the forelimb vein before (0min), 5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, and 8h after administration, and treated according to the blood sample treatment method of example 21, and the concentration of bremer red in Beagle dog plasma samples was measured by hplc tandem mass spectrometry and analyzed by software analyst1.6.3(AB Sciex). Peak time T of blood concentration_maxPeak concentration C_maxArea under the time curve AUC_0-TThe results of the tests are shown in Table 15 below:

TABLE 15 results of examples 23-28 pharmacokinetic indices

Examples 29 to 30

TABLE 16 examples 29-30 prescription compositions (mg/unit preparation)

The breimei pellet is crushed and then is crushed,particle diameter D₉₀56 μm sodium 8- (2-hydroxybenzoylamino) caprylate (SNAC for short) and has a particle diameter D₉₀8.6 μm. According to the test report, after the acetate content is converted by the Bremelanotide, the corresponding base is 100 mg. Weighing the bremer langdan, the sodium 8- (2-hydroxybenzamido) caprylate, the microcrystalline cellulose and the povidone k-30 according to the prescription amount, mixing for 3 minutes, adding a proper amount of water for granulation, sieving by a 18-mesh sieve for granulation, drying at 40-60 ℃ until the drying weight loss is less than 3%, sieving by a 20-mesh sieve for granulation, adding the magnesium stearate, mixing for 2 minutes, filling into a No. 00 capsule shell, filling 1 in example 29 and filling 2 in example 30. To obtain capsule. Examples 29-30 Using the apparatus of the first method for determining dissolution in the 2020 th edition of the Chinese pharmacopoeia, in 900ml of 0.1MHCl medium, at a rotation speed of 50rpm, 1 tablet was taken in example 29, 2 tablets were taken in example 30, and the dissolution rate was more than 85% of the labeled amount in 15 minutes.

TABLE 17 dissolution results of examples 29 to 30

Time (minutes)	Example 29	Example 30
			15	97％	86％
30	99％	95％

As can be seen from the data, when the administration dose is between 80mg and 120mg, and the SNAC usage amount is between 120 and 180mg, when the oral administration of the Braameria delavayi capsule is carried out, the ratio of the Cmax and the AUC0-T in BEAGLE dogs is between 80.71% and 112.83% and 88.99% and 111.29% compared with the subcutaneous injection of 1.75mg (example 22), the oral preparation and the injection can be considered to have the same effect.

The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.

Claims

1. A oral pharmaceutical composition of bremer lang dan, wherein the composition comprises the bremer lang dan, sodium 8- (2-hydroxybenzamido) caprylate, adhesive, excipient and lubricant; the weight ratio of the bremer langdan to the sodium 8- (2-hydroxybenzamido) caprylate is 8-12: 12-18, and the weight of the bremer langdan is calculated in a free alkali form; the particle size D90 of the Braimer wave lead material is less than 56 μm, and the particle size D90 of the sodium 8- (2-hydroxybenzamido) caprylate is less than 8.6 μm; the adhesive is povidone K30; the excipient is microcrystalline cellulose; the lubricant is magnesium stearate; the weight of the adhesive is 0.1-10% of the total weight of the Bramerlandine and the sodium 8- (2-hydroxybenzamido) caprylate, the weight of the excipient is 0.2-200% of the total weight of the Bramerlandine and the sodium 8- (2-hydroxybenzamido) caprylate, the weight of the lubricant is 0.1-10% of the total weight of the Bramerlandine and the sodium 8- (2-hydroxybenzamido) caprylate, and the weight of the Bramerlandine is calculated in a free base form; the oral preparation prepared from the composition is a tablet, a capsule, a granule or an oral solution.

2. The oral pharmaceutical composition of claim 1, wherein the weight ratio of the bremer langdan to the sodium 8- (2-hydroxybenzamido) caprylate is 8-12: 15.

3. The oral pharmaceutical composition of claim 1, wherein the weight of the binder is 0.5-5% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate, the weight of the excipient is 1-150% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate, and the weight of the lubricant is 0.2-5% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate.

4. The oral pharmaceutical composition of claim 3, wherein the weight of the binder is 0.5-2.5% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate, the weight of the excipient is 2-100% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate, and the weight of the lubricant is 0.5-2.0% of the total weight of the bremer lang and the sodium 8- (2-hydroxybenzamido) caprylate.

5. The oral pharmaceutical composition of any one of claims 1 to 4, further comprising one or more of a sweetener and an aroma; wherein the sweetening agent is 0.1-15% of the total weight of the bremer lang and the SNAC, the essence is 0.1-2% of the total weight of the bremer lang and the SNAC, and the weight of the bremer lang is calculated in a free alkali form; the sweetener is one or more selected from sucralose, stevioside and aspartame, and the essence is one or more selected from banana essence, raspberry essence, beef tallow essence and vanillin.

6. Use of an oral pharmaceutical composition according to any one of claims 1 to 5 in the manufacture of a product for the treatment of female hypoactive sexual desire.