Oral water-soluble polypeptide pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an oral water-soluble polypeptide pharmaceutical composition and a preparation method thereof. The composition comprises at least one effective dose of water-soluble polypeptide, at least one absorption enhancer, at least one pH regulator and at least one other excipient. The pharmaceutical composition provided by the invention effectively promotes the absorption of the water-soluble polypeptide drug, and further improves the bioavailability of the water-soluble polypeptide drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral water-soluble polypeptide pharmaceutical composition and a preparation method thereof. Background Art

[0002] Parathyroid hormone (PTH) is a water-soluble polypeptide containing 84 amino acids secreted by the parathyroid gland. PTH regulates serum calcium levels by increasing calcium release from bones (bone resorption) and increasing calcium absorption in the intestine.

[0003] Abaloparatide is a synthetic analogue of 34 amino acids of human parathyroid hormone-related peptide (PTHrP (1-34)) (molecular weight: 3961). As an agonist at the PTH1 receptor (PTH1R), it can treat osteoporosis in postmenopausal women at high risk of fracture. It has 41% homology to human parathyroid hormone 1-34 (hPTH (1-34)) and 76% homology to human parathyroid hormone-related peptide 1-34 (hPTHrP (1-34)). The currently marketed drug is for injection. The recommended dose is 80 μg, administered once daily by subcutaneous injection. After 7 days of subcutaneous administration of abalotriptyline 80 μg, the mean C max The mean AUC was 812 (SD = 118) pg / mL and 0-24h The median time to peak concentration after subcutaneous administration of 80 μg of abalotriptyline is 1622 (SD=641) pg·hr / mL. The median time (range) to peak concentration after subcutaneous administration of 80 μg of abalotriptyline is 0.51 h (0.25 to 0.52 h). The absolute bioavailability of abalotriptyline after subcutaneous administration of an 80 μg dose in healthy women is 36%. The in vitro plasma protein binding of abalotriptyline is about 70%. The volume of distribution is about 50 L. The mean half-life of abalotriptyline is 1.7 (SD=0.7) h. Abalotriptyline clearance is mainly degraded to smaller peptide fragments by nonspecific hydrolysis, followed by elimination by renal excretion.

[0004] Although it was approved by the FDA in 2017 for the treatment of postmenopausal women at risk of osteoporosis, it is administered by subcutaneous injection. The incidence of redness at the injection site was higher (58% vs. 28%), and severe redness (2.9%), severe edema (0.4%), and severe pain (0.4%) at the injection site were also reported. Therefore, the development of oral abalotriptyline could effectively improve patient compliance.

[0005] Compared with small molecule drugs, peptide drugs (such as abalotriptyline) are more easily degraded in the digestive system after oral administration. The physiological environment of the stomach and intestines, such as pH, enzymes, mucus layer and permeability of epithelial cells, are more likely to affect the absorption of peptide drugs, resulting in low bioavailability and poor efficacy of peptide drugs after oral administration. In order to overcome the above obstacles, research and development teams in various countries have tried different methods to break through the development bottleneck of oral peptide drugs. For example, the FDA approved the (Cyclosporin A, a cyclic peptide with a molecular weight of 1202), although generally classified as a poorly soluble drug, is also recognized as the first oral peptide dosage form. Five years later, Novartis developed an improved version of cyclosporin A using a nanoemulsion self-emulsifying drug delivery system (SNEDDS) FDA-approved drugs for the treatment of lupus nephritis in 2021 (Cyclosporin, a cyclic peptide with a molecular weight of 1215) is also based on SNEDDS technology. Although SNEDDS technology can effectively improve the oral absorption of oil-soluble cyclic peptides, this technology cannot greatly improve the oral bioavailability of water-soluble peptides.

[0006] For water-soluble peptides, Novo Nordisk successfully developed an oral formulation of semaglutide in 2019 by adding the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate (SNAC) to the oral formulation. It was approved by the FDA for the treatment of type II diabetes. Subsequently, CHIASMA used transient permeability enhancers Octreotide sustained-release capsules developed with sodium octanoate (C8) It was also approved by the FDA in 2020. In 2021, Merck announced the human data of the first oral PCSK9 inhibitor (small molecule cyclic peptide MK-0616) at the American Heart Association. After using absorption enhancers (caprylic acid capric acid macrogol glyceride or sodium caprate), the maximum blood concentration of MK-0616 was 5-6 times higher than the maximum blood concentration without absorption enhancers. Although the mechanism by which these absorption enhancers promote the absorption of water-soluble peptides is not yet fully understood, it is generally accepted that these absorption enhancers can (1) regulate the pH of the gastrointestinal tract and reduce the activity of degradative enzymes in the gastrointestinal tract, thereby preventing the degradation of water-soluble peptides; (2) increase the permeability of gastrointestinal epithelial cell membranes, open tight junctions, enhance the delivery of peptide drugs, and promote the absorption of peptide drugs. Compared with water-soluble peptides, these absorption enhancers are easily protonated in the gastrointestinal tract (for example, carboxylates are converted to carboxylic acids), resulting in reduced solubility and slower dissolution rate. It is difficult to achieve synchronous release with water-soluble peptide drugs, and the absorption promotion function is reduced. Summary of the invention

[0007] The present invention provides an oral water-soluble polypeptide pharmaceutical composition, comprising at least one effective dose of water-soluble polypeptide, at least one absorption enhancer, and at least one pH adjuster. The pH of the gastrointestinal tract is adjusted to improve the solubility and dissolution rate of the absorption enhancer in the gastrointestinal tract, thereby achieving simultaneous release with the water-soluble polypeptide drug, more effectively promoting the absorption of the water-soluble polypeptide drug, and further improving the bioavailability of the water-soluble polypeptide drug.

[0008] The present invention provides an oral composition of abalotriptide, which is an agonist on a PTH1 receptor (PTH1R) and is suitable for treating postmenopausal women with osteoporosis. The present invention provides an oral release formulation comprising abalotriptide or a pharmaceutically acceptable salt thereof. The formulation described herein has a desired pharmacokinetic profile.

[0009] According to aspects of some embodiments of the present invention, a pharmaceutical composition is provided for use in treating osteoporosis by orally administering the composition to a subject in need thereof, the composition comprising: parathyroid hormone or a fragment thereof or an analog of a parathyroid hormone-related peptide; an effective dose of an absorption enhancer, and an effective dose of a pH regulator.

[0010] According to some embodiments of the invention, the treatment comprises oral administration of parathyroid hormone or a fragment thereof or an analog of parathyroid hormone-related peptide in the range of 200 μg to 20 mg. Preferably, abalotriptide or a pharmaceutically acceptable salt thereof is used.

[0011] According to some embodiments of the invention, the composition and / or medicament is for once-daily oral administration.

[0012] According to an aspect of some embodiments of the present invention there is provided a method of treating osteoporosis in a subject in need thereof.

[0013] According to some embodiments of the invention, the fragment comprises abalotriptyline or a pharmaceutically acceptable salt thereof.

[0014] According to some embodiments of the present invention, the absorption enhancer is selected from 8-N-(2-hydroxybenzoyl)aminocaprylate (NAC), 10-N-(2-hydroxybenzoyl)aminodecanoic acid (NAD), 8-N-(5-chlorosalicyloyl)aminocaprylic acid (5-CNAC), 8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid (4-MOAC), 4-N-(2-hydroxy-4-chlorobenzoyl)aminobutyric acid (4-CNAB), caprylic acid, capric acid and their salts, or a group consisting of the above absorption enhancers; preferably NAC and its salts such as SNAC, i.e. sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

[0015] According to some embodiments of the invention, the combination comprises the absorption enhancer SNAC.

[0016] According to some embodiments of the present invention, the at least one pH adjuster is selected from a group including but not limited to NaOH (sodium hydroxide), KOH (potassium hydroxide), Na2CO3 (sodium carbonate), NaHCO3 (sodium bicarbonate), K2CO3 (potassium carbonate), KHCO3 (potassium bicarbonate), Na2HPO4 (disodium hydrogen phosphate), NaH2PO4 (sodium dihydrogen phosphate), K2HPO4 (dipotassium hydrogen phosphate), KH2PO4 (potassium dihydrogen phosphate), or a group consisting of the above pH adjusters.

[0017] According to some embodiments of the invention, the combination comprises a pH adjuster Na2CO3 (sodium carbonate).

[0018] According to some embodiments of the present invention, the composition is formulated into tablets or capsules; preferably enteric-coated tablets or enteric-coated capsules.

[0019] The pharmaceutical composition of the present invention further comprises at least one other excipient suitable for oral medication to prepare the pharmaceutical composition. Suitable excipients include fillers such as sugars (including lactose, sucrose, mannitol or sorbitol); cellulose preparations (including microcrystalline cellulose, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose); and / or polymers available for oral medication, such as polyvinyl pyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinyl pyrrolidone, sodium starch glycolate, agar or alginic acid, or its salts such as sodium alginate, can be added; and / or lubricants such as talc or magnesium stearate; and / or glidants such as colloidal silicon dioxide.

[0020] According to some embodiments of the invention, wherein the composition is formulated such that after oral administration of the composition, the absorption of the water-soluble polypeptide is characterized by C max In the range of 1 ng / mL to 100 ng / mL.

[0021] According to some embodiments of the invention, after oral administration of the composition, the absorption of abalotriptide is characterized by C max In the range of 5 ng / mL to 50 ng / mL.

[0022] According to some embodiments of the invention, wherein the composition is formulated such that after oral administration of the composition, the absorption of abalotriptide or the fragment thereof is characterized by AUC vs. C max The ratio is 3 hours or less.

[0023] According to some embodiments of the invention, wherein AUC and C max The ratio is 2 hours or less.

[0024] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or test of embodiments of the present invention, exemplary methods and / or materials are described below. In the case of contradiction, the patent specification (including definition) will be taken as the criterion. In addition, materials, methods and embodiments are only illustrative and are not intended to be necessary restrictions.

[0025] Before explaining in detail at least one embodiment of the present invention, it should be understood that the present invention is not necessarily limited in its application to the details described in the following description or exemplified by the Examples. The present invention is capable of other embodiments or can be practiced or carried out in various ways.

[0026] As described above, parathyroid hormone or fragments thereof or analogs of parathyroid hormone-related peptide are known to be effective in the treatment of osteoporosis and have been used for this effect by subcutaneous injection of parathyroid hormone or fragments thereof or analogs of parathyroid hormone-related peptide. The present inventors have now discovered that by using a composition designed to overcome the poor absorption of parathyroid hormone or fragments thereof or analogs of parathyroid hormone-related peptide after oral administration, oral administration of parathyroid hormone or fragments thereof or analogs of parathyroid hormone-related peptide can be used instead of subcutaneous injection to advantageously treat osteoporosis.

[0027] The present invention relates to an oral parathyroid hormone or its fragment or an analog of a parathyroid hormone-related peptide, preferably abalotriptide or a pharmaceutically acceptable salt thereof.

[0028] The present invention relates to an oral release composition of abalotriptide or a pharmaceutically acceptable salt thereof, and a composition and method for treating osteoporosis. The release of abalotriptide or a pharmaceutically acceptable salt thereof can be achieved by any dosage form known in the pharmaceutical field, including tablets, capsules, etc.

[0029] As used herein, the phrase "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, cocrystals, pseudoisomorphs, neutral forms, acid addition salt forms, and prodrugs. An acceptable acid addition salt of abalotriptide is prepared in a conventional manner by treating a solution or suspension of the free base with one or two chemical equivalents of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are used to separate the salt. Examples of suitable acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, aminosulfonic acid, sulfonic acids (such as methanesulfonic acid, benzenesulfonic acid), and related acids. A preferred salt of abalotriptide is in the form of abalotriptide acetate.

[0030] The present invention provides a once-daily pharmaceutical dosage form comprising abalotriptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the dosage form is a tablet or a capsule, and the absorption of abalotriptide is characterized by C max In the range of 1 ng / mL to 100 ng / mL, AUC and C max In another embodiment of the present invention, the pharmaceutical dosage form can be characterized by the absorption of abalotriptyline in that C max In another embodiment of the present invention, the pharmaceutical dosage form can be characterized by the absorption of abalotriptyline in the range of 5 ng / mL to 50 ng / mL, and the AUC is in the range of 1 ng·hr / mL to 50 ng·hr / mL. max In another embodiment of the present invention, the pharmaceutical dosage form can be characterized by the absorption of abalotriptyline in the range of 5 ng / mL to 40 ng / mL, and the AUC is in the range of 1.5 ng·hr / mL to 40 ng·hr / mL. max In the range of 10 ng / mL to 20 ng / mL, the AUC was in the range of 10 ng·hr / mL to 20 ng·hr / mL.

[0031] In some embodiments of any of the embodiments described herein, the content of abalotriptide in the composition described herein is in the range of 200 μg to 20 mg. In one embodiment of the invention, the pharmaceutical dosage form may include 800 μg to 20 mg of abalotriptide, preferably 20 mg of abalotriptide. In another embodiment of the invention, the pharmaceutical dosage form may include 600 μg to 14 mg of abalotriptide, preferably 14 mg of abalotriptide. In another embodiment of the invention, the pharmaceutical dosage form may include 400 μg to 5 mg of abalotriptide, preferably 5 mg of abalotriptide.

[0032] In some embodiments of any of the embodiments described herein, the content of NaOH in the composition described herein is in the range of 200 μg to 30 mg. In another embodiment of the invention, the pharmaceutical dosage form may include 800 μg to 10 mg NaOH, preferably 10 mg NaOH. In another embodiment of the invention, the pharmaceutical dosage form may include 600 μg to 30 mg NaOH, preferably 30 mg NaOH. In another embodiment of the invention, the pharmaceutical dosage form may include 400 μg to 20 mg NaOH, preferably 20 mg NaOH.

[0033] In some embodiments of any of the embodiments described herein, the content of KH2PO4 in the composition described herein is in the range of 20 mg to 700 mg. In another embodiment of the invention, the pharmaceutical dosage form may include 80 mg to 150 mg KH2PO4, preferably 150 mg KH2PO4. In another embodiment of the invention, the pharmaceutical dosage form may include 60 mg to 350 mg KH2PO4, preferably 350 mg KH2PO4. In another embodiment of the invention, the pharmaceutical dosage form may include 40 mg to 650 mg KH2PO4, preferably 650 mg KH2PO4.

[0034] In some embodiments of any of the embodiments described herein, the content of Na2CO3 in the composition described herein is in the range of 10 mg to 300 mg. In another embodiment of the invention, the pharmaceutical dosage form may include 15 mg to 60 mg Na2CO3, preferably 60 mg Na2CO3. In another embodiment of the invention, the pharmaceutical dosage form may include 70 mg to 90 mg Na2CO3, preferably 90 mg Na2CO3. In another embodiment of the invention, the pharmaceutical dosage form may include 100 mg to 300 mg Na2CO3, preferably 200 mg Na2CO3.

[0035] In some embodiments of any of the embodiments described herein, the content of SNAC in the composition described herein is in the range of 10 mg to 600 mg. In another embodiment of the invention, the pharmaceutical dosage form may include 10 mg to 100 mg SNAC, preferably 100 mg SNAC. In another embodiment of the invention, the pharmaceutical dosage form may include 30 mg to 300 mg SNAC, preferably 300 mg SNAC. In another embodiment of the invention, the pharmaceutical dosage form may include 50 mg to 500 mg SNAC, preferably 500 mg SNAC.

[0036] In some embodiments of any of the embodiments described herein, the weight ratio of SNAC to abalotriptide is in the range of 10:1 to 300:1 (SNAC: abalotriptide). In some embodiments, the ratio is about 15:1. In some embodiments, the composition further comprises a pH adjuster. In some of the above embodiments wherein the composition comprises a pH adjuster, the weight ratio of the pH adjuster to abalotriptide is in the range of 1:1 to 50:1 (pH adjuster: abalotriptide). In some embodiments, the ratio is in the range of 5:1 to 30:1, optionally about 20:1.

[0037] In some embodiments of any of the embodiments described herein, the weight ratio of SNAC to abalotriptide is in the range of 50:1 to 200:1 (SNAC: abalotriptide). In some embodiments, the ratio is about 50:1. In some embodiments, the composition further comprises a pH adjuster. In some of the above embodiments wherein the composition comprises a pH adjuster, the weight ratio of the pH adjuster to abalotriptide is in the range of 1:1 to 40:1 (pH adjuster: abalotriptide). In some embodiments, the ratio is in the range of 1:1 to 20:1, optionally about 10:1.

[0038] In some embodiments of any of the embodiments described herein, the weight ratio of SNAC to abalotriptide is in the range of 100:1 to 170:1 (SNAC: abalotriptide). In some embodiments, the ratio is about 135:1. In some embodiments, the composition further comprises a pH adjuster. In some of the above embodiments wherein the composition comprises a pH adjuster, the weight ratio of the pH adjuster to abalotriptide is in the range of 1:1 to 30:1 (pH adjuster: abalotriptide). In some embodiments, the ratio is in the range of 3:1 to 15:1, optionally about 5:1.

[0039] In another embodiment of the present invention, the dosage form is in the form of a tablet, and the tablet contains an enteric coating layer.

[0040] In another embodiment of the present invention, the dosage form is in the form of a hard capsule, and the hard capsule contains an enteric coating layer.

[0041] In another embodiment of the present invention, the dosage form is in the form of a hard capsule, and the hard capsule does not contain an enteric coating layer.

[0042] In some embodiments of any one of the embodiments described herein related to an enteric coating layer, the enteric coating layer is soluble in an aqueous solution at pH 5.0 or above. In some of these embodiments, soon after the drug delivery system reaches the intestine, e.g., in the duodenum, the enteric coating layer begins to dissolve.

[0043] In some embodiments of any one of the embodiments described herein related to an enteric coating layer, the enteric coating layer is soluble in an aqueous solution at pH 5.5 or above. In some of these embodiments, soon after the drug delivery system reaches the intestine, e.g., in the duodenum, the enteric coating layer begins to dissolve.

[0044] Herein, the phrase "enteric coating layer" refers to a coating that dissolves under conditions in the intestine (e.g., at a pH of at least 5.0 and / or in an aqueous environment in the presence of colonic bacteria), but does not dissolve under conditions in the stomach (e.g., an aqueous environment of pH 1.0 to 3.5). The enteric coating may optionally dissolve in the duodenum, optionally dissolve in the jejunum, optionally dissolve in the ileum and optionally dissolve in the colon, thereby exposing the core.

[0045] In some embodiments of any of the embodiments described herein, the pharmaceutical dosage form can include one or more excipients that are pharmaceutically acceptable.

[0046] In this article, the phrase "excipient" refers to an additive (excipient) other than the raw material, which is added to the pharmaceutical composition to further facilitate the administration of the active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, low-substituted cellulose, cross-linked polyvinylpyrrolidone, cross-linked partially carboxymethylated cellulose sodium salt (CCNa), sodium carboxymethyl starch, magnesium stearate, colloidal silicon dioxide.

[0047] Pharmaceutical compositions according to some embodiments of the present invention can be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, polishing, emulsifying, encapsulating, entrapping or lyophilizing processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 :Experimental example: Drug-time curve of relative bioavailability study DETAILED DESCRIPTION

[0049] The present invention will be further described below in conjunction with specific examples. Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodology, scheme and reagent described herein, and simple improvements to the present invention under the premise of the technical solution of the present invention all belong to the protection scope of the present invention. It should also be understood that the terms used herein are only for describing specific embodiments, and are not intended to limit the scope of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs.

[0050] Example 1: 20 mg abalotriptyline soft capsule preparation

[0051] Weigh purified water, NaOH, gelatin, and SNAC according to the prescription amount (see Table 1 for the prescription) and heat to dissolve. After the temperature drops to room temperature, weigh abalotriptide and purified water to mix and dissolve, and add to the above solution to mix evenly. Weigh the prescribed amount of purified water, propylene glycol, and gelatin and add them to the gelling tank, stir and heat to make a gelatin solution. Press the mixture and gelatin solution into soft capsules under specific process conditions, and dry them for standby use.

[0052] Table 1

[0053] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 NaOH pH Adjusters 10 3 SNAC Absorption enhancers 100 4 gelatin excipient 285 5 Propylene glycol excipient 16 6 Purified water Solvents 250

[0054] Example 2: 20 mg abalotriptyline enteric-coated tablets

[0055] Weigh NaOH, SNAC, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (prescription see Table 2). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then tablet it. Prepare an enteric coating solution of methacrylic acid-ethyl acrylate copolymer aqueous dispersion (Eudragit L30D-55), and enteric-coat the tablets.

[0056] Table 2

[0057]

[0058] Example 3: 20 mg abalotriptyline enteric-coated capsule preparation

[0059] Weigh NaOH, SNAC, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (see Table 3 for the prescription). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0060] Table 3

[0061] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 NaOH pH Adjusters 30 3 SNAC Absorption enhancers 144 4 Microcrystalline Cellulose excipient 110 5 Crospovidone excipient 20 6 Magnesium Stearate excipient 5 7 Enteric coated capsule shell Capsule shell 100

[0062] Example 4: 20 mg abalotriptyline enteric-coated capsule preparation

[0063] Weigh NaOH, SNAC, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (prescription see Table 4). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0064] Table 4

[0065] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 NaOH pH Adjusters 20 3 SNAC Absorption enhancers 200 4 Crospovidone excipient 20 5 Magnesium Stearate excipient 3 6 Enteric coated capsule shell Capsule shell 100

[0066] Example 5: 20 mg abalotriptyline enteric-coated capsule preparation

[0067] Weigh NaOH, SNAD, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (see Table 5 for the prescription). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0068] Table 5

[0069] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 NaOH pH Adjusters 20 3 SNAD Absorption enhancers 250 4 Crospovidone excipient 20 5 Magnesium Stearate excipient 3 6 Enteric coated capsule shell Capsule shell 100

[0070] Example 6: 20 mg abalotriptyline enteric-coated capsule preparation

[0071] Weigh NaOH, 5-CNAC, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (see Table 6 for the prescription). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0072] Table 6

[0073]

[0074]

[0075] Example 7: 20 mg abalotriptyline enteric-coated capsule preparation

[0076] Weigh NaOH, 4-MOAC, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (see Table 7 for the prescription). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0077] Table 7

[0078] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 NaOH pH Adjusters 20 3 4-MOAC Absorption enhancers 250 4 Crospovidone excipient 20 5 Magnesium Stearate excipient 3 6 Enteric coated capsule shell Capsule shell 100

[0079] Example 8: 20 mg abalotriptyline enteric-coated tablets

[0080] KH2PO4, SNAC, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and magnesium stearate were weighed according to the prescription amount (prescription see Table 8). The above materials were sieved and mixed evenly, and the mixed powder was dry granulated. After the granulation was completed, dry granulation was performed to obtain dry granulated granules. Abalotriptide in the prescription amount was weighed, sieved, mixed with the granules and a certain amount of magnesium stearate, and then tableted. Methacrylic acid-ethyl acrylate copolymer aqueous dispersion (Eudragit L30D-55) enteric coating solution was prepared, and the tablets were enteric coated.

[0081] Table 8

[0082]

[0083] Example 9: 20 mg abalotriptyline soft capsule preparation

[0084] Weigh purified water, KH2PO4, gelatin, and SNAC according to the prescription amount (see Table 9 for the prescription) and heat to dissolve. After the temperature drops to room temperature, weigh abalotriptide and purified water to mix and dissolve, and add to the above solution to mix evenly. Weigh the prescription amount of purified water, glycerol, propylene glycol, and gelatin and add them to the gelatin tank, stir and heat to make a gelatin solution. Press the mixture and gelatin solution into soft capsules under specific process conditions, and dry them for standby use.

[0085] Table 9

[0086] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 <![CDATA[KH2PO4]]> pH Adjusters 650 3 SNAC Absorption enhancers 150 4 gelatin excipient 355 5 glycerin excipient 12 6 Propylene glycol excipient 22 7 Purified water Solvents 300

[0087] Example 10: 20 mg abalotriptyline enteric-coated capsule preparation

[0088] Weigh Na2CO3, SNAC, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (see Table 10 for the prescription). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then fill it into the enteric-coated capsule shell.

[0089] Table 10

[0090] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 <![CDATA[Na2CO3]]> pH Adjusters 30 3 SNAC Absorption enhancers 300 4 Crospovidone excipient 40 5 Magnesium Stearate excipient 5 6 Enteric coated capsule shell Capsule shell 100

[0091] Example 11: 20 mg abalotriptyline enteric-coated tablets

[0092] Weigh Na2CO3, SNAC, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and magnesium stearate according to the prescription amount (prescription see Table 11). Sieve the above materials and mix them evenly, and dry granulate the mixed powder. After granulation, dry granulate is performed to obtain dry granulated granules. Weigh the prescription amount of abalotriptide, sieve it, mix it with the granules and a certain amount of magnesium stearate, and then tablet it. Prepare an enteric coating solution of methacrylic acid-ethyl acrylate copolymer aqueous dispersion (Eudragit L30D-55), and enteric-coat the tablets.

[0093] Table 11

[0094]

[0095]

[0096] Example 12: 20 mg abalotriptyline enteric-coated capsule preparation

[0097] Na2CO3, SNAC, crospovidone, magnesium stearate, and abalotriptyline were weighed according to the prescription amount (see Table 12 for the prescription), sieved and mixed, and then filled into enteric-coated capsule shells.

[0098] Table 12

[0099] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 <![CDATA[Na2CO3]]> pH Adjusters 100 3 SNAC Absorption enhancers 200 4 Crospovidone excipient 21 5 Magnesium Stearate excipient 7 6 Enteric coated capsule shell Capsule shell 100

[0100] Example 13: 20 mg abalotriptyline enteric-coated capsule preparation

[0101] SNAC, crospovidone, magnesium stearate, and abalotriptyline were weighed according to the prescription amount (see Table 13 for the prescription), sieved and mixed, and then filled into enteric-coated capsule shells.

[0102] Table 13

[0103] serial number Material Function Composition (mg / tablet) 1 Abalotriptyline Active substances 20 2 SNAC Absorption enhancers 200 3 Crospovidone excipient 21 4 Magnesium Stearate excipient 7 5 Enteric coated capsule shell Capsule shell 100

[0104] Experimental Example: Relative Bioavailability Study

[0105] The relative bioavailability (F%) of a single oral dose of 20 mg abalotriptide relative to a single injection dose of 0.04 mg / kg was determined, and the following pharmacokinetic parameters of abalotriptide were determined: max , T max , AUC last , AUC infThis study was a randomized, open-label, single-dose, 4-crossover study in 4 female cynomolgus monkeys (see Table 14). Subjects received different abalotriptyline formulations with a 4-day washout period between doses.

[0106] Table 14

[0107]

[0108] TF1 (Example 4) and TF2 (Example 12) contain pH regulators, while TF3 (Example 13) does not contain pH regulators; RF is an injection. TF1, TF2, and TF3 are administered orally, and 20 mL of water is given immediately after each administration. R is administered subcutaneously at the back of the neck. All monkeys fasted for at least 12 hours before administration, and were prohibited from drinking water for at least 2 hours before administration, and were prohibited from drinking water within 4 hours after administration. The pharmacokinetic parameters, relative bioavailability (F%), and drug-time curves are as follows (see Tables 15 and Figure 1 ):

[0109] Table 15

[0110] Pharmacokinetic parameters RF TF1 TF2 TF3 <![CDATA[C max (ng / mL)]]> 2.3 22.7 23.1 0.2 <![CDATA[AUC last (mg / mL)]]> 2.9 18.0 19.9 0.2 <![CDATA[T max (h)]]> 0.3 0.7 0.7 0.7 F％ / 7.3 9.0 0.1

[0111] As shown in Table 15 and Figure 1 As shown in the figure, after adding the pH adjuster, the relative bioavailability of the oral preparation is significantly improved, and the relative bioavailability can be increased by up to 90 times compared with the formulation without the pH adjuster.

[0112] The above results indicate that the addition of a pH adjuster to the formulation as described herein together with an absorption enhancer can significantly increase the relative bioavailability of a water-soluble polypeptide.

Claims

1. An oral water-soluble polypeptide pharmaceutical composition, wherein the components thereof comprise: at least one effective dose of water-soluble polypeptide, at least one absorption enhancer, at least one pH regulator, and at least one other excipient.

2. The pharmaceutical composition according to claim 1, wherein the water-soluble polypeptide is abalotriptyline or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the absorption enhancer is selected from one or more of 8-N-(2-hydroxybenzoyl)aminocaprylate (NAC), 10-N-(2-hydroxybenzoyl)aminodecanoic acid (NAD), 8-N-(5-chlorosalicyloyl)aminocaprylic acid (5-CNAC), 8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid (4-MOAC), 4-N-(2-hydroxy-4-chlorobenzoyl)aminobutyric acid (4-CNAB), caprylic acid, capric acid and their salts; preferably NAC and its salts such as SNAC, i.e. sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

4. The pharmaceutical composition according to claim 1, wherein the pH adjuster is selected from one or more of NaOH, KOH, Na2CO3, NaHCO3, K2CO3, KHCO3, Na2HPO4, NaH2PO4, K2HPO4, and KH2PO4; preferably Na2CO3.

5. The pharmaceutical composition according to claim 1, which is in the form of tablets or capsules; preferably enteric-coated tablets or enteric-coated capsules.

6. The pharmaceutical composition according to claim 1, wherein the other excipients include fillers such as sugars selected from one or more of lactose, sucrose, mannitol or sorbitol; and / or cellulose preparations selected from one or more of microcrystalline cellulose, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose; and / or polymers available for oral medications, such as polyvinyl pyrrolidone (PVP); and / or disintegrants selected from one or more of cross-linked polyvinyl pyrrolidone, sodium starch glycolate, agar or alginic acid or its salts; and / or lubricants selected from talc or magnesium stearate; and / or glidants, such as colloidal silicon dioxide.

7. The pharmaceutical composition according to claim 1, wherein the effective dose of the water-soluble polypeptide is in the range of 200 μg to 20 mg.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, comprising uniformly mixing the water-soluble polypeptide, absorption enhancer and pH regulator with other excipients and then compressing the mixture into tablets or filling the mixture into capsules.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is for oral administration once a day.

10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is formulated such that after oral administration of the composition, the absorption of the abalotriptide or the fragment thereof is characterized by C max In the range of 1 ng / mL to 100 ng / mL; preferably in the range of 5 ng / mL to 50 ng / mL.

11. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is formulated such that after oral administration of the composition, the absorption of the abalotriptide or the fragment thereof is characterized by AUC vs. C max The ratio is 3 hours or less; preferably 2 hours or less.

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