CN114984191B - Oral delivery composition of polypeptide drugs - Google Patents
Oral delivery composition of polypeptide drugs Download PDFInfo
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- CN114984191B CN114984191B CN202210894656.7A CN202210894656A CN114984191B CN 114984191 B CN114984191 B CN 114984191B CN 202210894656 A CN202210894656 A CN 202210894656A CN 114984191 B CN114984191 B CN 114984191B
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- 229920001184 polypeptide Polymers 0.000 title abstract description 12
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Bioinformatics & Cheminformatics (AREA)
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- Gastroenterology & Hepatology (AREA)
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Abstract
The invention relates to a pharmaceutical composition suitable for oral delivery of polypeptide drugs, which comprises a first type of particles and a second type of particles; the first type of particles comprises 280-300 mg of SNAC and 5-20% of a GLP-1 receptor agonist and the second type of particles comprises 5-20 mg of SNAC and 80-95% of a GLP-1 receptor agonist. The oral delivery pharmaceutical composition can more effectively deliver the GLP-1 derivative or the GLP-1 related multi-target agonist orally, has excellent oral bioavailability and wide application prospect.
Description
Technical Field
The invention relates to the technical field of polypeptide and oral delivery thereof, in particular to an oral delivery composition of a polypeptide drug, and particularly relates to an oral delivery pharmaceutical composition suitable for a GLP-1 receptor agonist and a GLP-1 receptor-related multi-target co-agonist.
Background
In modern society, diabetes and its complications gradually become a serious chronic noninfectious disease after cardiovascular and cerebrovascular diseases and cancer. Diabetes is largely classified into type i diabetes, type ii diabetes and other specific types of diabetes. The insulin secreted by the patient can not effectively play a role as the pathogenic cause of the type II diabetes, and the disease proportion of the type II diabetes is the highest and reaches more than 90 percent.
At present, clinically used drugs for treating type II diabetes mainly include biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors and long-acting glucagon-like peptide-1 derivatives (GLP-1 derivatives). Among them, GLP-1 derivatives have a similar hypoglycemic effect to insulin, almost no hypoglycemic risk, and a weight-reducing effect and a cardiovascular protection function, and thus are gradually becoming a major therapeutic agent and a research focus for type II diabetes.
Somaglutide is a long-acting GLP-1 derivative developed by Novonide, which requires only once weekly subcutaneous administration and is currently approved for sale in many countries. Structurally, the somaglutide is obtained by connecting the 26 th Lys position to AEEA, glutamic acid and octadecane fatty diacid side chain on GLP-1 (7-37) chain, and replacing the 8 th amino acid with unnatural amino isobutyric acid (Aib) to replace the original Ala and replacing the 34 th Lys position with Arg. Compared with liraglutide, the fat chain of the soraglutide is longer, the hydrophobicity is increased, but the hydrophilicity is greatly enhanced after the soraglutide is modified by short-chain AEEA. After AEEA modification, the modified protein can be tightly combined with albumin to cover DPP-4 enzyme hydrolysis sites, and can also reduce renal excretion, prolong the biological half-life and achieve the effect of long circulation. The soxhlet peptide is proved to be capable of effectively controlling blood sugar by combining different oral hypoglycemic drugs in a plurality of clinical trial researches, and can reduce the weight of a patient, reduce systolic pressure and improve the function of islet beta cells.
At present, two formulations of the somaglutide medicine are respectively an injection and an oral preparation, wherein the injection is injected subcutaneously once a week, which is painful for diabetic patients needing long-term treatment and even lifelong treatment, not only has poor compliance, but also is easy to cause infection, and brings physical and psychological burdens to the patients. Compared with injection, the oral preparation has great advantages in curative effect, safety, applicable population and drug interaction, and can greatly increase the compliance of patients. However, from the structural point of view, the somaglutide is obtained by replacing Ala at position 8 in GLP-1 (7-37) chain with Aib, lys at position 34 with Arg, and Lys at position 26 with octadecanoic acid fatty chain, that is, a long fatty chain exists in the structure of somaglutide, hydrophobicity is increased, and the dissolution behavior of oral administration is difficult to ensure.
CN201611150925.X discloses a sustained-release oral preparation containing somatolide and its preparation method, wherein the active ingredient is GLP-1 analog somatolide, and sulfonylurea, biguanide or thiazolidinedione hypoglycemic agent having synergistic effect with somatolide, and is coated in sustained-release carrier material to prepare sustained-release microsphere, and then mixed with pharmaceutically acceptable adjuvants to make into tablet with certain shape for oral administration, thereby having long-acting sustained-release effect. The defects of the method are that the Somalutide is easy to be prematurely decomposed in the subsequent taking process, the stability of the Somalutide is difficult to ensure, and the Somalutide is easy to waste.
Since the somaglutide has low oral bioavailability and can only be detected in blood in a very small amount or even can not be detected after oral administration, an optimized pharmaceutical composition for oral administration is needed, so that the somaglutide has better oral bioavailability.
Disclosure of Invention
In order to solve the technical problems, the invention provides a polypeptide drug oral delivery composition. The oral delivery composition provided by the invention has excellent oral bioavailability and wide application prospect.
In the present invention, the term "GLP-1 receptor agonist" may be defined as a compound that binds to a receptor and elicits a response typical of natural ligands. A full agonist can be defined as an agonist that elicits a response of the same magnitude as the natural ligand (see, e.g., "Principles of Biochemistry", AL Lehninger, DL Nelson, MMCox, second edition, worth Publishers, 1993, page 763). Thus, for example, a "GLP-1 receptor agonist" may be defined as a compound capable of binding to and activating the GLP-1 receptor.
In the present invention, the term SNAC meansN- [8- (2-hydroxybenzoyl) amino group]Sodium caprylate (Sodium caprylate)N-[8-(2-hydroxybenzoyl)amino]caprylate, a low toxicity oral penetration enhancer.
In the present invention, the term "somaglutide" refers toN-ε 26 -[2-(2-{2-[2-(2-{2-[(S) -4-carboxy-4- (17-carboxyheptadecanoylamino) butanoylamino]Ethoxy } ethoxy) acetylamino group]Ethoxy } ethoxy) acetyl][Aib 8 Arg 34 ]GLP-1(7-37)。
In the present invention, the term "derivative" with respect to a peptide (e.g., GLP-1 or insulin) means a chemically modified (e.g., covalently modified, etc.) peptide or an analog thereof. Typical modifications are amides, sugars, alkyl, acyl, esters, and the like. Examples of GLP-1 (7-37) derivatives areN-ε 26 -((4S) -4- (hexadecylamino) -carboxy-butyryl) [ Arg 34 Lys 26 ]GLP-1-(7-37)。
In the present invention, the term "adjuvant" broadly refers to any component other than the active therapeutic ingredient (also referred to in the art as drug substance or active pharmaceutical ingredient). Adjuvants may be inert substances in the sense that they do not have substantially any therapeutic and/or prophylactic effect per se. Adjuvants may be used for a variety of different purposes, for example, as enhancers, absorption enhancers, vehicles, fillers (also known as diluents), binders, lubricants, glidants, disintegrants, crystallization retarders, acidifying agents, alkalizing agents, preservatives, antioxidants, buffers, chelating agents, complexing agents, surfactants, emulsifiers and/or solubilizers, sweeteners, wetting agents, stabilizers, colorants, flavors, and/or to improve the administration and/or absorption of an active substance.
In the context of the present invention, the term "lubricant" is intended to mean, for example, stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, waxes, glycerides, light mineral oil, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates or sodium benzoate.
In the present invention, the term "filler" is used, such as lactose (e.g. spray-dried lactose, alpha-lactose, beta-lactose, various grades), microcrystalline cellulose (various grades), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (e.g. alkaline calcium phosphate, calcium hydrogen phosphate, hydrated dicalcium phosphate), calcium sulfate, calcium carbonate or sodium alginate.
In the present invention, the term "binder" is used, such as lactose (e.g. spray-dried lactose, alpha-lactose, beta-lactose, various grades), microcrystalline cellulose (various grades), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hypromellose (HPMC, e.g. Methocel E, F and K, shin-Etsu, metolose SH of Ltd, e.g. Methocel E of 4,000 cps grade and Methocel 60 SH of 4,000 cps grade and Methocel F of Methocel 65 SH,4,000, 15,000 and 100,000 cps grade and Methocel K of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of methose 90 SH), methylcellulose polymers (e.g., methocel A4C, methocel a15C, methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch (including potato, corn and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG or povidone.
In the present invention, the term "bioavailability" refers to the proportion of an administered dose of a drug substance (e.g., a GLP-1 peptide or derivative thereof) that reaches the systemic circulation to remain unchanged. By definition, the bioavailability of a drug substance is 100% when administered intravenously. However, when the drug substance is administered by other routes (e.g., orally), its bioavailability may decrease (due to degradation and/or incomplete absorption and first pass metabolism). Knowledge about bioavailability is very important when calculating the dose for a non-intravenous route of administration of a drug substance. Plasma concentrations are plotted against time after oral and intravenous administration. The absolute bioavailability is (AUC-oral divided by dose) divided by (AUC-intravenous divided by dose).
In a first aspect, the present invention provides a solid composition for oral administration of a GLP-1 receptor agonist, the solid composition comprises a first type of particles and a second type of particles, and further comprises a pharmaceutically acceptable excipient added to the above particles, the excipient is preferably magnesium stearate, wherein the particles may be:
(1) The first type of particles comprises 280-300 mg of SNAC and 5-20% of a GLP-1 receptor agonist and the second type of particles comprises 80-95% of a GLP-1 receptor agonist and 5-20 mg of SNAC; the total amount of the GLP-1 receptor agonist is 2-25 mg, preferably 2-20 mg, 3-15 mg, 2 mg, 3 mg, 5 mg, 7 mg, 9 mg, 12 mg, 14 mg, 15 mg and 20 mg.
Preferably, the GLP-1 receptor agonist in said first type of particle is 5-20%,5-15% or 10-15% of the total amount of polypeptide; the GLP-1 receptor agonist is present in the second type of particle in an amount of 80-95%,85-95% or 85-90% of the total amount. Or, GLP-1 receptor agonist comprises 5-15% of the total amount of polypeptide in said first type of particle; (ii) GLP-1 receptor agonist in the second type of particles comprises 85-95% of the total; or GLP-1 receptor agonist in the first type of particle comprises 10-15% of the total amount of polypeptide; the GLP-1 receptor agonist in the second type of particle is 85-90% of the total amount.
Further, the SNAC content in the first type of particle is 290 mg or 300 mg; the SNAC content in the second type of particle is 10 mg or 20 mg. Preferably, the SNAC content of the first type of particle is 290 mg; the SNAC content in the second type of particles was 10 mg. Alternatively, the SNAC content in the first type of particle is 300 mg; the SNAC content in the second type of particle is 20 mg.
Further, the amount of SNAC in the first type of particle is 290 mg and the amount of glp-1 agonist is 0.5 mg; the amount of SNAC in the second type of particle is 10 mg and the amount of glp-1 agonist is 2.5 mg. Preferably, the amount of SNAC in said first type of particle is 290 mg and the amount of glp-1 agonist is 1 mg; the amount of SNAC in the second type of particle is 10 mg and the amount of glp-1 agonist is 6 mg. Alternatively, the amount of SNAC in the first type of particle is 290 mg and the amount of glp-1 agonist is 2 mg; the amount of SNAC in said second type of particles is 10 mg and the amount of GLP-1 agonist is 12 mg.
Preferably, the first type of particle further comprises a lubricant, such as magnesium stearate; and/or fillers, such as microcrystalline cellulose. The second type of particles further comprises fillers, such as microcrystalline cellulose; and/or a binder, such as povidone. Further, the composition comprises magnesium stearate in addition to the first type of granules and the second type of granules described above. Preferably, in the compositions described in this section, the first type of particle further comprises magnesium stearate and microcrystalline cellulose; the second type of particle further comprises microcrystalline cellulose and povidone. Preferably, the microcrystalline cellulose is microcrystalline cellulose PH101 and the povidone is povidone K90.
Preferably, the content of microcrystalline cellulose PH101 in the first type granules is 20-60mg, and the content of magnesium stearate is 5-10 mg; the content of the microcrystalline cellulose PH101 in the second type of particles is 5-30 mg, and the content of the povidone K90 in the second type of particles is 5-10 mg; the amount of magnesium stearate outside the particles is 1-5 mg. Preferably, the content of microcrystalline cellulose PH101 in the first type of granules is 57 mg, and the content of magnesium stearate is 7.7 mg; the content of the microcrystalline cellulose PH101 in the second type of particles is 23 mg, and the content of the povidone K90 in the second type of particles is 8 mg; the amount of extra-granular magnesium stearate was 2 mg. Alternatively, preferably, the content of microcrystalline cellulose PH101 in the first type of granulate is 37 mg and the content of magnesium stearate is 7.7 mg; the content of the microcrystalline cellulose PH101 in the second type of particles is 13 mg, and the content of the povidone K90 in the second type of particles is 8 mg; the amount of extra-granular magnesium stearate was 2 mg.
In a second aspect, the present invention provides a process for preparing the solid composition for oral administration of the first aspect, the process comprising:
(1) Mixing and granulating formula amounts of a GLP-1 receptor agonist and SNAC with optional lubricants and fillers to obtain a first type of granulate;
(2) Mixing and granulating the formulated amounts of GLP-1 receptor agonist and SNAC with optional fillers and binders to obtain a second type of granule;
(3) Mixing the granules obtained in the steps (1) and (2) and an optional lubricant to obtain the oral administration solid composition.
Preferably, the step (1) is: mixing magnesium stearate and SNAC using an equal increment method to obtain a first mixture; mixing the Somalide and the microcrystalline cellulose, sieving, mixing with the first mixture with the same volume of the microcrystalline cellulose, mixing with the rest first mixture, and granulating to obtain the first type of granules.
Preferably, the step (2) is: and sieving the Somalufide and the Povidone respectively, and then mixing, tabletting, crushing and sieving the Somalufide, the Povidone, the SNAC and the microcrystalline cellulose to obtain the second type of granules.
Preferably, the step (3) is: and (3) mixing the granules obtained in the steps (1) and (2), mixing with magnesium stearate, and tabletting to obtain the oral administration solid composition.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
the oral delivery pharmaceutical composition can more effectively deliver the GLP-1 derivative or the GLP-1 related multi-target agonist orally, has excellent oral bioavailability and wide application prospect.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the invention may be practiced otherwise than as described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Example 1
This example provides a method for preparing oral polypeptide tablets
(1) The formulation is shown in table 1:
TABLE 1
(2) Preparation of oral tablets
2.1 Preparation of formula 1:
preparation of granule 1: weighing materials according to a prescription, mixing magnesium stearate and the SNAC with the same volume in a weighing boat for 60 s, then mixing the SNAC with the same volume in the weighing boat for 60 s, and mixing the mixture with the rest SNAC for 6 min; taking out the mixture with the same volume as the microcrystalline cellulose, mixing the mixture with the microcrystalline cellulose in a weighing boat for 60 s, mixing the mixture with the rest of the mixture of the SNAC and the magnesium stearate for 3 min, and then controlling a dry granulation machine to carry out granulation, wherein the parameters of the dry granulation machine are shown in Table 2:
TABLE 2
Preparation of granule 2: sieving the Somalutide by a 80-mesh sieve, and weighing; sieving polyvidone with 50 mesh sieve, and weighing; mixing the Somalutide, microcrystalline cellulose and polyvidone in a weighing boat for 3 min, sieving with 50 mesh sieve for 2 times, mixing for 4 min, pressing into tablet of granule 2 with a tablet press, crushing with mortar, and sieving with 24 mesh sieve.
And (3) total mixing and tabletting: weighing granule 1, granule 2 and magnesium stearate according to the conversion of the prescription; mixing granule 1 and granule 2 for 5 min, and mixing the mixture with magnesium stearate for 2 min; the mixture is prepared into tablets.
2.2 Preparation of formula 2:
preparation of granule 1: sieving the Somalutide with a 80-mesh sieve and weighing; mixing magnesium stearate and equal volume of SNAC in a weighing boat for 60 s, then mixing equal volume of SNAC in the weighing boat for 60 s, and mixing the mixture with the rest SNAC for 6 min. Mixing the somaglutide and the microcrystalline cellulose in a weighing boat, sieving with a 50-mesh sieve, taking out the mixture of SNAC and magnesium stearate with the same volume as the microcrystalline cellulose, mixing the mixture of SNAC and magnesium stearate with the microcrystalline cellulose and the somaglutide in the weighing boat for 60 s, adding the rest of the mixture of SNAC and magnesium stearate, and mixing for 3 min. The above mixture was granulated in a granulator with the dry granulator parameters controlled as shown in table 3:
TABLE 3
Preparation of granule 2: sieving the Somalutide by a 80-mesh sieve, and weighing; sieving polyvidone with 50 mesh sieve, and weighing; mixing Somalutide, microcrystalline cellulose, polyvidone and SNAC in a weighing boat for 3 min, sieving with 50 mesh sieve for 2 times, and mixing for 4 min; tablets of granule 2 were compressed using a tablet press, crushed using a mortar and sieved through a 24 mesh sieve.
Total mixing and tabletting: weighing granule 1, granule 2 and magnesium stearate according to the conversion of the prescription; mixing granule 1 and granule 2 for 5 min; mixing the mixture with magnesium stearate for 2 min; the mixture is prepared into tablets.
Example 2: disintegration and dissolution test
(1) 3 of the tablets prepared in example 1 were randomly subjected to disintegration test, and the results are shown in Table 4:
TABLE 4
(2) Dissolution testing was performed according to the method of table 5:
TABLE 5
The results of the somalutide dissolution are shown in table 6, and the snac dissolution are shown in table 7:
TABLE 6
TABLE 7
As can be seen from tables 5-7, the polypeptide oral tablet of formula 2 provided by the present invention has disintegration and dissolution results substantially identical to those of formula 1.
Example 3: bioavailability assay
(1) Experimental materials:
a. animal experiments:
selecting healthy male beagle dogs with 7-9 months old, and weighing 9-10 kg;
b. dosing regimens
The administration was carried out according to the specific dosing schedule shown in table 8:
TABLE 8
(2) Results of the experiment
The plasma concentrations 2 h after each administration are shown in table 9:
TABLE 9
Bioavailability (by Cmax) 2 h after each administration Is administered orally : Cmax Vein Calculation) are shown in table 10:
watch 10
From tables 9-10, in animal experiments, the bioavailability of the polypeptide oral tablet of formula 2 provided by the invention is gradually increased within 7 days, which is significantly higher than that of formula 1, and at 7 days, the bioavailability is more than 2 times that of formula 1.
It is noted that, in this document, relational terms such as "first" and "second," and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrases "comprising one of 8230; \8230;" 8230; "does not exclude the presence of additional like elements in a process, method, article, or apparatus that comprises the element.
The above description is merely illustrative of particular embodiments of the invention that enable those skilled in the art to understand or practice the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A solid composition for oral administration, wherein the solid composition comprises a first type of particle and a second type of particle;
wherein the first type of particles comprises between 280 and 300 mg of the GLP-1 receptor agonist in 5 to 20% of the total amount of SNAC and GLP-1 receptor agonist and the second type of particles comprises between 5 and 20 mg of the GLP-1 receptor agonist in 80 to 95% of the total amount of SNAC and GLP-1 receptor agonist, wherein the total amount of GLP-1 receptor agonist is between 5 and 15 mg;
the GLP-1 receptor agonist is somaglutide.
2. The orally administrable solid composition of claim 1, wherein the first type of particles comprises 290 mg of GLP-1 receptor agonist of 5 to 20% of the total amount of SNAC and GLP-1 receptor agonist and the second type of particles comprises 10 mg of GLP-1 receptor agonist of 80 to 95% of the total amount of SNAC and GLP-1 receptor agonist.
3. The orally administrable solid composition of claim 2, wherein the GLP-1 receptor agonist is present in a total amount of 5 mg, 7 mg, 14 mg, or 15 mg.
4. The orally administrable solid composition of claim 3, wherein the first type of particle further comprises a lubricant and a filler, and the second type of particle further comprises a filler and a binder.
5. The orally administered solid composition of claim 4, wherein the lubricant in the first type of particle is magnesium stearate and the filler is microcrystalline cellulose; the filler in the second type of particles is microcrystalline cellulose and the binder is povidone.
6. The solid composition for oral administration according to claim 5, wherein the microcrystalline cellulose is microcrystalline cellulose PH101, and the povidone is povidone K90; wherein the content of microcrystalline cellulose PH101 in the first type of particles is 20-60mg, and the content of magnesium stearate is 5-10 mg; the content of the microcrystalline cellulose PH101 in the second type of particles is 5-30 mg, and the content of the povidone K90 in the second type of particles is 5-10 mg; the amount of magnesium stearate outside the particles is 1-5 mg.
7. The orally administrable solid composition of claim 6, wherein the first type of particle comprises 57 mg microcrystalline cellulose PH101 and 7.7 mg magnesium stearate; the content of the microcrystalline cellulose PH101 in the second type of particles is 23 mg, and the content of the povidone K90 in the second type of particles is 8 mg.
8. The orally administrable solid composition according to any one of claims 4 to 7, wherein the constituent components of the solid composition further comprise a lubricant added in addition to the first type of granules and the second type of granules, the lubricant being selected from magnesium stearate.
9. The orally administrable solid composition of claim 8, wherein the extra-granular magnesium stearate is in an amount of 2 mg.
10. The method of preparing an orally administrable solid composition of any one of claims 1 to 9, wherein the preparation method comprises:
(1) Mixing and granulating formula amounts of a GLP-1 receptor agonist and SNAC with optional lubricants and fillers to obtain a first type of granulate;
(2) Mixing and granulating formula amounts of GLP-1 receptor agonist and SNAC with optional fillers and binders to obtain a second type of granulate;
(3) Mixing the granules obtained in the steps (1) and (2) and an optional lubricant to obtain the oral administration solid composition;
wherein the GLP-1 receptor agonist is somaglutide.
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| EP2863895B1 (en) * | 2012-06-20 | 2021-04-14 | Novo Nordisk A/S | Tablet formulation comprising a peptide and a delivery agent |
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| CN114984191B (en) * | 2022-07-04 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Oral delivery composition of polypeptide drugs |
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Address after: 100025 21 floor, 2 building, 2000 business center, Eight Mile Village, Chaoyang District, Beijing. Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd. Patentee after: Jilin Huisheng Biopharmaceutical Co.,Ltd. Address before: 100025 21 floor, 2 building, 2000 business center, Eight Mile Village, Chaoyang District, Beijing. Patentee before: Beijing huizhiheng Biotechnology Co.,Ltd. Patentee before: Jilin Huisheng biopharmaceutical Co.,Ltd. |