CN112494485A - Saxagliptin and metformin hydrochloride sustained-release tablet - Google Patents
Saxagliptin and metformin hydrochloride sustained-release tablet Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—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
Abstract
The invention develops a saxagliptin and metformin hydrochloride sustained-release tablet, which sequentially comprises a metformin hydrochloride sustained-release tablet core, an isolation layer, a saxagliptin drug-containing layer and a protective layer from inside to outside; wherein the metformin hydrochloride sustained-release tablet core comprises metformin hydrochloride, cellulose acetate, erodible framework material and adhesive; the drug-containing layer of saxagliptin comprises saxagliptin, adipic acid and a coating material. The sustained release tablet can solve the problem that the content uniformity is not easy to control due to the great difference of the dosage of the saxagliptin and the metformin hydrochloride, and can effectively overcome the instability of the saxagliptin and reduce the degradation of the saxagliptin; and the effect that the release curves of the metformin hydrochloride and the saxagliptin are consistent with those of the products on the market originally researched can be realized.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a saxagliptin and metformin hydrochloride sustained-release tablet and a preparation method thereof.
Background
Saxagliptin is a hypoglycemic drug jointly developed by Baishimeibao and Aslicon, is a high-efficiency dipeptidyl peptidase-4 (DPP-4) inhibitor, and can increase the levels of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by selectively inhibiting DPP-4, so that the blood sugar is regulated. Saxagliptin can effectively reduce glycated hemoglobin and postprandial blood glucose, does not affect body weight, has no obvious risk of hypoglycemia, and can be used as monotherapy or combined therapy with metformin, sulfonylurea and thiazolidinedione drugs. Saxagliptin is chemically (1S,3S,5S) -2- [ (2S) -2-amino-2- (3-hydroxy-l-adamantyl) -l-carbonylethyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile; the structural formula is as follows:
metformin hydrochloride has the effects of improving the blood sugar tolerance of type 2 diabetes patients and reducing the basal and postprandial blood sugar. The medicine can promote glucose uptake by adipose tissue, reduce glucose absorption in intestine and gluconeogenesis, and inhibit glucagon release, so as to improve insulin sensitivity, and metformin hydrochloride will not cause hypoglycemia for type 2 diabetes patients or normal blood sugar patients.
Saxagliptin is an unstable compound, is easy to generate intramolecular cyclization reaction and is degraded into cyclic amidine which has no therapeutic activity and is a main impurity of the saxagliptin. The cyclization reaction of the saxagliptin can occur in both solid and liquid states, is sensitive to external conditions, and can accelerate the degradation speed of the saxagliptin by light, humidity, heat and production processes. At the same time, the mixing of saxagliptin with most of the usual excipients also accelerates the degradation rate.
CN103976997B discloses a compound sustained-release capsule for reducing blood sugar and a preparation method thereof, wherein the content of the compound sustained-release capsule preparation consists of metformin hydrochloride combined sustained-release pellets and saxagliptin quick-release pellets, and the metformin hydrochloride combined sustained-release pellets are prepared by mixing the metformin hydrochloride quick-release pellets and the metformin hydrochloride sustained-release pellets according to a certain proportion; the formulation comprises 250mg of metformin hydrochloride and 0.625mg to 2.5mg of saxagliptin. Because the dosage difference of the saxagliptin and the metformin hydrochloride in the preparation is very large, the problem of poor content uniformity caused by incomplete uniform mixing is easily caused after the saxagliptin and the metformin hydrochloride are respectively prepared into a slow-release pellet and a quick-release pellet and then mixed.
In summary, how to solve the problems of poor content uniformity and unstable saxagliptin caused by great variation in the dosage of medicinal components and the realization of the consistency of the release curves of metformin hydrochloride and saxagliptin with the original products in the research and marketing are the problems to be solved currently.
Disclosure of Invention
The invention develops a saxagliptin and metformin hydrochloride sustained-release tablet, which can solve the problem that the content uniformity is difficult to control due to great difference of the dosage of the saxagliptin and the metformin hydrochloride, and obtains the sustained-release tablet with uniform content; meanwhile, the instability of the saxagliptin can be effectively overcome, and the degradation of the saxagliptin is reduced; and the effect that the release curves of the metformin hydrochloride and the saxagliptin are consistent with those of the products on the market originally researched can be realized. The invention also provides a method for preparing the saxagliptin and metformin hydrochloride sustained-release tablets, which is simple and easy to operate, can meet the production requirements by conventional equipment, has controllable quality, and is suitable for industrial large-scale production.
In the saxagliptin and metformin hydrochloride sustained-release tablet, the amount of the saxagliptin is 2.5-5 parts, the amount of the metformin hydrochloride is 500-1000 parts, and the two amounts are very different, so that the two active ingredients of the saxagliptin and the metformin hydrochloride are difficult to be uniformly mixed in the preparation of a compound preparation, and the content uniformity of the preparation is influenced. In addition, saxagliptin is easy to undergo intramolecular cyclization reaction and is degraded into cyclic amidine, and is sensitive to external conditions, and the degradation speed of saxagliptin can be accelerated by light, humidity, heat and production processes. When the combination of saxagliptin and metformin hydrochloride is used for treating diabetes, the saxagliptin needs to be quickly released to quickly exert the drug effect, and the metformin hydrochloride needs to be slowly released to stably exert the hypoglycemic effect, so that the synergistic effect of the saxagliptin and the metformin hydrochloride is exerted.
In view of the problems, the invention provides a saxagliptin and metformin hydrochloride sustained-release tablet, which sequentially comprises a metformin hydrochloride sustained-release tablet core, an isolation layer, a saxagliptin drug-containing layer and a protective layer from inside to outside; wherein the metformin hydrochloride sustained-release tablet core comprises metformin hydrochloride, cellulose acetate, erodible framework material and adhesive; the drug-containing layer of saxagliptin comprises saxagliptin, adipic acid and a coating material.
In order to control the release of the metformin hydrochloride and ensure that the metformin hydrochloride is stably released without sudden release or over-slow release, the invention adds the fiber-acetate process ester and the erodible framework material into the metformin hydrochloride sustained-release tablet core, and can well control the release of the metformin hydrochloride under the matching of the fiber-acetate process ester and the erodible framework material. The character of the saxagliptin is unstable, and through a large amount of researches, the inventor adds adipic acid into the saxagliptin medicine-containing layer and mixes the saxagliptin with the adipic acid to prepare the medicine-containing layer, so that the saxagliptin can be relatively stable, and the degradation of the saxagliptin in the production and storage processes can be reduced. The saxagliptin is used for coating the metformin hydrochloride sustained-release tablet core in a medicament-containing layer mode, so that the problem that the content uniformity is difficult to control due to the great dosage difference of the saxagliptin and the metformin hydrochloride can be well solved.
In order to better control the release of the metformin hydrochloride, the dosage of the fiber-acetate-process ester and the erodible framework material in the metformin hydrochloride sustained-release tablet core is considered, and the mass dosage ratio of the fiber-acetate-process ester to the erodible framework material is 1-4: 2-6. The erodible framework material is one or more of beeswax, hydrogenated vegetable oil, carnauba wax, synthetic wax, butyl stearate, glyceryl stearate and stearic acid.
In the saxagliptin and metformin hydrochloride sustained-release tablets, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and povidone.
In the saxagliptin and metformin hydrochloride sustained-release tablet, the metformin hydrochloride sustained-release tablet core further comprises one or two of a filling agent and a lubricating agent. Wherein the filler is one or more of microcrystalline cellulose, pregelatinized starch, lactose, calcium hydrogen phosphate, sorbitol, starch, sucrose, calcium sulfate, and calcium carbonate. The lubricant is one or more of magnesium stearate, silica gel micropowder and pulvis Talci.
In certain embodiments, the pH of the saxagliptin drug-containing layer is 1.5 to 3; furthermore, the pH of the saxagliptin medicine-containing layer is adjusted to 1.5-3 by adipic acid or adipic acid matched with hydrochloric acid or sodium hydroxide.
The saxagliptin and metformin hydrochloride sustained-release tablets comprise the following components in parts by mass:
furthermore, in the saxagliptin and metformin hydrochloride sustained-release tablets, when the adhesive is sodium carboxymethyl cellulose and the lubricant is magnesium stearate, the sustained-release tablets comprise the following components in parts by mass:
in certain embodiments, the saxagliptin drug-containing layer coating weight gain is 4-10%.
In the saxagliptin and metformin hydrochloride sustained-release tablets, the coating materials in the isolation layer and the protective layer are stomach-soluble coating premix series, and the coating materials in the drug-containing layer of the saxagliptin are stomach-soluble coating premix series.
The invention also provides a method for preparing the saxagliptin and metformin hydrochloride sustained-release tablets, which comprises the following steps:
(1) uniformly mixing metformin hydrochloride, cellulose acetate, an erodible framework material and an adhesive to obtain a mixture, performing wet granulation and size stabilization to obtain medicinal granules, and performing tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) coating the sustained-release tablet core obtained in the step (1) with an isolation layer;
(3) uniformly mixing saxagliptin, adipic acid and a coating material to prepare a coating solution, and coating the slow release tablet core obtained in the step (2) with a drug-containing layer of saxagliptin;
(4) and (4) coating the sustained-release tablet core obtained in the step (3) with a protective layer.
The step (1) also comprises adding a filling agent into the mixture; the step (1) further comprises the step of mixing a lubricant with the drug particles.
Drawings
FIG. 1 is a graph showing the total impurity increase after 1 month acceleration for example 1, comparative example 1, formulations 3 to 5, comparative examples 2 to 3, and commercial products.
FIG. 2 shows the dissolution profiles of saxagliptin of the samples of example 1, comparative examples 1 to 3 and commercial products.
FIG. 3 is a graph showing the dissolution profiles of example 1, comparative example 1, formulations 1-2, comparative examples 2-3, and commercially available metformin hydrochloride.
As can be seen from fig. 1, the saxagliptin and metformin hydrochloride sustained-release tablets of the present invention can effectively control the increase of total impurities, and are lower than those of the commercial products, while the total impurity amounts of the accelerated experiments of the formulas 3 to 5 in comparative example 1 and comparative examples 2 and 3 are obviously increased and uncontrollable.
As can be seen from the figures 2 and 3, the dissolution of the saxagliptin and the metformin hydrochloride of the slow release tablet of the invention is consistent with that of the original product sold in the research, while the formulations 1 to 2 in the comparative example 1 and the comparative examples 2 and 3 have the phenomenon that the release of the metformin hydrochloride is too fast or too slow, and the quality is not controllable.
Detailed Description
Example 1
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, carnauba wax and sodium carboxymethylcellulose, adding water, performing wet granulation, drying, granulating to obtain medicinal granules, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (3).
Example 2
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, beeswax and sodium carboxymethylcellulose, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicinal granules, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 3% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 4% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding the hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2.5% of the weight of the sustained-release tablet core obtained in the step (3).
Example 3
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, hydrogenated vegetable oil and sodium carboxymethylcellulose, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicinal granules, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 3% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 3 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 6% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (3).
Example 4
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, synthetic wax, glyceryl stearate, polyvidone, microcrystalline cellulose and lactose, adding wetting agent water, wet granulating, drying, grading to obtain medicinal granules, uniformly mixing the medicinal granules and magnesium stearate, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 10% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (3).
Example 5
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, butyl stearate, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch and calcium hydrogen phosphate, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicinal granules, uniformly mixing the medicinal granules with superfine silica gel powder and talcum powder, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 1% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 1.5 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 1.5 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to 6% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 3% of the weight of the sustained-release tablet core obtained in the step (3).
Example 6
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, carnauba wax, hydroxypropyl methyl cellulose, sucrose and calcium carbonate, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicinal granules, and tabletting to obtain the metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 3 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 1% of the weight of the sustained-release tablet core obtained in the step (3).
Example 7
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, stearic acid, povidone and microcrystalline cellulose, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicine granules, uniformly mixing the medicine granules and magnesium stearate, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (3).
Example 8
The preparation method comprises the following steps:
(1) preparation of metformin hydrochloride sustained-release tablet core
Uniformly mixing metformin hydrochloride, cellulose acetate, beeswax, sodium carboxymethylcellulose, sorbitol and starch, adding wetting agent water, performing wet granulation, drying, granulating to obtain medicinal granules, uniformly mixing the medicinal granules with aerosil, and tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) isolating layer coating
Adding hydrochloric acid solution into Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (1);
(3) saxagliptin drug-containing layer coating
Adding saxagliptin and adipic acid into a hydrochloric acid solution, uniformly stirring, adjusting the pH to 2 by using sodium hydroxide or hydrochloric acid, adding Opadry II, uniformly stirring, adjusting the pH to 2.5 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 5% of the weight of the sustained-release tablet core obtained in the step (2);
(4) protective layer coating
And (3) adding hydrochloric acid solution into the Opadry II, uniformly stirring to prepare coating solution with the concentration of 15% (g/g), adjusting the pH value to be 2 by using sodium hydroxide or hydrochloric acid, and increasing the weight of the coating to be 2% of the weight of the sustained-release tablet core obtained in the step (3).
Comparative example 1
The preparation method is the same as example 1.
Comparative example 2
The saxagliptin metformin sustained release tablet sample is prepared by referring to the prescription process disclosed in example 1 in patent CN 103933031A.
Comparative example 3
The sample of the saxagliptin and metformin hydrochloride compound sustained-release capsule is prepared by referring to the prescription process disclosed in example 1 in patent CN 103976997B.
Test for content uniformity
The content uniformity of saxagliptin in the samples obtained in examples and comparative examples was determined by HPLC method, and the results were as follows:
according to the invention, the content uniformity of the saxagliptin with a small dosage is investigated, and the test data show that the saxagliptin of the sample prepared according to the scheme of the invention has good content uniformity and conforms to the specification of Chinese pharmacopoeia. In comparative example 3, the content uniformity of saxagliptin in the sustained-release capsule prepared by respectively preparing the saxagliptin and the metformin hydrochloride into the pellets and then mixing the pellets was poor.
Stability test
The samples prepared in examples and comparative examples were allowed to stand at 40 ℃. + -. 2 ℃ and RH 75%. + -. 5% for 1 month to perform accelerated experiments, and total impurities (%) were measured by HPLC as follows:
the test data show that the sustained-release tablet prepared by the invention can effectively control the amount of impurities, the increase amplitude of the impurities is small after accelerating for 1 month, the sustained-release tablet belongs to a controllable range, the content of the impurities is lower than that of the original commercially available product, and the sustained-release tablet is suitable for industrial production. In the schemes of formulas 3-5 in comparative example 1 and comparative examples 2 and 3 without adding adipic acid, impurities are not easy to control, and in the process of accelerated test, the impurities are increased greatly and the quality is not controllable.
Dissolution determination
Taking samples obtained in the examples and the comparative examples, according to a dissolution rate measuring method (second method of 0931 of the fourth general rule of pharmacopoeia of China 2015 edition), taking phosphate buffer solution with pH6.8 as a dissolution medium, rotating at 75rpm, measuring the dissolution rate (%) of saxagliptin at 5min, 10min, 15min, 20min, 30min and 45min, and taking dissolution solution at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 18h to measure the dissolution rate (%) of metformin hydrochloride. The results obtained were as follows:
saxagliptin dissolution (%)
| NO | 5min | 10min | 15min | 20min | 30min | 45min | |
| Example 1 | Saxagliptin | 79.2 | 95.0 | 97.4 | 98.1 | 98.7 | 100.0 |
| Example 2 | Saxagliptin | 81.0 | 94.5 | 96.5 | 97.6 | 98.4 | 99.9 |
| Example 3 | Saxagliptin | 79.5 | 94.7 | 96.7 | 97.8 | 98.3 | 99.9 |
| Example 4 | Saxagliptin | 80.4 | 93.9 | 97.0 | 98.0 | 98.6 | 100.1 |
| Example 5 | Saxagliptin | 80.6 | 94.7 | 95.8 | 97.9 | 98.2 | 99.8 |
| Example 6 | Saxagliptin | 79.5 | 93.5 | 95.5 | 97.6 | 98.3 | 100.1 |
| Example 7 | Saxagliptin | 81.2 | 94.8 | 96.4 | 98.3 | 98.7 | 100.2 |
| Example 8 | Saxagliptin | 80.5 | 94.3 | 96.3 | 98.1 | 98.8 | 99.9 |
| Prescription 1 | Saxagliptin | 79.5 | 93.5 | 95.6 | 97.2 | 98.3 | 99.8 |
| Prescription 2 | Saxagliptin | 80.1 | 94.1 | 95.1 | 97.8 | 97.9 | 99.7 |
| Prescription 3 | Saxagliptin | 76.5 | 90.2 | 92.5 | 95.6 | 97.2 | 99.4 |
| Prescription 4 | Saxagliptin | 75.6 | 90.5 | 91.6 | 94.8 | 97.6 | 99.3 |
| Prescription 5 | Saxagliptin | 76.4 | 89.4 | 91.5 | 94.6 | 97.0 | 99.6 |
| Comparative example 2 | Saxagliptin | 77.1 | 91.9 | 95.8 | 97.3 | 98.9 | 99.4 |
| Comparison 3 | Saxagliptin | 69.4 | 91.3 | 95.6 | 97.4 | 98.7 | 99.7 |
| Commercially available product | Saxagliptin | 80.3 | 94.3 | 96.5 | 97.8 | 98.3 | 99.6 |
Dissolution rate of metformin hydrochloride (%)
From the above test data, the dissolution of saxagliptin and metformin hydrochloride in the sustained-release tablet prepared by the present invention was consistent with that of the commercially available product of the original research. In contrast, in the solutions of formulas 1 to 2 in comparative example 1 and comparative examples 2 and 3, which are not added with the cellulose acetate ester and the eroding matrix material at the same time, the release of metformin hydrochloride is too fast or too slow, and the quality is not controllable.
Claims (13)
1. The saxagliptin and metformin hydrochloride sustained-release tablet is characterized in that the sustained-release tablet sequentially comprises a metformin hydrochloride sustained-release tablet core, an isolation layer, a saxagliptin drug-containing layer and a protective layer from inside to outside; wherein the metformin hydrochloride sustained-release tablet core comprises metformin hydrochloride, cellulose acetate, erodible framework material and adhesive; the drug-containing layer of saxagliptin comprises saxagliptin, adipic acid and a coating material.
2. The sustained-release tablet according to claim 1, wherein the erodible matrix material is one or more of beeswax, hydrogenated vegetable oil, carnauba wax, synthetic wax, butyl stearate, glyceryl stearate, and stearic acid.
3. The sustained-release tablet according to claim 1, wherein the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and povidone.
4. The extended release tablet of claim 1, wherein the metformin hydrochloride extended release core further comprises one or both of a filler and a lubricant.
5. The sustained-release tablet according to claim 4, wherein the filler is one or more of microcrystalline cellulose, pregelatinized starch, lactose, calcium hydrogen phosphate, sorbitol, starch, sucrose, calcium sulfate, and calcium carbonate.
6. The sustained-release tablet according to claim 4, wherein the lubricant is one or more of magnesium stearate, aerosil and talcum powder.
7. The sustained-release tablet of claim 1, wherein the pH of the saxagliptin drug-containing layer is 1.5 to 3.
8. The sustained-release tablet according to claim 1, wherein the sustained-release tablet comprises the following components by mass:
9. the sustained-release tablet according to claim 6, wherein the binder is sodium carboxymethylcellulose, the lubricant is magnesium stearate, and the sustained-release tablet comprises the following components in parts by mass:
10. the sustained-release tablet according to claim 8 or 9, wherein the weight increase of the saxagliptin drug-containing layer coating is 4-10%.
11. The sustained-release tablet of claim 1, wherein the coating material in the isolation layer and the protective layer is Opadry series of gastric-soluble coating premixes, and the coating material in the drug-containing layer of saxagliptin is Opadry series of gastric-soluble coating premixes.
12. A method of preparing the extended release tablet of claim 1, comprising the steps of:
(1) uniformly mixing metformin hydrochloride, cellulose acetate, an erodible framework material and an adhesive to obtain a mixture, performing wet granulation and size stabilization to obtain medicinal granules, and performing tabletting to obtain a metformin hydrochloride sustained-release tablet core;
(2) coating the sustained-release tablet core obtained in the step (1) with an isolation layer;
(3) uniformly mixing saxagliptin, adipic acid and a coating material to prepare a coating solution, and coating the slow release tablet core obtained in the step (2) with a drug-containing layer of saxagliptin;
(4) and (4) coating the sustained-release tablet core obtained in the step (3) with a protective layer.
13. The method of claim 12, wherein step (1) further comprises adding a filler to the mixture.
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| CN117338740A (en) * | 2023-11-14 | 2024-01-05 | 北京百奥药业有限责任公司 | Saxagliptin metformin sustained-release tablet and preparation method thereof |
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