CN113116844A - Stomach retention tablet - Google Patents

Stomach retention tablet Download PDF

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Publication number
CN113116844A
CN113116844A CN202011613560.6A CN202011613560A CN113116844A CN 113116844 A CN113116844 A CN 113116844A CN 202011613560 A CN202011613560 A CN 202011613560A CN 113116844 A CN113116844 A CN 113116844A
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Prior art keywords
present disclosure
certain embodiments
tablet
core
gastric retention
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CN202011613560.6A
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Chinese (zh)
Inventor
李伟
潘阳
童伟勤
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Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
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Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
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    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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Abstract

Disclosed is a gastric retention tablet comprising a core and a sustained release layer, wherein the core comprises metformin or a pharmaceutically acceptable salt thereof, the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.

Description

Stomach retention tablet
FIELD
The present disclosure relates generally to the field of medicine. More specifically, the present application relates to the field of pharmaceutical formulations.
Background
Metformin hydrochloride can reduce the absorption of glucose by intestinal tracts, reduce hepatic gluconeogenesis, reduce the level of basic and postprandial blood sugar, improve the glucose tolerance of a type II diabetic patient, and is clinically used for treating type II diabetes, which is a first-line medicament.
SUMMARY
In one aspect, the present disclosure relates to a gastric retention tablet comprising a core and a sustained release layer, wherein the core comprises a first active pharmaceutical ingredient, the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In another aspect, the present disclosure relates to a method of making a gastric retention tablet comprising: preparing a core comprising a first active pharmaceutical ingredient and a bulking agent; and coating the core with a sustained release layer to obtain the gastric retention tablet, wherein the sustained release layer contains a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In yet another aspect, the present disclosure relates to a gastric retention tablet prepared by a method comprising the steps of preparing a core comprising a first active pharmaceutical ingredient and an expansion agent; and coating the core with a sustained release layer to obtain the gastric retention tablet, wherein the sustained release layer contains a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In yet another aspect, the present disclosure relates to a method of improving compliance in a subject comprising administering to said subject in need thereof a gastric retentive tablet, wherein the gastric retentive tablet comprises a core and a sustained release layer, wherein the core comprises a first active pharmaceutical ingredient, the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof comprises 70% or more by weight of the core.
Brief description of the drawings
Fig. 1 shows the cumulative release profile of metformin hydrochloride sustained-release tablets of examples 2 to 4 of the present disclosure.
Detailed description of the invention
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Throughout this specification and the claims which follow, unless the context requires otherwise, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".
Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
Definition of
In the present disclosure, the term "pharmaceutically acceptable salts" includes "acceptable acid addition salts" and "acceptable base addition salts".
In the present disclosure, the term "acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, and the like, Mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
In the present disclosure, the term "acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
In the present disclosure, the term "active pharmaceutical ingredient" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
In the present disclosure, the term "bulking agent" refers to an excipient that absorbs water and undergoes volumetric bulking when placed in an aqueous environment.
In the present disclosure, the term "pore-forming agent" refers to a water-soluble auxiliary material dispersed in the polymer material of the sustained-release coating film, which is dissolved when the tablet contacts with aqueous liquid, so that the sustained-release coating film has micropores and permeability.
In the present disclosure, the term "binder" refers to an auxiliary material that binds the material and facilitates granulation.
In the present disclosure, the term "glidant" refers to an excipient that reduces friction between particles, thereby improving powder flowability.
In the present disclosure, the term "lubricant" refers to an adjuvant that reduces friction between particles, thereby improving powder flowability.
In the present disclosure, the term "plasticizer" refers to an auxiliary material having polarity or partially having polarity in structure, which has the characteristics of high boiling point, difficult volatilization, good miscibility with polymer, etc., and the plasticizer is distributed among macromolecular chains, so that the intermolecular force can be reduced, the viscosity of the polymer can be reduced, and the flexibility can be enhanced.
In the present disclosure, the term "opacifier" refers to a substance that can absorb, scatter or reflect light.
In the present disclosure, the term "antifoaming agent" refers to a substance that is capable of reducing the surface tension of water, solutions, suspensions, etc., preventing foam formation, or reducing or eliminating the original foam.
In the present disclosure, the term "surfactant" refers to a substance that causes a significant reduction in the surface tension of a liquid.
In the present disclosure, the term "aqueous medium" refers to water or a liquid system in which water is the vehicle.
In the present disclosure, the term "minor diameter" refers to the shortest diameter of the gastro-retentive formulation.
In the present disclosure, the term "compliance" refers to the individual performing a treatment as prescribed by a physician, whose behavior is in accordance with the order; otherwise, it is called non-compliance.
In this disclosure, the term "hardness" means the hardness of a tablet as measured by the pressure required to break the tablet by standing it between two platens and pressing it across the diameter of the tablet.
Detailed Description
In one aspect, the present disclosure relates to a gastric retention tablet comprising a core and a sustained release layer, wherein the core comprises a first active pharmaceutical ingredient, the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 8 kp.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 6 kp.
In certain embodiments, illustrative examples of mixtures comprising polyvinyl acetate and povidone that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000051
SR。
In certain embodiments, the sustained release layer of the present disclosure comprises a polyvinyl alcohol-polyethylene glycol graft polymer.
In certain embodiments, illustrative examples of polyvinyl alcohol-polyethylene glycol graft polymers that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000052
IR。
In certain embodiments, the tablet core of the present disclosure comprises a bulking agent.
In certain embodiments, illustrative examples of bulking agents that can be used in the present disclosure include, but are not limited to, crospovidone, carboxymethyl starch sodium, pregelatinized starch, croscarmellose sodium, croscarmellose calcium, and low substituted hydroxypropyl cellulose.
In certain embodiments, the sustained release layer of the present disclosure comprises a porogen.
In certain embodiments, illustrative examples of porogens that can be used in the present disclosure include, but are not limited to, water soluble polymers.
In certain embodiments, illustrative examples of water-soluble polymers useful as porogens that can be used in the present disclosure include, but are not limited to, sodium alginate, hypromellose, hydroxypropyl cellulose, povidone, and polyethylene glycol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the porogens of the present disclosure include, but are not limited to, hypromellose, hydroxypropyl cellulose, povidone, polyethylene glycol, and polyvinyl alcohol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the present disclosure as porogens include, but are not limited to, hypromellose, whose 2% solution has a viscosity of above 3 mpa-s to below 50 mpa-s at about 20 ℃, hydroxypropyl cellulose, whose 2% solution has a viscosity of above 75 mpa-s to below 3,000 mpa-s at about 20 ℃, povidone K12, povidone K17, povidone K25, povidone K30, povidone K90, polyethylene glycol having a molecular weight of above 1,000 to below 20,000, and polyvinyl alcohol-polyethylene glycol graft polymers.
In certain embodiments, illustrative examples of water-soluble polymers as porogens that can be used in the present disclosure include, but are not limited to, MethocelTME3、MethocelTME5、MethocelTME6、BenecelTME3、BenecelTME5、BenecelTME6 and
Figure BDA0002873612460000061
IR。
in certain embodiments, the sustained release layer of the present disclosure comprises a glidant.
In certain embodiments, illustrative examples of glidants that can be used in the tablet cores of the present disclosure include, but are not limited to, colloidal silicon dioxide, aerosil, polyethylene glycol, magnesium stearate, stearic acid, talc, and starch.
In certain embodiments, the extended release layer of the present disclosure comprises a sunscreen agent.
In certain embodiments, illustrative examples of opacifiers that can be used in the present disclosure include, but are not limited to, titanium dioxide and talc.
In certain embodiments, the sustained release layer of the present disclosure comprises an antifoaming agent.
In certain embodiments, illustrative examples of defoamers that can be used in the present disclosure include, but are not limited to, dimethicone and mixtures of dimethicone and silica.
In certain embodiments, the extended release layer of the present disclosure comprises a surfactant.
In certain embodiments, illustrative examples of surfactants that can be used in the present disclosure include, but are not limited to, gum arabic, xanthan gum, gelatin, propylene glycol monostearate, glycerol monostearate, vinyl distearate, diglyceride monoglyceride, sodium lauryl sulfate, Span 20, Span 40, Span 60, Span 65, Span 80, Span 83, Span 85, potassium oleate, sodium oleate, triethanolamine oleate, lecithin, sucrose esters, poloxamer 188, Atlas G-263, tween 20, tween 21, tween 40, tween 60, tween 61, tween 65, tween 80, tween 81, tween 85, Myrj 45, Myrj 49, Myrj 51, Myrj 52, polyoxyethylene 400 monolaurate, polyoxyethylene 400 monostearate, polyoxyethylene 400 monooleate, Brij 35, Brij 30, cetylmethylnaphthol, polyoxyethylene hydrogenated castor oil, gum arabic, xanthan gum, gelatin, propylene glycol monostearate, glycerol distearate, sodium stearate, sodium lauryl sulfate, Span 40, Span 60, Span 65, Span 80, tween 81, tween 85, Myrj 45, Myrj 49, Myrj 51, Myrj 52, polyoxyethylene 400 monolaurate, polyoxyethylene alkylphenols and polyoxyethylene nonylphenol ethers.
In certain embodiments, the sustained release layer of the present disclosure comprises a plasticizer.
In certain embodiments, illustrative examples of plasticizers that can be used in the present disclosure include, but are not limited to, phthalates, aliphatic dibasic esters, phosphate esters, epoxides, fatty acid esters, and polyethylene glycols.
In certain embodiments, illustrative examples of phthalates that can be used in the present disclosure include, but are not limited to, dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate (DOP), and octyl phthalate (DnOP).
In certain embodiments, illustrative examples of aliphatic dibasic acid esters that can be used in the present disclosure include, but are not limited to, bis (2-ethylhexyl) adipate (DOA), diisodecyl adipate (DIDA), 2-ethylhexyl Diazodicarboxylate (DOZ), diethylhexyl sebacate (DOS), and dibutyl sebacate (DBS).
In certain embodiments, illustrative examples of phosphate esters that can be used in the present disclosure include, but are not limited to, tributyl phosphate (TBP), tris (2-ethylhexyl) phosphate (TOP), diphenyloctyl phosphate (DPOP), triphenyl phosphate (TPP), and triisopropylphenyl phosphate (IPPP).
In certain embodiments, illustrative examples of epoxides that can be used in the present disclosure include, but are not limited to, Epoxidized Soybean Oil (ESO), epoxidized linseed oil, epoxidized fatty acid butyl ester (EBSt), octyl oleate epoxide, and di-2-ethylhexyl) 4, 5-epoxy tetrahydrophthalate (EPS).
In certain embodiments, the polyethylene glycols (PEGs) useful in the present disclosure have a relative molecular weight of at least about 4,000.
In certain embodiments, the polyethylene glycols (PEGs) useful in the present disclosure have a relative molecular weight of at least about 6,000.
In certain embodiments, the polyethylene glycols (PEGs) useful in the present disclosure have a relative molecular weight of at least about 8,000.
In certain embodiments, illustrative examples of polyethylene glycols (PEGs) useful in the present disclosure include, but are not limited to:
Figure BDA0002873612460000071
4000、
Figure BDA0002873612460000072
6000、
Figure BDA0002873612460000073
8000、
Figure BDA0002873612460000074
4000、
Figure BDA0002873612460000075
6000、
Figure BDA0002873612460000076
8000、
Figure BDA0002873612460000077
E4000、
Figure BDA0002873612460000078
e6000 and
Figure BDA0002873612460000079
E 8000。
in certain embodiments, the gastric retention tablets of the present disclosure comprise a first coating layer outside the sustained release layer.
In certain embodiments, the first coating layer comprises a water soluble polymer.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the first coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the first coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the first coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of mixtures comprising polyethylene glycol and polyvinyl alcohol that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000081
II。
In certain embodiments, illustrative examples of polyvinyl alcohol-polyethylene glycol graft polymers that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000082
IR。
In certain embodiments, the first coating layer contains a second active pharmaceutical ingredient.
In certain embodiments, illustrative examples of second active pharmaceutical ingredients that can be used in the present disclosure include, but are not limited to, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT-2) inhibitors, sulfonylurea drugs (sulfoureas), non-sulfonylurea drugs (non-sulfoureas), alpha-glucosidase inhibitors (glucosidase inhibitors), and insulin sensitizers (insulin sensitizers).
In certain embodiments, illustrative examples of dipeptidyl peptidase-4 (DPP-4) inhibitors that can be used in the present disclosure include, but are not limited to, sitagliptin (sitagliptin), vildagliptin (vildagliptin), saxagliptin (saxagliptin), alogliptin (alogliptin), linagliptin (linagliptin), gitagliptin (gemagliptin), and tegravelin.
In certain embodiments, illustrative examples of Sodium/glucose cotransporter 2 (SGLT-2) inhibitors that can be used in the present disclosure include, but are not limited to, tolagliflozin (tofogliflozin), engagliflozin (empagliflozin), epragliflozin (ipragliflozin L-proline), lucagliflozin (luceogliflozin), dapagliflozin propylene glycol (dapagliflozin propylene glycol), canagliflozin (canagliflozin), and egagliflozin (ertugliflozin).
In certain embodiments, illustrative examples of sulfonylurea drugs (sulfonylureas) capable of the present disclosure include, but are not limited to: glipizide (glipizide), gliclazide (gliclazide), glibenclamide (glibenclamide), glibornuride (glibornuride), glimepiride (glimepiride), and gliquidone (gliquidone).
In certain embodiments, illustrative examples of non-sulfonylurea drugs (non-sulfonylureas) that can be used in the present disclosure include, but are not limited to, repaglinide (repaglinide) and nateglinide (nateglinide).
In certain embodiments, illustrative examples of α -glucosidase inhibitors (gluconase inhibitors) that can be used in the present disclosure include, but are not limited to, acarbose (acarbose) and voglibose (voglibose).
In certain embodiments, illustrative examples of insulin sensitizers (insulin sensitizers) that can be used in the present disclosure include, but are not limited to, rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone).
In certain embodiments, the tablet core of the present disclosure comprises a third active pharmaceutical ingredient.
In certain embodiments, illustrative examples of the third active pharmaceutical ingredient that can be used in the present disclosure include, but are not limited to, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose cotransporter 2 (SGLT-2) inhibitors, sulfonylurea drugs (sulfoureas), non-sulfonylurea drugs (non-sulfoureas), alpha-glucosidase inhibitors (glucosidase inhibitors), and insulin sensitizers (insulin sensitizers).
In certain embodiments, illustrative examples of dipeptidyl peptidase-4 (DPP-4) inhibitors that can be used in the present disclosure include, but are not limited to, sitagliptin (sitagliptin), vildagliptin (vildagliptin), saxagliptin (saxagliptin), alogliptin (alogliptin), linagliptin (linagliptin), gitagliptin (gemagliptin), and tegravelin.
In certain embodiments, illustrative examples of sodium/glucose cotransporter 2 (SGLT-2) inhibitors that can be used in the present disclosure include, but are not limited to, tolagliflozin (tofogliflozin), engagliflozin (empagliflozin), epragliflozin L-proline (ipragliflozin L-proline), lucagliflozin (lucagogliflozin), dapagliflozin propylene glycol (dapagliflozin propylene glycol), canagliflozin (canagliflozin), and egagliflozin (ertgliflozin).
In certain embodiments, illustrative examples of sulfonylurea drugs (sulfonylureas) capable of the present disclosure include, but are not limited to: glipizide (glipizide), gliclazide (gliclazide), glibenclamide (glibenclamide), glibornuride (glibornuride), glimepiride (glimepiride), and gliquidone (gliquidone).
In certain embodiments, illustrative examples of non-sulfonylurea drugs (non-sulfonylureas) that can be used in the present disclosure include, but are not limited to, repaglinide (repaglinide) and nateglinide (nateglinide).
In certain embodiments, illustrative examples of α -glucosidase inhibitors (gluconase inhibitors) that can be used in the present disclosure include, but are not limited to, acarbose (acarbose) and voglibose (voglibose).
In certain embodiments, illustrative examples of insulin sensitizers (insulin sensitizers) that can be used in the present disclosure include, but are not limited to, rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone).
In certain embodiments, the gastric retention tablets of the present disclosure comprise a second coating layer outside the sustained release layer.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the second coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the second coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of mixtures comprising polyethylene glycol and polyvinyl alcohol that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000101
II。
In certain embodiments, illustrative examples of polyvinyl alcohol-polyethylene glycol graft polymers that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000102
IR。
In certain embodiments, the gastric retention tablets of the present disclosure comprise a first coating layer outside the sustained release layer and a second coating layer outside the first coating layer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure further comprises a filler.
In certain embodiments, illustrative examples of fillers that can be used in the present disclosure include, but are not limited to, lactose, glucose, sucrose, xylitol, mannitol, sorbitol, maltodextrin, powdered sugar, dextrins, microcrystalline cellulose, inorganic salts, mannitol, and starch.
In certain embodiments, the core of the gastric retention tablet of the present disclosure further comprises a glidant.
In certain embodiments, illustrative examples of glidants that can be used in the tablet cores of the present disclosure include, but are not limited to, colloidal silicon dioxide, aerosil, polyethylene glycol, magnesium stearate, stearic acid, talc, and starch.
In certain embodiments, the core of the gastric retention tablet of the present disclosure further comprises a binder.
In certain embodiments, illustrative examples of binders that can be used in the tablet cores of the present disclosure include, but are not limited to, polyvinyl alcohol, sodium carboxymethylcellulose, starch paddles, povidone, copovidone, sucrose solutions, hypromellose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, hydroxyethyl cellulose, methyl cellulose, maltodextrin, starch, sodium carboxymethyl starch, pregelatinized starch, hydroxypropyl cellulose, sodium carboxymethyl starch, gelatin, gum arabic, guar gum, locust bean gum, tamarind gum, sesbania gum, flaxseed gum, gleditsia gum, pectin, abelmoschus gum, carrageenan, agar, sodium alginate, potassium alginate, gelatin, chitin, xanthan gum, beta-cyclodextrin, polydextrose, gellan gum, and acrylic resins.
In certain embodiments, the core of the gastric retention tablet of the present disclosure further comprises a lubricant.
In certain embodiments, exemplary examples of lubricants that can be used in the present disclosure include, but are not limited to, fatty acids and their metal soaps, esters, hydrogenated vegetable oils, polyethylene glycols, and magnesium lauryl sulfate.
In certain embodiments, illustrative examples of fatty acids and their metal soaps that can be used in the present disclosure include, but are not limited to, magnesium stearate, stearic acid, zinc stearate, calcium stearate, lead stearate, barium stearate, and sodium stearyl fumarate.
In certain embodiments, illustrative examples of esters that can be used in the present disclosure include, but are not limited to, glyceryl behenate, glyceryl tristearate, glyceryl monostearate, and butyl stearate.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a single layer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a bilayer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a trilayer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a single compartment.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a dual chamber.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a triple chamber.
In certain embodiments, the gastric retention tablets of the present disclosure are capable of rising in an aqueous medium within about 10 minutes.
In certain embodiments, the gastric retention tablets of the present disclosure are capable of immediate floating in aqueous media.
In certain embodiments, the gastric retention sheets of the present disclosure have a minor dimension of no greater than about 9mm and a thickness of no greater than the minor dimension.
In certain embodiments, the gastric retentive tablets of the present disclosure have a tablet weight of no greater than about 800 mg.
In certain embodiments, the gastric retention sheets of the present disclosure have a minor diameter of no less than about 11mm after swelling in aqueous media.
In certain embodiments, the extended release layer coating has good tonicity after the gastric retention tablet of the present disclosure is expanded in an aqueous medium.
In another aspect, a method of making a gastric retention tablet, comprising:
preparing granules comprising metformin or a pharmaceutically acceptable salt thereof;
preparing a tablet core using said granules; and
coating the tablet core with a sustained release layer to obtain the gastric retention tablet,
wherein the extended release layer comprises a mixture comprising polyvinyl acetate and povidone, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 8 kp.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 6 kp.
In certain embodiments, the methods of the present disclosure comprise performing a first coating after performing the extended release layer coating, thereby obtaining a first coating layer.
In certain embodiments, the methods of the present disclosure comprise a first coating layer comprising a second active pharmaceutical ingredient.
In certain embodiments, illustrative examples of second active pharmaceutical ingredients that can be used in the disclosure include, but are not limited to, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT-2) inhibitors, sulfonylurea drugs (sulfenylureas), non-sulfonylurea drugs (non-sulfenylureas), alpha-glucosidase inhibitors (glucosidase inhibitors), and insulin sensitizers (insulin sensitizers).
In certain embodiments, illustrative examples of dipeptidyl peptidase-4 (DPP-4) inhibitors that can be used in the present disclosure include, but are not limited to, sitagliptin (sitagliptin), vildagliptin (vildagliptin), saxagliptin (saxagliptin), alogliptin (alogliptin), linagliptin (linagliptin), gitagliptin (gemagliptin), and tegravelin.
In certain embodiments, illustrative examples of Sodium/glucose cotransporter 2 (SGLT-2) inhibitors that can be used in the present disclosure include, but are not limited to, tolagliflozin (tofogliflozin), engagliflozin (empagliflozin), epragliflozin (ipragliflozin L-proline), lucagliflozin (luceogliflozin), dapagliflozin propylene glycol (dapagliflozin propylene glycol), canagliflozin (canagliflozin), and egagliflozin (ertugliflozin).
In certain embodiments, illustrative examples of sulfonylurea drugs (sulfonylureas) capable of the present disclosure include, but are not limited to: glipizide (glipizide), gliclazide (gliclazide), glibenclamide (glibenclamide), glibornuride (glibornuride), glimepiride (glimepiride), and gliquidone (gliquidone).
In certain embodiments, illustrative examples of non-sulfonylurea drugs (non-sulfonylureas) that can be used in the present disclosure include, but are not limited to, repaglinide (repaglinide) and nateglinide (nateglinide).
In certain embodiments, illustrative examples of α -glucosidase inhibitors (gluconase inhibitors) that can be used in the present disclosure include, but are not limited to, acarbose (acarbose) and voglibose (voglibose).
In certain embodiments, illustrative examples of insulin sensitizers (insulin sensitizers) that can be used in the present disclosure include, but are not limited to, rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone).
In certain embodiments, the tablet core of the present disclosure comprises a third active pharmaceutical ingredient.
In certain embodiments, illustrative examples of the third active pharmaceutical ingredient that can be used in the present disclosure include, but are not limited to, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose cotransporter 2 (SGLT-2) inhibitors, sulfonylurea drugs (sulfoureas), non-sulfonylurea drugs (non-sulfoureas), alpha-glucosidase inhibitors (glucosidase inhibitors), and insulin sensitizers (insulin sensitizers).
In certain embodiments, illustrative examples of dipeptidyl peptidase-4 (DPP-4) inhibitors that can be used in the present disclosure include, but are not limited to, sitagliptin (sitagliptin), vildagliptin (vildagliptin), saxagliptin (saxagliptin), alogliptin (alogliptin), linagliptin (linagliptin), gitagliptin (gemagliptin), and tegravelin.
In certain embodiments, illustrative examples of sodium/glucose cotransporter 2 (SGLT-2) inhibitors that can be used in the present disclosure include, but are not limited to, tolagliflozin (tofogliflozin), engagliflozin (empagliflozin), epragliflozin L-proline (ipragliflozin L-proline), lucagliflozin (lucagogliflozin), dapagliflozin propylene glycol (dapagliflozin propylene glycol), canagliflozin (canagliflozin), and egagliflozin (ertgliflozin).
In certain embodiments, illustrative examples of sulfonylurea drugs (sulfonylureas) capable of the present disclosure include, but are not limited to: glipizide (glipizide), gliclazide (gliclazide), glibenclamide (glibenclamide), glibornuride (glibornuride), glimepiride (glimepiride), and gliquidone (gliquidone).
In certain embodiments, illustrative examples of non-sulfonylurea drugs (non-sulfonylureas) that can be used in the present disclosure include, but are not limited to, repaglinide (repaglinide) and nateglinide (nateglinide).
In certain embodiments, illustrative examples of α -glucosidase inhibitors (gluconase inhibitors) that can be used in the present disclosure include, but are not limited to, acarbose (acarbose) and voglibose (voglibose).
In certain embodiments, illustrative examples of insulin sensitizers (insulin sensitizers) that can be used in the present disclosure include, but are not limited to, rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone).
In certain embodiments, the methods of the present disclosure comprise applying a second coating after applying the extended release layer coating, thereby obtaining a second coating layer.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the second coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of water-soluble polymers that can be used in the second coating layer of the present disclosure include, but are not limited to, sodium alginate, hypromellose, polyvinyl alcohol-polyethylene glycol graft polymers, and mixtures comprising polyethylene glycol and polyvinyl alcohol.
In certain embodiments, illustrative examples of mixtures comprising polyethylene glycol and polyvinyl alcohol that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000152
II。
In certain embodiments, illustrative examples of polyvinyl alcohol-polyethylene glycol graft polymers that can be used in the present disclosure include, but are not limited to
Figure BDA0002873612460000151
IR。
In certain embodiments, a method of preparing a particle comprising metformin or a pharmaceutically acceptable salt thereof comprises: fluid bed granulation was used.
In certain embodiments, illustrative examples of methods that can be used in the present disclosure for preparing granules comprising metformin or a pharmaceutically acceptable salt thereof include, but are not limited to, wet granulation and dry granulation.
In certain embodiments, examples of wet granulation that can be used in the present disclosure include, but are not limited to, fluid bed granulation, wet granulator granulation, and manual wet granulation.
In certain embodiments, illustrative examples of dry granulation that can be used in the present disclosure include, but are not limited to, dry granulator granulation.
In yet another aspect, the present disclosure relates to a gastric retention tablet prepared by a method comprising the steps of preparing a core comprising a first active pharmaceutical ingredient and an expansion agent; and
coating the tablet core with a sustained release layer to obtain the gastric retention tablet,
wherein the extended release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 8 kp.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 6 kp.
In certain embodiments, the methods of the present disclosure comprise applying a first coating after applying the extended release layer coating, thereby obtaining a tablet having a first coating layer.
In certain embodiments, the first coating layer of the present disclosure comprises a water soluble polymer.
In certain embodiments, the first coating layer of the present disclosure contains a second active pharmaceutical ingredient.
In certain embodiments, the gastric retentive tablets of the present disclosure comprise a second coating following the slow release coating to provide tablets having a second coating layer.
In certain embodiments, the second coating layer of the present disclosure comprises a water soluble polymer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a single layer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a bilayer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a trilayer.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a single compartment.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a dual chamber.
In certain embodiments, the core of the gastric retention tablet of the present disclosure is a triple chamber.
In certain embodiments, the gastric retention tablets of the present disclosure are capable of rising in aqueous media within 10 minutes.
In certain embodiments, the gastric retention tablets of the present disclosure are capable of immediate floating in aqueous media.
In certain embodiments, the gastric retention sheets of the present disclosure have a minor dimension of no greater than about 9mm and a thickness of no greater than the minor dimension.
In certain embodiments, the gastric retentive tablets of the present disclosure have a tablet weight of no greater than about 800 mg.
In certain embodiments, the gastric retention sheets of the present disclosure have a minor diameter of no less than about 11mm after swelling in aqueous media.
In certain embodiments, the extended release layer coating has good tonicity after the gastric retention tablet of the present disclosure is expanded in an aqueous medium.
In yet another aspect, the present disclosure relates to a method of improving compliance in a subject comprising administering to said subject in need thereof a gastric retentive tablet, wherein the gastric retentive tablet comprises a core and a sustained release layer, wherein the core comprises a first active pharmaceutical ingredient, the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof comprises 70% or more by weight of the core.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 8 kp.
In certain embodiments, the core hardness of the gastric retention tablets of the present disclosure is about 3 to 6 kp.
In certain embodiments, the gastric retention tablets of the present disclosure comprise a first coating layer outside the sustained release layer.
In certain embodiments, the first coating layer of the present disclosure comprises a water soluble polymer.
In certain embodiments, the first coating layer of the present disclosure contains a second active pharmaceutical ingredient.
In certain embodiments, the gastric retention tablets of the present disclosure comprise a second coating layer outside the sustained release layer.
In certain embodiments, the second coating layer of the present disclosure comprises a water soluble polymer.
In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, mammals.
In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.
In certain embodiments, the mammal is a human.
Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand various aspects of the present application and advantages thereof. It should be understood, however, that the following examples are not limiting and are merely illustrative of certain embodiments of the present disclosure.
Examples
The reagents and equipment used in the examples of the present disclosure are conventional and commercially available. For example:
TABLE 1 sources of raw and auxiliary materials
Figure BDA0002873612460000171
Figure BDA0002873612460000181
TABLE 2 main experimental instruments and equipment
Figure BDA0002873612460000182
Figure BDA0002873612460000191
Example 1
500mg metformin hydrochloride sustained release tablet
(1) Granulating
Weighing polyvinyl acetate (PVA) with the prescription amount, preparing a 4% solution by using purified water, weighing metformin hydrochloride with a 30-mesh sieve, adding colloidal silicon dioxide and carboxymethyl starch sodium with the prescription amount into a fluidized bed, preparing metformin hydrochloride particles by adopting a top spray granulation mode, and controlling the material temperature of the fluidized bed at 35-45 ℃.
(2) Mixing and tabletting
Mixing the prepared metformin hydrochloride particles with the colloidal silicon dioxide according to the prescription amount for 40 turns, adding the crospovidone according to the prescription amount, mixing for 100 minutes, finally adding the glyceryl behenate according to the prescription amount, lubricating for 50 turns, and tabletting. The prescription is shown in table 3.
(3) Sustained release layer coating
Weighing the sustained-release layer auxiliary materials, dispersing or dissolving the sustained-release layer auxiliary materials into pure water, and stirring the mixture until the mixture is uniform to be used as sustained-release layer coating liquid. In the process of coating the slow release layer, the temperature of the materials is controlled to be 30-45 ℃, and the weight of the coating is increased by 5-15%.
TABLE 3 metformin hydrochloride sustained release tablet formulation
Figure BDA0002873612460000192
Figure BDA0002873612460000201
Example 2
500mg metformin hydrochloride sustained release tablet
(1) Granulating
Weighing polyvinyl acetate (PVA) with the prescription amount, preparing a 4% solution by using purified water, weighing metformin hydrochloride with a 30-mesh sieve, adding colloidal silicon dioxide and carboxymethyl starch sodium with the prescription amount into a fluidized bed, preparing metformin hydrochloride particles by adopting a top spray granulation mode, and controlling the material temperature of the fluidized bed at 35-45 ℃.
(2) Mixing and tabletting
Mixing the prepared metformin hydrochloride particles with the colloidal silicon dioxide according to the prescription amount for 40 turns, adding the crospovidone according to the prescription amount, mixing for 100 minutes, finally adding the glyceryl behenate according to the prescription amount, lubricating for 50 turns, and tabletting, wherein the tabletting hardness is 3-5 kp. The prescription is shown in table 4.
(3) Sustained release layer coating
Weighing the sustained-release layer auxiliary materials, dispersing or dissolving the sustained-release layer auxiliary materials into pure water, and stirring the mixture until the mixture is uniform to be used as sustained-release layer coating liquid. In the process of coating the slow release layer, the temperature of the materials is controlled to be 30-45 ℃, and the weight of the coating is increased by 5-15%.
TABLE 4 metformin hydrochloride sustained release tablet formulation
Figure BDA0002873612460000211
Example 3
500mg metformin hydrochloride sustained release tablet
(1) Granulating
Weighing polyvinyl acetate (PVA) with the prescription amount, preparing a 4% solution by using purified water, weighing metformin hydrochloride with a 30-mesh sieve, adding colloidal silicon dioxide and carboxymethyl starch sodium with the prescription amount into a fluidized bed, preparing metformin hydrochloride particles by adopting a top spray granulation mode, and controlling the material temperature of the fluidized bed at 35-45 ℃.
(2) Mixing and tabletting
Mixing the prepared metformin hydrochloride particles with the colloidal silicon dioxide according to the prescription amount for 40 turns, adding the crospovidone according to the prescription amount, mixing for 100 minutes, finally adding the glyceryl behenate according to the prescription amount, lubricating for 50 turns, tabletting, and the tabletting hardness is 5-8 kp. The prescription is shown in Table 5.
(3) Sustained release layer coating
Weighing the sustained-release layer auxiliary materials, dispersing or dissolving the sustained-release layer auxiliary materials into pure water, and stirring the mixture until the mixture is uniform to be used as sustained-release layer coating liquid. In the process of coating the slow release layer, the temperature of the materials is controlled to be 30-45 ℃, and the weight of the coating is increased by 5-15%.
TABLE 5 metformin hydrochloride sustained release tablet formulation
Figure BDA0002873612460000221
Example 4
500mg metformin hydrochloride sustained release tablet
(1) Granulating
Weighing polyvinyl acetate (PVA) with the prescription amount, preparing a 4% solution by using purified water, weighing metformin hydrochloride with a 30-mesh sieve, adding colloidal silicon dioxide and carboxymethyl starch sodium with the prescription amount into a fluidized bed, preparing metformin hydrochloride particles by adopting a top spray granulation mode, and controlling the material temperature of the fluidized bed at 35-45 ℃.
(2) Mixing and tabletting
Mixing the prepared metformin hydrochloride particles with the colloidal silicon dioxide of the prescription amount for 40 turns, adding the crospovidone of the prescription amount, mixing for 100 minutes, finally adding the glyceryl behenate of the prescription amount, lubricating for 50 turns, tabletting, and the tabletting hardness is 8-12 kp. The prescription is shown in table 6.
(3) Sustained release layer coating
Weighing the sustained-release layer auxiliary materials, dispersing or dissolving the sustained-release layer auxiliary materials into pure water, and stirring the mixture until the mixture is uniform to be used as sustained-release layer coating liquid. In the process of coating the slow release layer, the temperature of the materials is controlled to be 30-45 ℃, and the weight of the coating is increased by 5-15%.
TABLE 6 metformin hydrochloride sustained-release tablet formulation
Figure BDA0002873612460000231
Figure BDA0002873612460000241
Example 5
Determination of release degree of metformin hydrochloride sustained-release tablets
A sample to be tested:
examples 2 to 4 the metformin hydrochloride sustained-release tablets prepared in the above examples;
example 2 samples 3 replicates were set up;
example 3 samples 6 replicates were set up;
example 4 samples 3 replicates were set up.
The release test is carried out by a Sotax dissolution instrument and an Shimadzu ultraviolet spectrophotometer.
And (3) measuring the release degree:
referring to the FDA, United states Pharmacopeia and Chinese Pharmacopeia, the method for detecting the release rate of the metformin hydrochloride sustained release tablet and the technical guidance principle of the dissolution rate test of the common oral solid preparation, the method for determining the release rate of the sample is established: the rotation speed is 200rpm, the water bath temperature is (37.0 +/-0.5) DEG C, the dissolution medium is hydrochloric acid solution with the pH value of 1.2, and the volume of the medium is 1000 mL.
The preparation method of the hydrochloric acid solution with the pH value of the dissolution medium of 1.2 comprises the following steps: weighing 53.55mL of concentrated hydrochloric acid, adding water to dilute to 7000mL, and mixing uniformly to obtain a hydrochloric acid solution with the pH of 1.2.
Placing a sample to be tested in a rotary basket of a dissolution instrument, sampling 9mL in 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h and 16h respectively, filtering by using a 0.45 mu m microporous filter membrane, and taking filtrate and measuring the absorbance by using an ultraviolet spectrophotometer. The cumulative release of metformin hydrochloride at different release times was calculated as shown in tables 7 to 9, respectively.
Table 7 release rate results for metformin sustained release tablets of example 2
Figure BDA0002873612460000242
Figure BDA0002873612460000251
Table 8 metformin extended release tablet release profile results of example 3
Figure BDA0002873612460000252
Table 9 metformin extended release tablet release profile results of example 4
Figure BDA0002873612460000253
Figure BDA0002873612460000261
Example 6
Method for measuring bleaching time of metformin hydrochloride sustained-release tablets
A sample to be tested:
examples 2 to 4 the metformin hydrochloride sustained-release tablets prepared in the above examples;
example 2 samples 3 replicates were set up;
example 3 samples 6 replicates were set up;
example 4 samples 3 replicates were set up.
The measurement conditions were as follows:
the conditions for determining the release rate of the metformin hydrochloride sustained-release tablets in example 5 are as follows: the rotation speed is 200rpm, the water bath temperature is (37.0 +/-0.5) DEG C, the dissolution medium is hydrochloric acid solution with the pH value of 1.2, and the volume of the medium is 1000 mL.
The preparation method of the hydrochloric acid solution with the pH value of the dissolution medium of 1.2 comprises the following steps: weighing 53.55mL of concentrated hydrochloric acid, adding water to dilute to 7000mL, and mixing uniformly to obtain a hydrochloric acid solution with the pH of 1.2.
The sample to be tested was placed in a rotary basket of a dissolution apparatus, and the time required from the introduction to the rinsing of the metformin hydrochloride sustained-release tablet was observed and recorded as shown in table 10.
TABLE 10 measurement results of rising time of metformin sustained-release tablets of examples 2 to 4
Rise time/min Example 2 Example 3 Example 4
Sample 1 0 (instant floating) 0 (instant floating) 60-90
Sample 2 0 (instant floating) 0 (instant floating) 60-90
Sample 3 1.5 0 (instant floating) 60-90
Sample No. 4 NA Less than 1 NA
Sample No. 5 NA 1 NA
Sample No. 6 NA 14 NA
Example 7
Hardness determination of metformin hydrochloride sustained-release tablets
A sample to be tested:
examples 2 to 4 the metformin hydrochloride sustained-release tablets prepared in the above examples;
example 2 samples 5 replicates were set up;
example 3 samples 5 replicates were set up;
example 4 samples 5 replicates were set up.
And (3) hardness measurement:
the sample to be measured was placed between two pressing plates of a hardness tester, pressed in the diameter direction of the tablet, and the pressure required for crushing was measured, and the results are shown in table 11.
Table 11 hardness measurement results of metformin sustained-release tablets of examples 2 to 4
Hardness per kp Example 2 Example 3 Example 4
Sample 1 5.25 6.96 11.43
Sample 2 5.22 7.39 10.98
Sample 3 3.59 7.52 11.63
Sample No. 4 3.27 4.96 11.12
Sample No. 5 3.51 6.13 9.5
Mean value of 4.168 6.592 10.932
RSD％ 23.54 16.11 7.69
In the present disclosure, 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.
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure. Such variations and modifications are intended to fall within the scope of the appended claims of this disclosure.

Claims (10)

1. A gastric retentive tablet comprising a core and a sustained release layer, wherein the core comprises a first active pharmaceutical ingredient and the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
2. The gastric retention tablet of claim 1 wherein the hardness of the core is 3 to 8 kp.
3. Gastric retention tablet according to claim 1 or 2, wherein the core comprises a bulking agent, preferably the bulking agent is selected from the group consisting of crospovidone, sodium carboxymethyl starch, pregelatinized starch, croscarmellose sodium, croscarmellose calcium, low substituted hydroxypropyl cellulose and mixtures thereof.
4. The gastric retention tablet according to any one of claims 1 to 3, wherein the gastric retention tablet comprises a first coating layer outside the sustained release layer, preferably the first coating layer comprises a water soluble polymer, preferably the water soluble polymer is selected from hypromellose, polyvinyl alcohol-polyethylene glycol graft polymer, a mixture comprising polyethylene glycol and polyvinyl alcohol and mixtures thereof, more preferably a mixture comprising polyethylene glycol and polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft polymer and mixtures thereof.
5. The gastric retentive tablet of claim 4, wherein the first coating layer contains a second active pharmaceutical ingredient, preferably the second active pharmaceutical ingredient is selected from the group consisting of dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT-2) inhibitors, sulfonylurea drugs (sulfonyurea), non-sulfonylurea drugs (non-sulfonyurea), alpha-glucosidase inhibitors (glucosidase inhibitor), insulin sensitizers (insulin sensitizers), and mixtures thereof.
6. A method of making a gastric retention tablet comprising:
preparing a core comprising a first active pharmaceutical ingredient and a bulking agent; and
coating the tablet core with a sustained release layer to obtain the gastric retention tablet,
wherein the extended release layer comprises a mixture comprising polyvinyl acetate and povidone, the first active pharmaceutical ingredient is metformin or a pharmaceutically acceptable salt thereof, and the metformin or a pharmaceutically acceptable salt thereof accounts for 70% by weight or more of the core.
7. The method of claim 6, further comprising performing a first coating after performing the slow release coating, thereby obtaining a first coating layer, preferably the first coating layer comprises a second active pharmaceutical ingredient, more preferably the second active pharmaceutical ingredient is selected from the group consisting of dipeptidyl peptidase-4 (DPP-4) inhibitor, sodium-glucose co-transporter 2(sodium/glucose transporter 2, SGLT-2) inhibitor, sulfonylurea drug (sulfonylurea), non-sulfonylurea drug (non-sulfonylurea), alpha-glucosidase inhibitor (glucosidase inhibitor), insulin sensitizer (insulin sensitizer), and a mixture thereof.
8. The method according to claim 6 or 7, wherein the sustained release layer comprises a mixture comprising polyvinyl acetate and povidone, a polymer of ethyl acrylate and methyl methacrylate monomers, or a mixture comprising a mixture of polyvinyl acetate and povidone and a polymer of ethyl acrylate and methyl methacrylate monomers, preferably a mixture comprising polyvinyl acetate and povidone, a polymer of ethyl acrylate and methyl methacrylate monomers, or a mixture thereof.
9. A gastric retention tablet prepared by the method of any one of claims 6 to 8.
10. The gastric retention tablet of claim 9 wherein the tablet core hardness of the gastric retention tablet is 3 to 8 kp.
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