CN113116845B

CN113116845B - Gastric retention tablet

Info

Publication number: CN113116845B
Application number: CN202011613561.0A
Authority: CN
Inventors: 李伟; 潘阳; 童伟勤
Original assignee: Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
Current assignee: Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
Priority date: 2019-12-31
Filing date: 2020-12-30
Publication date: 2024-03-19
Anticipated expiration: 2040-12-30
Also published as: CN113116850A; CN113116846A; CN113116847A; CN113116844A; WO2021136494A1; CN113116841A; CN113116845A; CN113116839A; CN113116847B; WO2021136492A1; CN113116839B; CN113116842A; CN113116846B; CN113116851A; CN113116850B

Abstract

Disclosed is a gastroretentive tablet comprising a tablet core, a sustained release layer and a first coating layer, wherein the tablet core contains a first active pharmaceutical ingredient and a swelling agent, the first coating layer is outside the sustained release layer and contains a second active pharmaceutical ingredient, the sustained release layer contains a polymer comprising a mixture of polyvinyl acetate and povidone and a polymer of ethyl acrylate and methyl methacrylate monomers, wherein the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture of polyvinyl acetate and povidone is 1:4 to 1:8, the first active pharmaceutical ingredient is metformin hydrochloride, and the second active pharmaceutical ingredient is sitagliptin.

Description

Gastric 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

The gastric retention drug release system is a drug delivery system which uses the physiological characteristics of local pH value of gastrointestinal tract, gastrointestinal enzymes, transport mechanism of the preparation in the gastrointestinal tract and the like to prolong the retention time of the drug in the stomach by changing the physical and chemical properties of the preparation.

SUMMARY

In one aspect, the present disclosure relates to a gastroretentive tablet comprising a tablet core, a sustained release layer and a first coating layer, wherein the tablet core contains a first active pharmaceutical ingredient and a bulking agent, the first coating layer is outside the sustained release layer and contains a second active pharmaceutical ingredient, the sustained release layer contains a polymer comprising a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers, wherein the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture of polyvinyl acetate and povidone is 1:4 to 1:8, the first active pharmaceutical ingredient is metformin hydrochloride, and the second active pharmaceutical ingredient is sitagliptin.

In another aspect, the present disclosure is directed to a method of making a gastroretentive tablet, comprising preparing a tablet core comprising a first pharmaceutically active ingredient and a bulking agent; coating the tablet core with a slow release layer; and a first coating is performed after the coating of the slow release layer, thereby obtaining the gastric retentive tablet, wherein the first coating contains a second active pharmaceutical ingredient, wherein the slow release layer contains a polymer comprising a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers, wherein the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture of polyvinyl acetate and povidone is about 1:4 to 1:8, the first active pharmaceutical ingredient is metformin hydrochloride, and the second active pharmaceutical ingredient is sitagliptin.

In yet another aspect, the present disclosure relates to a gastric retentive tablet made by a process comprising the steps of preparing a tablet core comprising a first pharmaceutically active ingredient and a bulking agent; coating the tablet core with a slow release layer; and a first coating is performed after the coating of the slow release layer, thereby obtaining the gastric retentive tablet, wherein the first coating contains a second active pharmaceutical ingredient, wherein the slow release layer contains a polymer containing a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers, the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture containing polyvinyl acetate and povidone is about 1:4 to 1:8, the first active pharmaceutical ingredient is metformin hydrochloride, and the second active pharmaceutical ingredient is sitagliptin.

In yet another aspect, the present disclosure is directed to a method of improving compliance in an individual comprising administering to the individual in need of the method a gastroretentive tablet, wherein the gastroretentive tablet comprises a tablet core, a slow release layer and a first coating layer, wherein the tablet core contains a first active pharmaceutical ingredient and a bulking agent, the first coating layer is outside the slow release layer and contains a second active pharmaceutical ingredient, the slow release layer contains a polymer comprising a mixture of polyvinyl acetate and povidone and a polymer of ethyl acrylate and methyl methacrylate monomers in a weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture comprising polyvinyl acetate and povidone of about 1:4 to 1:8, the first active pharmaceutical ingredient is metformin hydrochloride, and the second active pharmaceutical ingredient is sitagliptin.

Brief description of the drawings

Fig. 1 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 1 of the present disclosure.

Fig. 2 shows an electron micrograph of the smoothness of the metformin hydrochloride sustained-release tablet of example 1 of the present disclosure.

Fig. 3 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 2 of the present disclosure.

Fig. 4 shows an electron micrograph of the smoothness of the metformin hydrochloride sustained release tablet of example 2 of the present disclosure.

Fig. 5 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 3 of the present disclosure.

Fig. 6 shows an electron micrograph of the smoothness of metformin hydrochloride sustained release tablets of example 3 of the present disclosure.

Fig. 7 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 4 of the present disclosure.

Fig. 8 shows an electron micrograph of the smoothness of metformin hydrochloride sustained release tablets of example 4 of the present disclosure.

Fig. 9 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 5 of the present disclosure.

Fig. 10 shows an electron micrograph of the smoothness of the metformin hydrochloride sustained release tablet of example 5 of the present disclosure.

Fig. 11 shows an electron micrograph of metformin hydrochloride sustained release tablet at the corner of example 6 of the present disclosure.

Fig. 12 shows an electron micrograph of the smoothness of the metformin hydrochloride sustained release tablet of example 6 of the present disclosure.

Fig. 13 shows an electron micrograph of sitagliptin hydrochloride metformin hydrochloride sustained release tablet at the corner of example 7 of the present disclosure.

Fig. 14 shows an electron micrograph of the smooth portion of the sitagliptin hydrochloride metformin sustained-release tablet of example 7 of the present disclosure.

Fig. 15 shows an electron micrograph of the edge of the sustained release tablet of engagliflozin hydrochloride, metformin hydrochloride of example 8 of the present disclosure.

Fig. 16 shows an electron micrograph of the smoothness of the engagliflozin hydrochloride metformin sustained-release tablet of example 8 of the present disclosure.

Fig. 17 shows an electron micrograph of acyclovir sustained-release tablets at the corner of example 9 of the present disclosure.

Fig. 18 shows an electron micrograph of the smoothing of acyclovir sustained release tablets of example 9 of the present disclosure.

Fig. 19 shows an electron micrograph of pregabalin sustained release tablet at the corner of example 10 of the present disclosure.

Fig. 20 shows an electron micrograph of the smoothing of pregabalin sustained release tablets of example 10 of the present disclosure.

Fig. 21 shows cumulative release curves of metformin hydrochloride sustained release tablets of examples 1 to 6 of the present disclosure.

Detailed description of the preferred embodiments

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 may be practiced without one or more of the specific details, or with other methods, components, materials, etc.

Throughout the specification and the claims which follow, unless the context requires otherwise, the words "comprise", "comprising", "includes" and "having" are to be construed in an open-ended, inclusive sense, i.e. "including but not limited to.

Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in some embodiments" means that a particular reference element, structure, or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

Definition of the definition

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 or organic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene carboxylic acid, 4-acetamidobenzene carboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexaneaminosulfonic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, 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, glutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, tartaric acid, sulfuric acid, sulfanilic acid, succinic acid, toluenesulfonic acid, tricarboxylic 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 appropriate. 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, cyclic amines, and salts of 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, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, 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 (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 adjuvant that absorbs moisture and undergoes volume expansion when placed in an aqueous environment.

In the present disclosure, the term "porogen" refers to a water-soluble auxiliary material dispersed in a polymeric material of a slow-release coating film, which dissolves when the tablet is contacted with an aqueous liquid, rendering the slow-release coating film microporous and permeable.

In the present disclosure, the term "binder" refers to an adjuvant that sticks together the material, facilitating pelletization.

In the present disclosure, the term "glidant" refers to an auxiliary material that reduces friction between particles, thereby improving powder flowability.

In this disclosure, the term "opacifier" refers to a substance that can absorb, scatter, or reflect light.

In the present disclosure, the term "defoamer" refers to a substance capable of reducing the surface tension of water, solutions, suspensions, etc., preventing foam formation, or reducing or eliminating 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 "lubricant" refers to an auxiliary material 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 polymers, etc., and the plasticizer is distributed between macromolecular chains, so that intermolecular force can be reduced, viscosity of the polymers is reduced, and flexibility is enhanced.

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 gastroretentive formulation.

In this disclosure, the term "compliance" refers to an individual being treated as prescribed by a doctor, with behavior consistent with an order; otherwise, non-compliance.

In the present disclosure, the term "metformin (metformin)" refers to 1, 1-dimethylbiguanide.

In the present disclosure, the term "sitagliptin" refers to 7- [ (3R) -3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4,3-a ] pyrazine.

Detailed Description

In one aspect, the present disclosure is directed to a gastric retentive tablet comprising a tablet core and a sustained release layer, wherein the tablet core comprises a first active pharmaceutical ingredient and a bulking agent, the sustained release layer comprises a polymer comprising a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers, wherein the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture comprising polyvinyl acetate and povidone is about 1:4 to about 1:8.

In certain embodiments, the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture comprising polyvinyl acetate and povidone is about 1:4.

In certain embodiments, the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture comprising polyvinyl acetate and povidone is about 1:6.

In certain embodiments, the weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture comprising polyvinyl acetate and povidone is about 1:8.

In certain embodiments, illustrative examples of polymers of ethyl acrylate and methyl methacrylate monomers that can be used in the present disclosure include, but are not limited to

In certain embodiments, can be used in the present disclosureIllustrative examples of (a) include, but are not limited toNE 30D、RL 100、RL PO、RL 30D、RS 100、RS PO、RS30D and->NM 30D。

In some embodiments of the present invention, in some embodiments, illustrative examples of first pharmaceutically active ingredients that can be used in the present disclosure include, but are not limited to, levodopa, methodiazepine hydrochloride, diazepam, furbenidic acid, captopril, metoprolol succinate, rosiglitazone maleate, verapamil, atenolol, losartan, pentoxifylline, nimodipine, cinnarizine, diltiazem, pyrroltanib, isosorbide nitrate, sotalol, propranolol, celecoxib hydrochloride, cholestyramine, nifedipine, dipyridamole, quinidine gluconate, lovastatin, trimetazidine hydrochloride, nicardipine, isosorbide mononitrate, metronidazole, clarithromycin nitrofurantoin, ofloxacin, cefalexin, zidovudine, ciprofloxacin, griseofulvin, ampicillin, ketoprofen, ibuprofen, piroxicam, flurbiprofen, indomethacin, sodium diclofenac, chlorpheniramine maleate, theophylline, fluorouracil, riboflavin-5' -sodium phosphate, misoprostol, ursodeoxycholic acid, tauroursodeoxycholic acid, pepstatin, tranilast, terfenadine, orlistat, albendazole, prednisone, loratadine, carbidopa and levodopa, levodopa and benserazide, pregabalin, metformin hydrochloride, amoxicillin, acyclovir and gabapentin.

In certain embodiments, illustrative examples of first pharmaceutically active ingredients that can be used in the present disclosure include, but are not limited to, carbidopa and levodopa, levodopa and benserazide, pregabalin, metformin hydrochloride, amoxicillin, acyclovir, and gabapentin.

In certain embodiments, the first pharmaceutically active ingredient of the present disclosure is metformin hydrochloride.

In certain embodiments, illustrative examples of bulking agents that can be used in the present disclosure include, but are not limited to, crospovidone, sodium carboxymethyl starch, pregelatinized starch, croscarmellose sodium, croscarmellose calcium, and low substituted hydroxypropylcellulose.

In certain embodiments, the slow release layer 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 that can be used in the present disclosure as porogens include, but are not limited to, sodium alginate, hypromellose, hydroxypropyl cellulose, povidone, polyethylene glycol, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol graft 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, hypromellose, hydroxypropyl cellulose, povidone, and polyethylene glycol.

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 having a 2% solution viscosity of 3 mpa-s or more and 50 mpa-s or less at about 20 ℃, hydroxypropyl cellulose having a 2% solution viscosity of 75 mpa-s or more and 3,000 mpa-s or less at about 20 ℃, povidone K12, povidone K17, povidone K25, povidone K30, povidone K90, polyethylene glycols having a molecular weight of 1,000 or more and 20,000 or less, and polyvinyl alcohol-polyethylene glycol graft polymers.

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 Methocel ^TM E3、Methocel ^TM E5、Methocel ^TM E6、Benecel ^TM E3、Benecel ^TM E5、Benecel ^TM E6 and E6IR。

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 core of the present disclosure include, but are not limited to, colloidal silicon dioxide, polyethylene glycol, magnesium stearate, stearic acid, talc, and starch.

In certain embodiments, the sustained release layer of the present disclosure comprises an opacifying 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 a mixture of dimethicone and silica.

In certain embodiments, the sustained 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, acacia, xanthan gum, gelatin, propylene glycol monostearate, glycerol monostearate, vinyl distearate, diglycerol 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, cetyl methyl naphthol, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkylphenol, and polyoxyethylene nonylphenol ether.

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 acid esters, phosphoric acid 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), diazo diacid (2-ethylhexyl ester) (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), tri (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 butyl fatty acid ester (EBSt), octyl oleate epoxide, and di (2-ethylhexyl) 4, 5-Epoxytetrahydrophthalate (EPS).

In certain embodiments, polyethylene glycols (PEG) capable of use in the present disclosure have a relative molecular weight of at least about 4,000.

In certain embodiments, polyethylene glycols (PEG) capable of use in the present disclosure have a relative molecular weight of at least about 6,000.

In certain embodiments, polyethylene glycols (PEG) capable of use in the present disclosure have a relative molecular weight of at least about 8,000.

In certain embodiments, illustrative examples of polyethylene glycols (PEG) that can be used in the present disclosure include, but are not limited to4000、6000、8000、4000、6000、8000、E4000、E6000 and->E 8000。

In certain embodiments, the tablet cores of the present disclosure comprise an adhesive.

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 carboxymethyl cellulose, starch paddles, povidone, copovidone, sucrose solutions, hypromellose, hydroxypropyl cellulose, methyl hydroxyethyl cellulose, methyl cellulose, maltodextrin, starch, sodium carboxymethyl starch, pregelatinized starch, hydroxypropyl cellulose, sodium carboxymethyl starch, gelatin, acacia, guar gum, locust bean gum, tamarind gum, sesbania gum, flaxseed gum, honey locust gum, pectin, abelmoschus manihot gum, carrageenan, agar, sodium alginate, potassium alginate, gelatin, chitin, xanthan gum, beta-cyclodextrin, polydextrose, gellan gum, and acrylic resins.

In certain embodiments, the gastric-retentive tablets of the present disclosure comprise a first coating layer outside the slow-release layer.

In certain embodiments, the first coating layer of the present disclosure 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, a mixture comprising polyethylene glycol and polyvinyl alcohol, sodium alginate, hypromellose, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol graft 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, a mixture comprising polyethylene glycol and polyvinyl alcohol, and a polyvinyl alcohol-polyethylene glycol graft polymer.

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 toII。

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 toIR。

In certain embodiments, the first coating layer of the present disclosure comprises 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 (dipeptidyle peptidase-4, dpp-4) inhibitors, sodium-glucose co-transporter 2 (sodium/glucose cotranspoter 2, sglt-2) inhibitors, sulfonylurea drugs (sulfonylurea), non-sulfonylurea drugs (non-sulfonylurea), alpha-glucosidase inhibitors (glucosidase inhibitor), and insulin sensitizers (insulin sensitizer).

In certain embodiments, illustrative examples of dipeptidyl peptidase-4 (dipeptidyle 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), gemigliptin (gemigliptin), and telagliptin.

In certain embodiments, illustrative examples of sodium-glucose co-transporter 2 (sodium/glucose cotranspoter, sglt-2) inhibitors that can be used in the present disclosure include, but are not limited to, tolagliflozin (tofogliflozin), engagliflozin (empagliflozin), elagliflozin L-proline (ipraggliflozin L-relin), lu Gelie (lucogliflozin), dapagliflozin propylene glycol (dapagliflozin propanediol), canagliflozin (canagliflozin), and elgliflozin (ertugliflozin).

In certain embodiments, illustrative examples of sulfonylureas(s) that can be used in the present disclosure include, but are not limited to: glipizide (glipizide), gliclazide (gliclazide), glibenclamide (glibenclamide), 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 alpha-glucosidase inhibitors (glucosidase inhibitor) 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 sensitizer) that can be used in the present disclosure include, but are not limited to, rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone).

In certain embodiments, the second active pharmaceutical ingredient is sitagliptin.

In certain embodiments, the gastric-retentive tablets of the present disclosure comprise a second coating layer outside the slow-release layer.

In certain embodiments, the second coating layer of the present disclosure comprises a water-soluble polymer.

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, a gastric-retentive tablet of the present disclosure comprises a first coating layer outside the slow-release layer and a second coating layer outside the first coating layer.

In certain embodiments, the core of the gastroretentive 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, dextrose, sucrose, xylitol, mannitol, sorbitol, maltodextrin, sugar powders, dextrins, microcrystalline cellulose, inorganic salts, mannitol, and starch.

In certain embodiments, the core of the gastroretentive sheet of the present disclosure further comprises a glidant.

In certain embodiments, illustrative examples of glidants that can be used in the tablet core of the present disclosure include, but are not limited to, colloidal silicon dioxide, PEG, magnesium stearate, stearic acid, talc, and starch.

In certain embodiments, the core of the gastroretentive sheet of the present disclosure further comprises a binder.

In certain embodiments, the core of the gastroretentive tablet of the present disclosure further comprises a lubricant.

In certain embodiments, illustrative examples of lubricants that can be used in the tablet cores of the present disclosure include, but are not limited to, glyceryl behenate, fatty acids and metal soaps thereof, esters, hydrogenated vegetable oils, polyethylene glycols, and magnesium lauryl sulfate.

In certain embodiments, illustrative examples of fatty acids and metal soaps thereof 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 retentive sheet of this disclosure is a single layer.

In certain embodiments, the core of the gastric retentive sheet of the present disclosure is bilayer.

In certain embodiments, the core of the gastric retentive sheet of the present disclosure is three layers.

In certain embodiments, the core of the gastric retentive sheet of the present disclosure is a single chamber.

In certain embodiments, the core of the gastric retentive sheet of this disclosure is a dual chamber.

In certain embodiments, the core of the gastric retentive sheet of this disclosure is three-compartment.

In certain embodiments, the gastric retentive sheet of the present disclosure has a core hardness of about 5 to 15kp.

In certain embodiments, the gastric-retentive sheet of the present disclosure is capable of bleaching in an aqueous medium within 10 minutes.

In certain embodiments, the gastric-retentive sheet of the present disclosure is capable of immediate bleaching in an aqueous medium.

In certain embodiments, the gastric retentive sheet of the present disclosure has a minor diameter of no greater than about 9mm and a thickness of no greater than the minor diameter.

In certain embodiments, the gastric-retentive sheet of the present disclosure has a sheet weight of no greater than about 800mg.

In certain embodiments, the gastric-retentive sheet of the present disclosure has a minor diameter of not less than about 11mm after swelling in an aqueous medium.

In certain embodiments, the delayed release layer coating has good tonicity after swelling of the gastroretentive tablet of the present disclosure in an aqueous medium.

In another aspect, the present disclosure is directed to a method of making a gastric retentive sheet comprising

Preparing a tablet core comprising a first pharmaceutically active ingredient and a bulking agent; and

coating the tablet core with a slow release layer to obtain the gastric retention tablet,

wherein the sustained release layer comprises a polymer comprising a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers in a weight ratio of about 1:4 to about 1:8.

In certain embodiments, the methods of preparing a gastroretentive tablet described in the present disclosure further comprise performing a first coating after performing the slow release layer coating, thereby obtaining a tablet having a first coating layer, wherein the first coating layer comprises 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 (dipeptidyle peptidase-4, dpp-4) inhibitors, sodium-glucose co-transporter 2 (sodium/glucose cotransporter 2, sglt-2) inhibitors, sulfonylurea drugs (sulfonylurea), non-sulfonylurea drugs (non-sulfonylurea), alpha-glucosidase inhibitors (glucosidase inhibitor), insulin sensitizers (insulin sensitizer).

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 II。

In certain embodiments, illustrative examples of bulking agents that can be used in the present disclosure include, but are not limited to, sodium carboxymethyl starch, pregelatinized starch, croscarmellose sodium, croscarmellose calcium, and low substituted hydroxypropyl cellulose.

In certain embodiments, illustrative examples of methods that can be used in the present disclosure to prepare 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 retentive tablet made by a process comprising the steps of preparing a tablet core comprising a first pharmaceutically active ingredient and a bulking agent; and

In certain embodiments, the methods of the present disclosure include a first coating after a slow release coating is performed, thereby having a tablet that results in a first coating layer.

In certain embodiments, the first coating layer of the present disclosure contains a second active pharmaceutical ingredient.

In certain embodiments, the gastroretentive tablet of the present disclosure comprises a second coating after the slow release coating is performed, thereby resulting in a tablet having a second coating layer.

In yet another aspect, the present disclosure is directed to a method of improving compliance in an individual comprising administering to the individual in need of the method a gastric-retentive tablet, wherein the gastric-retentive tablet comprises a tablet core and a sustained release layer, wherein the tablet core comprises a first active pharmaceutical ingredient and a bulking agent, the sustained release layer comprises a polymer comprising a mixture of polyvinyl acetate and povidone and ethyl acrylate and methyl methacrylate monomers in a weight ratio of the polymer of ethyl acrylate and methyl methacrylate monomers to the mixture of polyvinyl acetate and povidone of about 1:4 to 1:8.

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, cattle, 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 the aspects of the present application and the advantages thereof. However, it should be understood that the following examples are non-limiting and are merely illustrative of certain embodiments of the present disclosure.

Examples

Reagents and equipment used in the examples of the present disclosure were all conventional and commercially available. For example:

TABLE 1 sources of raw and auxiliary materials

Table 2 main instrument and equipment for experiment

Example 1

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

Weighing prescription amount of polyvinyl acetate (polyvinyl acetate, PVA), preparing 4% solution by purified water, weighing metformin hydrochloride which is sieved by a 30-mesh sieve, adding prescription amount of colloidal silicon dioxide and carboxymethyl starch sodium into a fluidized bed, preparing metformin hydrochloride particles by adopting a top-spraying granulating mode, and controlling the temperature of the fluidized bed material at 35-45 ℃.

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The recipe is shown in Table 3.

(3) Sustained release coating

And (3) weighing the slow-release layer auxiliary materials, dispersing or dissolving the slow-release layer auxiliary materials into pure water, and stirring the mixture uniformly to obtain the slow-release layer coating liquid. In the coating process of 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

Example 2

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The recipe is shown in Table 4.

(3) Sustained release coating

Table 4 metformin hydrochloride sustained release tablet formulation

Example 3

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The recipe is shown in Table 5.

(3) Sustained release coating

Table 5 metformin hydrochloride sustained release tablet formulation

Example 4

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The prescription is shown in Table 6.

(3) Sustained release coating

Table 6 metformin hydrochloride sustained release tablet formulation

Example 5

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The recipe is shown in Table 7.

(3) Sustained release coating

Table 7 metformin hydrochloride sustained release tablet formulation

Example 6

Metformin hydrochloride sustained release tablet 500mg

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The prescription is shown in Table 8.

(3) Sustained release coating

Table 8 metformin hydrochloride sustained release tablet formulation

Example 7

50mg/500mg sitagliptin hydrochloride metformin sustained release tablet

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The recipe is shown in Table 9.

(3) Sustained release coating

(4) Sitagliptin coating medicine

And (3) weighing sitagliptin phosphate into pure water, stirring and dissolving the sitagliptin, and weighing PVA and PEG 3350, adding the PVA and the PEG 3350, and stirring for 1 hour. In the coating process, the temperature of the materials is controlled to be 30-40 ℃, and the weight of the coating is increased by 5-15%.

Table 9 sitagliptin hydrochloride metformin sustained release tablet prescription

Example 8

5mg/500mg Engliflozin hydrochloride metformin sustained-release tablet

(1) Granulating

(2) Mixing and tabletting

Mixing the prepared metformin hydrochloride particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The prescription is shown in Table 10.

(3) Sustained release coating

(4) Engliflozin coating medicine

And weighing the enggliflozin into pure water, stirring and dissolving the enggliflozin while adding the pure water, weighing Opadry 00F690002-CN coating powder, adding the Opadry 00F690002-CN coating powder, and stirring for 1 hour. In the coating process, the temperature of the materials is controlled to be 30-40 ℃, and the weight of the coating is increased by 5-15%.

Table 10 Engliflozin metformin hydrochloride sustained release tablet prescription

Example 9

400mg acyclovir sustained-release tablet

(1) Granulating

Weighing prescription amount of polyvinyl acetate (polyvinyl acetate, PVA), preparing 4% solution by purified water, weighing acyclovir which is sieved by a 30-mesh sieve, adding prescription amount of colloidal silicon dioxide and carboxymethyl starch sodium into a fluidized bed, preparing acyclovir particles by adopting a top-spraying granulating mode, and controlling the temperature of the fluidized bed material at 35-45 ℃.

(2) Mixing and tabletting

Mixing the prepared acyclovir particles with the prescribed amount of colloidal silicon dioxide for 40 turns, adding the prescribed amount of crospovidone, mixing for 100 minutes, finally adding the prescribed amount of glyceryl behenate, lubricating for 50 turns, and tabletting. The prescription is shown in Table 11.

(3) Sustained release coating

Table 11 acyclovir sustained release tablet formulation

Example 10

330mg pregabalin slow-release tablet

(1) Granulating

Weighing prescription amount of polyvinyl acetate (polyvinyl acetate, PVA), preparing 4% solution by purified water, weighing pregabalin passing through a 30-mesh sieve, adding prescription amount of colloidal silicon dioxide and carboxymethyl starch sodium into a fluidized bed, preparing pregabalin particles by adopting a top-spraying granulating mode, and controlling the temperature of the fluidized bed material at 35-45 ℃.

(2) Mixing and tabletting

And (3) mixing the prepared pregabalin granules with 40 turns of mannitol with a prescription amount, adding the crospovidone with the prescription amount, mixing for 100 minutes, finally adding the glyceryl behenate with the prescription amount, lubricating for 50 turns, and tabletting. The prescription is shown in Table 12.

(3) Sustained release coating

Table 12 Pregabalin sustained release tablet formulation

Example 11

Determination of swelling Property of sustained Release layer film

(1) Medium: 0.1N HCl solution, 900mL;

(2) Placing the sustained release tablets of examples 1-11 in the above medium, keeping the temperature at 37 ℃ and stirring at 100rpm for 16 hours to obtain an expanded sustained release tablet;

(3) Scanning electron microscopy was used to scan the corners and smooth portions of the sustained release tablets of each example as follows:

taking out the expanded sustained release tablet, absorbing the water on the surface of the sustained release tablet, and then coating (metal spraying) the sustained release tablet by an ion sputtering instrument, wherein the vacuum degree is less than 10pa, and the current is 15mA;

placing the coated sustained release tablet into a sample bin of a scanning electron microscope, closing the sample bin, and vacuumizing;

setting acceleration voltage, working distance and beam spot current, selecting proper magnification (parameters of each embodiment are shown in table 13), obtaining an image, and storing the image.

TABLE 13

Example 12

Determination of release degree of metformin hydrochloride sustained release tablet

Sample to be measured:

metformin hydrochloride sustained-release tablets prepared in examples 1 to 6;

Example 1 samples were set up in 6 replicates;

examples 2 to 6 samples were set up in 3 replicates.

The release degree experiment is measured by a Sotax dissolution instrument and an Shimadzu ultraviolet spectrophotometer.

Release degree measurement

Referring to the release degree detection methods of the metformin hydrochloride sustained-release tablets in FDA, U.S. pharmacopoeia and Chinese pharmacopoeia, the method for determining the release degree of the sample is established in the technical guidelines of the dissolution test of common oral solid preparations: the rotation speed is 200rpm, the water bath temperature (37.0+/-0.5) DEG C, the dissolution medium is hydrochloric acid solution with pH of 1.2, and the medium volume is 1000mL.

The preparation method of the hydrochloric acid solution with the pH of the dissolution medium of 1.2 comprises the following steps: and (5) weighing 53.55mL of concentrated hydrochloric acid, adding water to dilute to 7000mL, and uniformly mixing to obtain the hydrochloric acid solution with the pH of 1.2.

The sample to be measured is placed in a rotating basket of a dissolution instrument, 9mL is sampled at 1h,2h,4h,6h,8h,10h,12h,14h and 16h respectively, the sample is filtered by a microporous filter membrane with the thickness of 0.45 mu m, and the absorbance of the filtrate is measured by an ultraviolet spectrophotometer. The cumulative release of metformin hydrochloride at different release times was calculated separately as shown in tables 14 to 19.

TABLE 14 Release results of metformin sustained release tablets of example 1

Time/h	Sheet 1	Sheet 2	Sheet 3	Sheet 4	Sheet 5	Sheet 6	Average value of	RSD(％)
									0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
1	12.98	12.65	13.26	12.26	13.02	11.79	12.66	4.33
									2	29.09	27.67	28.68	27.36	29.20	26.06	28.01	4.33
4	53.05	51.25	53.83	52.01	53.41	50.28	52.31	2.62
									6	71.70	70.40	72.56	70.56	71.97	69.34	71.09	1.68
8	83.83	83.15	84.76	83.18	83.77	81.72	83.40	1.21
									10	90.81	90.61	91.58	90.59	90.70	89.39	90.61	0.78
12	94.26	94.84	95.15	94.48	94.24	93.35	94.39	0.65
									14	95.85	97.05	97.13	96.50	96.08	95.49	96.35	0.69
16	96.75	97.62	97.58	97.52	96.98	96.46	97.15	0.51

TABLE 15 Release results of metformin sustained release tablets of example 2

TABLE 16 Release results of metformin extended release tablets of example 3

Time/h	Sheet 1	Sheet 2	Sheet 3	Average value of	RSD(％)
						0	0.00	0.00	0.00	0.00	0.00
1	12.97	13.00	12.85	12.94	0.60
						2	24.62	24.75	26.14	25.17	3.34
4	48.51	48.53	49.67	48.91	1.36
						6	67.17	66.41	67.58	67.05	0.89
8	80.08	78.58	79.69	79.45	0.98
						10	87.89	86.08	86.93	86.97	1.04
12	92.69	90.67	91.52	91.63	1.11
						14	95.45	93.57	93.83	94.28	1.08
16	96.64	94.50	94.86	95.33	1.20

TABLE 17 Release results of metformin sustained release tablets of example 4

TABLE 18 Release results of metformin sustained release tablets of example 5

Time/h	Sheet 1	Sheet 2	Sheet 3	Average value of	RSD(％)
						0	0.00	0.00	0.00	0.00	0.00
1	10.40	9.64	10.33	10.12	4.17
						2	22.65	20.69	22.78	22.04	5.31
4	44.09	41.80	44.08	43.32	3.05
						6	62.72	60.60	62.76	62.03	1.99
8	75.67	73.83	75.62	75.04	1.39
						10	84.28	83.04	84.22	83.85	0.84
12	89.86	88.77	89.59	89.40	0.63
						14	93.21	92.42	92.99	92.87	0.44
16	95.04	94.54	94.69	94.76	0.27

TABLE 19 Release degree results of metformin sustained release tablet of example 6

In this disclosure, relational terms such as first and second, and the like are 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 deviating from the spirit and scope of the disclosure. Such variations or modifications are intended to fall within the scope of the claims appended hereto.

Claims

1. A gastric retentive tablet consisting of a tablet core, a sustained release layer and a first coating layer, the tablet core and the sustained release layer comprising, by weight percent, 62.74% metformin hydrochloride, 0.75% colloidal silica, 9.54% polyvinyl alcohol, 2.13% sodium carboxymethyl starch, 6.15% crospovidone, 1.51% glyceryl behenate, 0.36% eudragit @ NE 30D, 2.18% kollicoat @ SR 30D, 1.02% kollicoat @ IR, 0.64% peg8000, 0.87% Talc400, 0.25% titanium dioxide, 0.07% dimethicone, 0.03% polysorbate 80, 0.29% triethyl acid and the balance purified water;

The tablet core consists of metformin hydrochloride, colloidal silicon dioxide, polyvinyl alcohol, carboxymethyl starch sodium, crosslinked povidone and glyceryl behenate, and the slow release layer consists of Eudragit's cube NE 30D, kollicoat cube SR 30D, kollicoat cube IR, PEG8000, talc400, titanium dioxide, simethicone, polysorbate 80, triethyl citrate and purified water; the first coating layer is arranged outside the slow release layer and contains sitagliptin phosphate, and consists of 8.06% sitagliptin phosphate, 3.17% PVA, 0.94% PEG8000 and the balance of purified water according to weight percentage.

2. The gastroretentive sheet of claim 1, which has a short diameter after swelling in an aqueous medium of not less than 11mm.

3. A method of preparing the gastroretentive sheet of any one of claims 1 to 2, comprising:

preparing a tablet core containing metformin hydrochloride;

and coating the tablet core with a slow release layer, and performing a first coating after the slow release layer coating, thereby obtaining the gastric retentive tablet, wherein the first coating contains sitagliptin phosphate.