CN112933057A - Canagliflozin compound controlled release tablet and preparation method thereof - Google Patents
Canagliflozin compound controlled release tablet and preparation method thereof Download PDFInfo
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- CN112933057A CN112933057A CN202110151299.0A CN202110151299A CN112933057A CN 112933057 A CN112933057 A CN 112933057A CN 202110151299 A CN202110151299 A CN 202110151299A CN 112933057 A CN112933057 A CN 112933057A
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- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 95
- 238000013270 controlled release Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- -1 Canagliflozin compound Chemical class 0.000 title claims abstract description 17
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 83
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 claims abstract description 82
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 58
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 55
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- 238000000576 coating method Methods 0.000 claims abstract description 51
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 9
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- 235000021355 Stearic acid Nutrition 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/33—Heterocyclic compounds
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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Abstract
The invention relates to a canagliflozin compound controlled release tablet and a preparation method thereof. The preparation method comprises the following steps: preparing a metformin hydrochloride tablet core, carrying out semipermeable membrane coating and punching on the metformin tablet core, and coating a canagliflozin quick-release layer and a moisture-proof layer. The controlled release tablet can improve the in vitro dissolution degree of canagliflozin, can continuously release the metformin for 24h, and reduces the administration frequency to once a day. And the medicine is slowly released in vivo, so that stable blood concentration is maintained, the use safety of the medicine is improved, the tablet weight is reduced, and the oral comfort level of a patient is improved.
Description
Technical Field
The present invention relates to the field of pharmaceutical formulations. Specifically, the invention relates to a compound canagliflozin metformin hydrochloride controlled release tablet and a preparation method thereof.
Background
Canagliflozin with the chemical name of (1S) -1, 5-dehydro-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl]Methyl radical]-4-methylphenyl radical]-D-glucitol of the formula (1) and the molecular formula C24H25FO5S, CAS number 842133-18-0.
The canagliflozin is a selective sodium-glucose co-transporter 2(SGLT2) inhibitor, a glucose transporter is a glucose transporter and has two subtypes, SGLT2 is one of the subtypes, is expressed near renal tubules and participates in reabsorption of glucose filtered in most lumens, so that the glucose in the renal tubules cannot be reabsorbed into blood and is discharged with urine, and the blood glucose concentration is reduced, and the canagliflozin is clinically used for type II diabetes.
Canagliflozin tablet (canagliflozin, trade name:
) The product is jointly developed by Yanseng drug (Janssen) under the vigorous growth of America and Mitsubishi Tanabe drug (Mitsubishi Tanabe Pharma), and is approved by FDA to be listed on the market at 29 th in 2013 in 03, 11 th and 15 th in 2013 in 11 th and NPMA to be listed on the market at 09 th in 2017 in. Canagliflozin is currently one of the most promising drugs for the hadean company, and the Janssen company has the right to sell the drug in north america, south america, europe, the middle east, australia, new zealand, africa, and other countries.
Carrageenan is poorly water soluble and is practically insoluble in aqueous media at pH1.0 to pH 8.0. Related information and patent reports that the crystalline forms of canagliflozin include the crystalline form I of hemihydrate, the crystalline form II of amorphous form, monohydrate and various anhydrous crystalline forms, wherein the crystalline form of hemihydrate is the most stable and is
The crystal form used in the products on the market. The FDA specification discloses that the absolute bioavailability of canagliflozin after oral administration is 65%, the canagliflozin belongs to BCS IV class medicines of a biological pharmaceutics classification system, and the improvement of the in vitro dissolution of the preparation is a technology which is urgently needed to be improved at present.
Metformin hydrochloride molecular formula C4H11N5HCl with molecular weight of 165.62 and structural formula shown in formula (2). Metformin hydrochloride mainly acts on tissues outside pancreatic islets, inhibits glucose absorption of intestinal tracts, increases the utilization and intake of glucose by peripheral tissues, and reduces hepatic gluconeogenesis, thereby achieving the effect of reducing blood sugar, and simultaneously has the effect of reducing insulin resistance.
The disadvantage of metformin hydrochloride as oral hypoglycemic agent is short half-life, low bioavailability, large administration dosage,the administration times per day are more, the incidence rate of gastrointestinal adverse reactions is high and the like. Patent application publication No. CN106176718A discloses a compound canagliflozin metformin tablet, which comprises 100 parts of metformin, 2-4 parts of canagliflozin and 30-100 parts of pharmaceutically acceptable auxiliary materials, wherein the canagliflozin and the metformin are combined to prepare compound granules which act synergistically and are used for treating type II diabetes, and the problems of excessive taking times, large blood pressure concentration fluctuation and low compliance exist. Therefore, the sustained-release preparation needs to be developed to improve the bioavailability, reduce the frequency of taking the medicine and reduce the incidence rate of adverse reactions. Compared with the common preparation, the sustained-release preparation prolongs the administration interval by reducing the release rate, can reduce the administration times, improve the compliance of patients, maintain the blood concentration of human bodies for a longer time and avoid the peak-valley phenomenon, thereby improving the safety, the effectiveness and the adaptability of the medicament. The current marketed compound canagliflozin metformin hydrochloride sustained-release tablet has the trade name of
The preparation comprises a first layer of a metformin hydrochloride sustained-release preparation and a second layer of canagliflozin; and an outermost optional coating film. The slow-release metformin is partially composed of metformin, a slow-release material and a pharmaceutically acceptable excipient, the preparation method is a skeleton slow-release technology, and the marketed dosage form has the problems that the mass and volume of the tablet are too large compared with those of Asians due to the adoption of the skeleton for preparing the slow-release metformin, the swallowing difficulty exists in taking the tablet, the slow-release effect achieved by the skeleton type slow-release tablet can only be maintained for 12 hours, the tablet still needs to be taken for 2 times every day, and the acceptance and compliance of patients are not high, so that the marketing popularization and application are not facilitated. The patent application with the publication number of CN111870585A discloses a preparation method of a metformin hydrochloride controlled release tablet, which comprises the steps of compressing metformin hydrochloride, a filling agent and a sustained release material into a tablet core, then wrapping the tablet core with a sustained release coating, and forming a dual controlled release system of controlled release medicines by the sustained release material of the tablet core and the sustained release coating outside the tablet core. This and the frameworks currently on the marketSustained release formulations all suffer from the following problems: firstly, the medicine release is uneven, and the phenomenon of sudden release or no release is caused; ② the tablet is heavy and difficult to swallow; ③ the core of tablet is slow-release preparation process uses skeleton material which is generally big in viscosity and difficult to clean in the production process; fourthly, the in vitro release degree is low, the in vitro release time of the sustained release tablet of the general framework material can only reach within 12 hours and can not reach within 24 hours.
Disclosure of Invention
Aiming at the problems that the compressibility of metformin hydrochloride is poor, the existing metformin hydrochloride sustained-release tablet is large in size, difficult to swallow, low in patient compliance and only capable of maintaining the sustained-release effect for 12 hours, and the problems that the solubility of canagliflozin in water is poor and the bioavailability in vivo is low, the invention aims to provide a compound preparation of canagliflozin metformin hydrochloride, wherein the controlled-release tablet can improve the in-vitro dissolution rate of the canagliflozin, can continuously release the metformin for 24 hours and reduce the taking frequency to once a day. And the medicine is slowly released in vivo, so that stable blood concentration is maintained, the use safety of the medicine is improved, the tablet weight is reduced, and the oral comfort level of a patient is improved.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a canagliflozin compound controlled release tablet and a preparation method thereof are disclosed, wherein the main medicines of canagliflozin and metformin hydrochloride respectively belong to SGLT2 inhibitors and biguanides, the sugar reducing mechanisms of the canagliflozin and the biguanides are different, and the canagliflozin and the metformin hydrochloride have a synergistic effect when combined with drugs and can reduce adverse reactions.
Specifically, the compound canagliflozin metformin controlled release tablet comprises the following four parts (a) to (d):
(a) a tablet core consisting of metformin hydrochloride, a water-soluble adhesive, a selective absorption enhancer and a lubricant;
the tablet core contains metformin hydrochloride with a pharmaceutically effective dose, and the mass percentage of the metformin hydrochloride is 60-99%, preferably 65-95%, and more preferably 70-90%.
The proportion of the water-soluble binder is 2 to 30%, preferably 4 to 25%, more preferably 6 to 20%.
The selective absorption enhancer is in a proportion of 0.1 to 10%, preferably 1 to 8%, more preferably 2 to 6%.
The tablet core further comprises an optional lubricant in a proportion of 0.01-3%, preferably 0.1-2%, more preferably 0.5-1.5%; the above are all mass percentages.
The adhesive is selected from one or more of hypromellose, hydroxypropyl cellulose and polyvidone.
The absorption enhancer is sodium dodecyl sulfate.
The lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.
(b) A controlled release coating layer with 1 or 2 pore channels surrounding the tablet core, wherein the controlled release coating layer comprises a semipermeable membrane and a pore-forming agent.
Wherein the semi-permeable membrane is selected from cellulose acetate, and the type can be CA-320S, CA-398-10 or the mixture of the two. The proportion is 80 to 100%, preferably 85 to 100%, most preferably 90 to 100%.
The pore-forming agent is selected from polyethylene glycol, and the preferred model is PEG 3350. The proportion of the polyethylene glycol PEG3350 is 0-20%, preferably 0-15%, most preferably 0-10%. The above are mass fractions.
(b) A canagliflozin quick-release layer surrounding the controlled-release coating layer, which consists of canagliflozin and a selective adhesive; the canagliflozin quick-release layer comprises 40-95%, preferably 45-90%, and more preferably 50-85% of canagliflozin; the binder proportion is 5-60%, preferably 10-55%, more preferably 15-50%; the above are mass fractions.
The canagliflozin is a canagliflozin crystal or a hemihydrate crystal thereof (purchased from Tianjin Fu and science and technology development Co., Ltd.), and the particle size distribution of the canagliflozin is controlled to be D90 or less than 50 um. The water-soluble adhesive is selected from one or more of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl cellulose EF, hydroxypropyl cellulose JF, hydroxypropyl cellulose LF, hydroxypropyl cellulose SL, hydroxypropyl cellulose L, hydroxypropyl cellulose M, polyvidone K30 and polyvidone K90.
(c) Moisture-proof film coating layer for surrounding canagliflozin quick-release layer
The film coating layer is a moisture-proof coating material, is a gastric-soluble coating powder premix consisting of one or more of hydroxypropyl methylcellulose, polyvinyl alcohol or hydroxypropyl cellulose, and also comprises other auxiliary materials, such as but not limited to an opacifier, an anti-sticking agent, a plasticizer, a coloring agent and the like. The moisture-proof coating material is preferably Opadry series gastric-soluble coating powder, and more preferably Opadry II series gastric-soluble coating powder.
The preparation method of the canagliflozin metformin hydrochloride compound controlled release tablet comprises the following steps:
(1) pulverizing metformin hydrochloride, sieving, adding selective absorption enhancer, sieving with 40 mesh sieve, stirring, mixing, wet granulating with binder water solution, sieving with 12-20 mesh sieve, granulating, and fluidized drying until water content is less than 3.5%.
(2) And (3) sieving the dried particles with a 14-24-mesh sieve, grinding and finishing the particles, adding a lubricant, uniformly mixing, and pressing the metformin hydrochloride tablet core with the hardness of between 150 and 300N.
(3) Adding cellulose acetate and polyethylene glycol into acetone to prepare a solution with the concentration of 5% -10%, coating a coating film on a metformin tablet core in a coating pan, wherein the air inlet temperature of the coating pan is 30-60 ℃, the air outlet temperature is 15-45 ℃, the weight of the coating is increased by 5% -15%, and after the coating is finished, drying is carried out for 2h-24h at the temperature of 40-60 ℃; and (3) placing the tablet coated with the semipermeable membrane coating on a punching machine, punching, and preparing the metformin controlled release tablet, wherein the pore size is 0.5-0.8 mm.
(4) Dissolving the selective adhesive with water, sieving canagliflozin with a 40-mesh sieve for dispersion, adding the canagliflozin into the adhesive solution, stirring or homogenizing to obtain a suspension containing canagliflozin, taking the suspension as a medicine applying solution, applying medicine to the metformin controlled release tablet in a coating pot, wherein the air inlet temperature is not lower than 50 ℃, and the material temperature is 35-50 ℃, so as to obtain the compound canagliflozin metformin hydrochloride controlled release tablet.
(5) And (4) preparing the moisture-proof film coating material into a coating solution, and coating the compound preparation obtained in the step (4) with a film coating to obtain the final canagliflozin metformin hydrochloride compound controlled release tablet.
Compared with the commercially available preparation, the compound preparation of the invention adopts the osmotic pump technology to prepare the canagliflozin metformin controlled release tablet, and has the advantages of stable drug release speed, small gastrointestinal tract irritation, convenient medicine taking, good patient compliance and convenient market popularization.
Drawings
Figure 1 shows the dissolution profile of canagliflozin hydrochloride in the compound metformin hydrochloride controlled-release tablets of examples 1-3.
Figure 2 shows the release profile of metformin in the complex controlled-release canagliflozin hydrochloride tablets of examples 1-3.
Detailed Description
The present invention will be described below with reference to specific examples to make the technical aspects of the present invention easier to understand and master. The invention is not so limited. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1: and (3) preparation of the compound canagliflozin metformin hydrochloride controlled release tablet.
(a) Preparation of a 500mg tablet core of metformin hydrochloride
Table 1 metformin hydrochloride tablet core composition
Weighing metformin and various auxiliary materials according to the proportion in the table 1, crushing metformin hydrochloride, sieving by a 40-mesh sieve, adding lauryl sodium sulfate, uniformly mixing, preparing hydroxypropyl cellulose into a 10% aqueous solution, carrying out high-shear wet granulation, sieving by a 12-mesh sieve, carrying out wet granulation, transferring to a fluidized bed for drying, controlling the moisture content to be lower than 3%, grinding, granulating, adding stearic acid, uniformly mixing, and tabletting to obtain the metformin hydrochloride tablet core.
(b) Preparation of metformin hydrochloride controlled release tablet
Table 2 metformin hydrochloride controlled release layer coating formulation composition
| Prescription composition | Percent (%) |
| Cellulose acetate CA-398-10 | 8.9 |
| Polyethylene glycol 3350 | 1.1 |
| Acetone (II) | 90 |
And (3) taking acetone as a solvent to prepare coating liquid with the solid content of 10% from cellulose acetate and polyethylene glycol 3350, and performing controlled-release coating on the metformin hydrochloride tablet core, wherein the weight of the coating is increased by about 45 mg/tablet. And after the coating is finished, continuously drying in a coating pan for 12-24 h. And (3) placing the coated tablet on a laser drilling machine to drill holes with the hole channel of about 0.7 mm.
(c) Preparation of canagliflozin quick-release layer
Table 3 canagliflozin quick release layer composition
| Composition of quick release layer | mg/tablet | Percent (%) |
| Canagliflozin hemihydrate | 102 | 80.95 |
| Hydroxypropyl cellulose | 24 | 19.05 |
| Total of | 126 | 100.00 |
Respectively weighing canagliflozin and hydroxypropyl cellulose according to the proportion in the table 3, dissolving the hydroxypropyl cellulose in water, sieving the canagliflozin with a 40-mesh sieve, dispersing, adding the canagliflozin into a hydroxypropyl solution, stirring or homogenizing and dispersing to prepare a canagliflozin medicine-applying solution, controlling the weight gain of the medicine-applying solution, and coating to obtain the quick-release layer containing the canagliflozin.
(d) Moisture-proof gastric-soluble film coating layer
And (c) preparing coating liquid with the solid content of 12-15% by using water as a solvent and carrying out film coating on the tablet obtained in the step (c), wherein the weight of the coating is increased by 3.0%, so as to obtain the compound canagliflozin hydrochloride controlled release tablet.
Example 2: preparation of compound canagliflozin metformin hydrochloride controlled release tablet
(a) Preparation of metformin hydrochloride tablet core
Table 4 metformin hydrochloride tablet core formulation composition
| Chip core groupBecome into | mg/tablet | Percent (%) | Batch size (1000g)/g |
| Metformin hydrochloride | 500.00 | 75.00 | 750 |
| Sodium dodecyl sulfate | 23.33 | 3.50 | 35 |
| Povidone | 133.33 | 20.00 | 200 |
| Magnesium stearate | 10.00 | 1.50 | 15 |
| Tablet weight | 666.66 | 100.00 | 1000 |
Weighing metformin and various auxiliary materials according to the prescription proportion of the table X, crushing the metformin hydrochloride, sieving the metformin hydrochloride with a 40-mesh sieve, sieving the lauryl sodium sulfate with a 40-mesh sieve, uniformly mixing the lauryl sodium sulfate and the metformin, preparing 10% aqueous solution by using povidone, performing fluidized granulation and drying, controlling the water content to be lower than 2.5%, grinding, finishing granules, adding stearic acid, uniformly mixing and tabletting to prepare the metformin hydrochloride tablet core.
(b) Preparation of metformin hydrochloride controlled release tablet
Table 5 metformin hydrochloride controlled release layer coating formulation composition
| Prescription composition | Percent (%) |
| Cellulose acetate CA-398-10 | 5 |
| Acetone (II) | 95 |
Dissolving cellulose acetate in acetone to obtain 5% solution, and coating to obtain 50 mg/tablet. And after the coating is finished, continuously drying for 2 hours in the coating pan. Punching the coated tablet on a punching machine, wherein the size of the pore channel is about 0.8 mm.
(c) Preparation of canagliflozin quick-release layer
Formulation composition of quick-release layer of Canagliflozin of Table 6
| Composition of quick release layer | mg/tablet | Percent (%) |
| Canagliflozin hemihydrate | 102 | 68.00 |
| Povidone | 48 | 32.00 |
| Total weight gain | 150 | 100.00 |
Weighing canagliflozin and povidone according to the prescription amount, dissolving povidone in water, sieving the canagliflozin with a 40-mesh sieve, uniformly dispersing, adding the canagliflozin into povidone solution, stirring or uniformly dispersing to obtain a suspension, coating the metformin controlled release tablet with the drug, and controlling the weight increment of the coating to obtain the metformin compound preparation containing the canagliflozin quick release layer.
(d) Moisture-proof gastric-soluble film coating layer
And (3) preparing the Opadry II into coating liquid with the solid content of 12-15% by taking water as a solvent, and performing film coating on the tablet obtained in the step (3), wherein the weight of the coating is increased by 2.5%, so as to obtain the compound canagliflozin metformin hydrochloride controlled release tablet.
Example 3: preparation of compound canagliflozin metformin hydrochloride controlled release tablet
(a) Preparation of metformin hydrochloride tablet core
Table 7 metformin hydrochloride tablet core formulation composition
| Tablet core composition | mg/tablet | Percent (%) | Batch size (1000g)/g |
| Metformin hydrochloride | 500 | 87.72 | 877.2 |
| |
15 | 2.63 | 26.3 |
| |
50 | 8.77 | 87.7 |
| |
5 | 0.88 | 8.8 |
| Tablet weight | 570 | 100.00 | 1000 |
Weighing metformin and various auxiliary materials according to the proportion in the table 7, crushing metformin hydrochloride, sieving with a 40-mesh sieve, sieving sodium dodecyl sulfate with a 40-mesh sieve, uniformly mixing with metformin, preparing 10% aqueous solution by povidone, performing fluidized granulation and drying, controlling the water content to be lower than 2.5%, grinding, finishing granules, adding stearic acid, uniformly mixing, and tabletting to obtain the metformin hydrochloride tablet core.
(b) Preparation of metformin hydrochloride controlled release tablet
TABLE 8 controlled Release layer recipe composition
| Prescription composition | Percent (%) |
| Cellulose acetate CA-398-10 | 12.5 |
| Cellulose acetate CA- |
5 |
| Polyethylene glycol 3350 | 2.5 |
| Acetone (II) | 80 |
Taking acetone as a solvent, preparing cellulose acetate and polyethylene glycol 3350 into a coating solution with the solid content of 20%, performing controlled-release coating on the metformin hydrochloride tablet core, and continuously drying in a coating pot for 12-24h after the coating is finished. The coated tablet is placed on a laser-beam drilling machine to be drilled, and the medicine release pore canal is about 0.7 mm.
(c) Preparation of canagliflozin quick-release layer
Formulation composition of quick-release layer of 9-Calgliflozin in table
| Composition of quick release layer | mg/tablet | Percent (%) |
| Canagliflozin hemihydrate | 102 | 87.18 |
| |
15 | 12.82 |
| Total weight gain | 117 | 100.00 |
Respectively weighing canagliflozin and hydroxypropyl methylcellulose according to the proportion in a table 9, dissolving the hydroxypropyl methylcellulose in water, sieving the canagliflozin with a 40-mesh sieve, dispersing, adding the dispersion into the hydroxypropyl methylcellulose, stirring or homogenizing and dispersing to prepare a canagliflozin drug-loading solution, controlling the weight gain of the drug-loading solution, and packaging to obtain the fast-release layer of the canagliflozin.
(d) Moisture-proof gastric-soluble film coating layer
And (3) preparing the Opadry II into coating liquid with the solid content of 12-15% by taking water as a solvent, and performing film coating on the tablet obtained in the step (3), wherein the weight of the coating is increased by 2.0%, so as to obtain the compound canagliflozin metformin hydrochloride controlled release tablet.
Example 4: hardness and friability measurements
The hardness and friability of the metformin hydrochloride core in the compound controlled release tablet of examples 1-3 were examined according to the friability test method of tablets of the general 0923 in the chinese pharmacopoeia 2015 edition, while the hardness and friability of the compound controlled release tablet of examples 1-3 were examined, with the results shown in table 10.
TABLE 10 metformin hydrochloride core hardness and friability
Example 5: measurement of Canagliflozin content uniformity
The content uniformity of canagliflozin hydrochloride in the compound canagliflozin metformin hydrochloride controlled-release tablets of examples 1-3 was examined according to the content uniformity examination method of 0941 on the basis of the chinese pharmacopoeia 2015 edition, and the results are shown in table 11.
TABLE 5 Calgliflozin content uniformity
| Examples | Canagliflozin content uniformity |
| 1 | 2.9 |
| 2 | 5.0 |
| 3 | 6.3 |
Example 6: determination of in vitro Release
The compound canagliflozin hydrochloride controlled-release tablets of examples 1-3 were used as samples, and the dissolution profile of canagliflozin was measured under the conditions of water + 0.2% SDS release medium of 900ml,50rpm, 37 ℃ according to the second method (paddle method) of dissolution and release determination of 0931 according to the general rules of chinese pharmacopoeia 2015 edition, and the results are shown in fig. 1. According to the second method (paddle method) of 0931 dissolution and release rate determination method of the pharmacopoeia 2015 edition, metformin release amount is measured at pH1.2, 900ml,50rpm, 37 ℃, and release curves are respectively drawn. The results are shown in FIG. 2. The quick-release layer of canagliflozin in the examples 1 to 3 is completely dissolved within 60 minutes, and the metformin hydrochloride is continuously released for 24 hours without burst release, thereby showing that the expected target is achieved by the invention.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, substitutions, combinations, simplifications, and modifications which do not depart from the spirit and principle of the present invention should be regarded as equivalent substitutions and equivalents, which are included in the scope of the present invention.
Claims (6)
1. The canagliflozin compound controlled-release tablet is characterized by comprising the following four parts (a) to (d):
(a) a tablet core consisting of metformin hydrochloride, a water-soluble adhesive, a selective absorption enhancer and a lubricant;
(b) a controlled release coating with 1 or 2 pore channels surrounding the core;
(c) a canagliflozin quick-release layer surrounding the controlled-release coating layer, which consists of canagliflozin and a selective adhesive;
(d) a moisture-proof film coating layer surrounding the canagliflozin quick-release layer.
2. The canagliflozin compound controlled-release tablet according to claim 1, wherein the compound controlled-release tablet of part (a): the tablet core contains metformin hydrochloride with a pharmaceutically effective dose, and the mass percentage is 60-99%; the proportion of the water-soluble adhesive is 2-30%; the proportion of the selective absorption enhancer is 0.1-10%; the tablet core also comprises a lubricant with the proportion of 0.01-3%; the above are all mass percentages;
the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone;
the absorption enhancer is sodium dodecyl sulfate;
the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.
3. The canagliflozin compound controlled-release tablet according to claim 1, wherein the component (b): the controlled release coating layer comprises a semipermeable membrane and a pore-foaming agent;
wherein the semi-permeable membrane is selected from cellulose acetate; the pore-forming agent is selected from polyethylene glycol, and the proportion is 0-20% by mass.
4. The canagliflozin compound controlled-release tablet according to claim 1, wherein the (c) portion: the canagliflozin quick-release layer comprises 40-95% of canagliflozin and 5-60% of adhesive; canagliflozin is crystalline or hemihydrate crystalline thereof.
5. The canagliflozin compound controlled-release tablet according to claim 1, wherein the component (d): the film coating layer is a gastric-soluble coating powder premix consisting of one or more of hydroxypropyl methylcellulose, polyvinyl alcohol or hydroxypropyl cellulose.
6. The preparation method of canagliflozin compound controlled release tablet as claimed in claim 1, which is characterized by comprising the following steps:
(1) pulverizing metformin hydrochloride, sieving, adding selective absorption enhancer, sieving, stirring, granulating with binder water solution, sieving, and drying;
(2) granulating, adding lubricant, mixing, and pressing to obtain metformin hydrochloride tablet core;
(3) adding cellulose acetate and polyethylene glycol into acetone to prepare a 5-10% solution, coating a coating film on a metformin tablet core in a coating pan, wherein the weight of the coating is increased by 5-15%, drying and punching after the coating is finished, and the pore size is 0.5-0.8 mm to prepare the metformin controlled release tablet;
(4) dissolving the selective adhesive in water, sieving and dispersing the canagliflozin, adding the canagliflozin into the adhesive solution, and uniformly mixing to obtain a suspension containing the canagliflozin, wherein the suspension is used as a medicine applying solution, and applying medicine to the metformin controlled release tablet in a coating pot to obtain a compound canagliflozin metformin hydrochloride controlled release tablet;
(5) and (4) preparing the moisture-proof film coating material into a coating solution, and coating the compound preparation obtained in the step (4) with a film coating to obtain the final canagliflozin metformin hydrochloride compound controlled release tablet.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120282336A1 (en) * | 2009-11-13 | 2012-11-08 | Astrazeneca Uk Limited | Bilayer tablet formulations |
| CN103933031A (en) * | 2014-05-13 | 2014-07-23 | 中国药科大学 | Compound preparation including DPP-4 inhibitor and metformin hydrochloride and preparation method thereof |
| CN106137999A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of compound recipe pioglitazone Metformin Extended-release Tablets and preparation method thereof |
| CN106176718A (en) * | 2016-08-03 | 2016-12-07 | 上海延安药业有限公司 | Compound recipe canagliflozin diformin tablet |
| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
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2021
- 2021-02-03 CN CN202110151299.0A patent/CN112933057A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120282336A1 (en) * | 2009-11-13 | 2012-11-08 | Astrazeneca Uk Limited | Bilayer tablet formulations |
| CN103933031A (en) * | 2014-05-13 | 2014-07-23 | 中国药科大学 | Compound preparation including DPP-4 inhibitor and metformin hydrochloride and preparation method thereof |
| CN106137999A (en) * | 2015-03-31 | 2016-11-23 | 深圳翰宇药业股份有限公司 | A kind of compound recipe pioglitazone Metformin Extended-release Tablets and preparation method thereof |
| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
| CN106176718A (en) * | 2016-08-03 | 2016-12-07 | 上海延安药业有限公司 | Compound recipe canagliflozin diformin tablet |
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