CN118236367A - Compound preparation and preparation method thereof - Google Patents
Compound preparation and preparation method thereof Download PDFInfo
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- CN118236367A CN118236367A CN202311765953.2A CN202311765953A CN118236367A CN 118236367 A CN118236367 A CN 118236367A CN 202311765953 A CN202311765953 A CN 202311765953A CN 118236367 A CN118236367 A CN 118236367A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 9
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960003105 metformin Drugs 0.000 claims abstract description 16
- 239000010410 layer Substances 0.000 claims description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims description 39
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 229960003943 hypromellose Drugs 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
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- 239000011230 binding agent Substances 0.000 claims description 12
- 239000003607 modifier Substances 0.000 claims description 12
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 11
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- 229920002472 Starch Polymers 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 8
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 8
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 7
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 7
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 7
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- 239000000454 talc Substances 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 235000012222 talc Nutrition 0.000 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 239000011247 coating layer Substances 0.000 claims description 6
- 239000008119 colloidal silica Substances 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
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- 239000003814 drug Substances 0.000 claims description 6
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 229920001531 copovidone Polymers 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000378 calcium silicate Substances 0.000 claims description 3
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 3
- 235000012241 calcium silicate Nutrition 0.000 claims description 3
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000391 magnesium silicate Substances 0.000 claims description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 3
- 235000019792 magnesium silicate Nutrition 0.000 claims description 3
- 229960001855 mannitol Drugs 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
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- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims 1
- 229940105329 carboxymethylcellulose Drugs 0.000 claims 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims 1
- 229960004667 ethyl cellulose Drugs 0.000 claims 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims 1
- 229960002900 methylcellulose Drugs 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 7
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 208000016097 disease of metabolism Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 3
- 229960004329 metformin hydrochloride Drugs 0.000 description 3
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
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- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
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- 239000003937 drug carrier Substances 0.000 description 1
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- 229940035732 metformin and rosiglitazone Drugs 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present disclosure relates to a compound preparation and a preparation method thereof. In particular, a bilayer tablet comprising metformin and Henggliflozin is provided.
Description
Technical Field
The present disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a bilayer tablet and a preparation method thereof.
Background
Type II diabetes is the most common form of diabetes, accounting for 90% of diabetes cases. There are many types of diabetes drugs that have been marketed, but to date, none of them have been able to maintain the blood glucose level of type II diabetics within a target range for a long period of time with a great effort.
In recent years, intensive researches on pathogenesis of diabetes mellitus provide more and more approaches for treating type II diabetes mellitus, and discovery of sodium-glucose cotransporter-2 (SGLT-2) inhibitors provides a new idea for treating diabetes mellitus. SGLT-2 inhibitors prevent the reabsorption of glucose into the blood by the kidneys. The kidneys continue to filter glucose from the glomeruli into the bladder, however, almost all of the filtered glucose is reabsorbed. SGLT-2 is a protein responsible for the reabsorption of most of glucose and helps the body retain glucose to meet its energy needs. For patients with diabetes, excess glucose retained by this pathway contributes to sustained hyperglycemia. Inhibition of SGLT-2 activity inhibits renal glucose reabsorption in the body, thereby leading to glucose excretion in the urine.
At present, a plurality of combination therapies exist for pathological blood sugar rising diseases which cannot be met by single drug treatment, the ideal pharmaceutical composition has complementary advantages or synergistic effects on a plurality of pathophysiological pathways or targets, can be applied to all stages of blood sugar control, is generally good in tolerance, does not increase the risk of hypoglycemia, cardiovascular events or weight gain, and also meets clinical blood sugar management, and improves the compliance of patients. For example, glucovanceTM (metformin and glyburide), AVANDAMENTTM (metformin and rosiglitazone) and METAGLIPTM (metformin and glibenclamide) are commercially available.
CN102711739a and CN105193761a disclose a bilayer tablet comprising metformin and an SGLT-2 inhibitor, which may be dapagliflozin or the like, and is used for the treatment of type II diabetes.
The present study provides a Henggliflozin-metformin compound bilayer tablet for oral administration for the treatment of diseases or disorders associated with SGLT-2 activity, which is convenient and effective in controlling blood glucose levels in type II diabetics.
Disclosure of Invention
The present disclosure provides a pharmaceutical composition comprising: henggliflozin or a pharmaceutically acceptable salt or a complex thereof, and dibasic calcium phosphate.
In some embodiments, the constant gliflozin or a pharmaceutically acceptable salt or complex thereof is praline constant gliflozin. In some embodiments, the calcium hydrogen phosphate is present in an amount of 1% to 20%, specifically 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% by weight of the total composition. 18%, 19%, 20%, or any value therebetween.
In some embodiments, the pharmaceutical composition further comprises a second active ingredient, metformin or a pharmaceutically acceptable salt thereof. In some embodiments, the metformin or a pharmaceutically acceptable salt thereof is metformin hydrochloride.
In some embodiments, the pharmaceutical composition further comprises one or more of a binder, a filler, a release modifier, a disintegrant, a lubricant, and a glidant.
The binder in the pharmaceutical composition includes, but is not limited to, one or more of polyvinylpyrrolidone, copovidone, starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose. In some embodiments, the binder is present in an amount of 2 to 10% by weight of the total composition.
Fillers in the pharmaceutical composition include, but are not limited to, one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinized starch, sucrose, lactose. In some embodiments, the filler is selected from one or more of microcrystalline cellulose, dibasic calcium phosphate, and pregelatinized starch. In some embodiments, the filler is present in an amount of 5 to 50% by weight of the total composition.
The release modifier in the pharmaceutical composition includes, but is not limited to, one or more of ethylcellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose. In some embodiments, the release modifier is present in an amount of 5 to 50% by weight of the total composition.
Disintegrants in the pharmaceutical composition include, but are not limited to, one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone. In some embodiments, the disintegrant is present in an amount of 0.05 to 5% by weight of the total composition.
Lubricants in the pharmaceutical compositions include, but are not limited to, one or more of magnesium stearate, talc, colloidal silica. In some embodiments, the lubricant is present in an amount of 0.05 to 5% by weight of the total composition.
Glidants in the pharmaceutical composition include, but are not limited to, one or more of colloidal silicon dioxide, calcium silicate, magnesium silicate, talc. In some embodiments, the glidant is present in an amount of 0.1-3% by weight of the total composition.
The pharmaceutical composition described herein is in the form of a bilayer tablet comprising: a) a slow release layer containing metformin or a pharmaceutically acceptable salt thereof, b) an immediate release layer containing constant gliflozin or a pharmaceutically acceptable salt thereof or a complex thereof, and c) a coating layer covering the slow release layer and the immediate release layer.
In some embodiments, the sustained release layer in the bilayer tablet form of the pharmaceutical composition further comprises one or more of a binder, a filler, a release modifier, a lubricant, and a glidant.
The binder in the slow release layer includes, but is not limited to, one or more of polyvinylpyrrolidone, copovidone, starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose. In some embodiments, the binder is present in an amount of 2-10% by weight, specifically 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or a value between any two thereof, based on the total weight of the sustained release layer.
The filler in the slow release layer includes, but is not limited to, one or more of microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, lactose. In some embodiments, the filler is present in an amount of 0-20%, specifically 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or any value therebetween, based on the total weight of the extended release layer.
The release modifier in the release layer includes, but is not limited to, one or more of ethylcellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose. In some embodiments, the release modifier is selected from hypromellose. In some embodiments, the hypromellose is of a type selected from one or more of K100M and E5. In some embodiments, the release modifier is present in an amount of 10-50%, specifically 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% of the total weight of the composition. In some embodiments, the release modifier is present in an amount of 10 to 25% by weight of the total composition. In some embodiments, the release modifier is present in an amount of 30-40% by weight of the total composition.
The lubricant in the slow release layer includes, but is not limited to, one or more of magnesium stearate, talc, colloidal silica. In some embodiments, the lubricant is selected from magnesium stearate. In some embodiments, the lubricant is present in an amount of 0.1-3%, specifically 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0% or any value therebetween, based on the total weight of the composition.
Glidants in the slow release layer include, but are not limited to, one or more of colloidal silicon dioxide, calcium silicate, magnesium silicate, talc. In some embodiments, the glidant is selected from colloidal silicon dioxide. In some embodiments, the glidant is present in an amount of 0.1-3%, specifically 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8%, 3.0% or any two or more thereof based on the total weight of the composition
In some embodiments, the immediate release layer in the bilayer tablet form of the pharmaceutical composition further comprises one or more of a binder, a filler, a disintegrant, and a lubricant.
The binder in the immediate release layer includes, but is not limited to, one or more of polyvinylpyrrolidone, copovidone, starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose. In some embodiments, the binder is present in an amount of 2-10% by weight, specifically 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0% or a value between any two thereof, based on the total weight of the immediate release layer.
The filler in the immediate release layer includes, but is not limited to, one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinized starch, sucrose, lactose. In some embodiments, the filler is selected from one or more of microcrystalline cellulose, dibasic calcium phosphate, and pregelatinized starch. In some embodiments, the filler is present in an amount of 20-80%, specifically 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or any value therebetween, based on the total weight of the immediate release layer.
Disintegrants in the immediate release layer include, but are not limited to, one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone. In some embodiments, the disintegrant is present in an amount of 1-20%, specifically 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or any value therebetween, by weight of the total weight of the immediate release layer.
The lubricant in the immediate release layer includes, but is not limited to, one or more of magnesium stearate, micro silica gel, talc, colloidal silica. In some embodiments, the lubricant is present in an amount of 0.5-5%, specifically 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0% or a value between any two thereof, based on the total weight of the immediate release layer.
In some embodiments, the coating layer is selected from the group consisting of opadry I or II.
The present disclosure also provides a pharmaceutical composition comprising:
a) A sustained release layer comprising: 30-60% metformin or a pharmaceutically acceptable salt thereof, 1-10% sodium carboxymethylcellulose, 20-50% hypromellose, 5-20% microcrystalline cellulose, 0.5-3% colloidal silicon dioxide and 0.1-1% magnesium stearate, based on the total weight of the slow release layer; or 60-85% of metformin or a pharmaceutically acceptable salt thereof, 1-10% of sodium carboxymethylcellulose, 10-30% of hypromellose, 0.5-3% of colloidal silica, and 0.1-1% of magnesium stearate;
b) An immediate release layer comprising: based on the total weight of the immediate release layer, 1-5% of Henggliflozin or a pharmaceutically acceptable salt or a compound thereof, 30-50% of calcium hydrophosphate, 30-50% of microcrystalline cellulose, 2-10% of hydroxypropyl cellulose, 1-10% of croscarmellose sodium and 0.5-3% of magnesium stearate.
C) A coating layer selected from the group consisting of opadry I or II.
Another aspect of the present disclosure provides a method of preparing the aforementioned pharmaceutical composition, comprising: preparing quick-release layer granule containing Henggliflozin or its pharmaceutically acceptable salt or its compound, preparing slow-release layer granule containing metformin or its pharmaceutically acceptable salt, and tabletting. In some embodiments, a method of preparing an immediate release layer particle and a sustained release layer particle comprises: wet granulating, fluidized bed drying, and mixing.
In another aspect, the present disclosure also provides the use of the aforementioned pharmaceutical composition in the manufacture of a medicament for the treatment of SGLT-2-associated diseases. In some embodiments, the SGLT-2-associated disease may be a metabolic disease, preferably diabetes, including type II diabetes.
In another aspect, the present disclosure also provides the use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of metabolic diseases. In some embodiments, the metabolic disease is selected from diabetes, including type II diabetes.
The present disclosure also provides a method of treating a SGLT-2-associated disease comprising administering to a patient an effective amount of the foregoing pharmaceutical composition and bilayer tablet. In some embodiments, the SGLT-2-associated disease may be a metabolic disease, preferably diabetes, including type II diabetes.
The present disclosure also provides a method of treating and metabolizing a disease comprising administering to a patient an effective amount of the aforementioned pharmaceutical composition and bilayer tablet. In some embodiments, the metabolic disease is selected from diabetes, including type II diabetes.
An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
In the present disclosure, the numerical value is an instrument measurement value or a calculated value after the instrument measurement, and errors exist to a certain extent, and in general, plus or minus 10% are within a reasonable error range. Of course the context in which the value is used, e.g. the total impurity content, is considered, the value is such that the measured error does not vary by more than plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to maintain the stability of the active ingredients of the antibody, promote the administration to organisms, and facilitate the absorption of the active ingredients so as to exert biological activity. As used herein, the terms "pharmaceutical composition" and "formulation" are not intended to be mutually exclusive.
Detailed Description
The present disclosure is further illustrated below with reference to specific examples. Those skilled in the art will appreciate that these examples are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure in any way.
Example 1
TABLE 1
1.1 Preparation method
1) Sustained release layer
Weighing metformin hydrochloride and sodium carboxymethylcellulose according to the prescription, granulating by a wet method, drying and finishing; adding prescribed amount of hypromellose K100M, hypromellose E5, microcrystalline cellulose and colloidal silicon dioxide, mixing; adding magnesium stearate and mixing.
2) Quick release layer
Weighing proline Henggliflozin, pregelatinized starch (or calcium hydrophosphate), microcrystalline cellulose, hydroxypropyl cellulose and part of magnesium stearate according to the prescription amount, granulating by a wet method, drying and finishing; adding the prescribed amount of croscarmellose sodium and mixing; the remaining amount of magnesium stearate was added and mixed.
3) Tabletting
And (3) carrying out double-layer tabletting on the total mixed particles which are qualified in detection (wherein the first layer is a metformin hydrochloride slow-release layer and the second layer is a praline constant gliclazide fast-release layer). The appearance quality of the plain tablets is checked, and the plain tablets are subjected to complete, smooth and uniform color and luster, weight difference and other project checks.
4) Coating layer
The Ophioglossi is weighed according to the prescription amount to prepare coating liquid, and the plain tablets are placed in a coating machine for coating.
1.2 Friability determination
According to the tablet friability checking method of four appendices <0923> of the edition 2020 of Chinese pharmacopoeia, 10 tablets of the tablet are taken, precisely weighed, placed in a tablet friability checking instrument and rotated for 100 times.
The experimental results show that the double-layer tablet adopting the calcium hydrophosphate as the filler of the quick-release layer has better friability detection result, the phenomena of sample powder falling and tablet knocking are obviously improved, and the coating is smoothly carried out.
Example 2
Bilayer tablets containing a metformin extended release layer and a constant gliflozin immediate release layer (prescriptions 4-6)) were prepared in a similar manner as described in example 1.
TABLE 2
Claims (18)
1. A pharmaceutical composition comprising: the first active ingredient is Henggliflozin or a pharmaceutically acceptable salt or a compound thereof, and calcium hydrophosphate.
2. The pharmaceutical composition according to claim 1, further comprising a second active ingredient, metformin or a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition of claim 1 or 2, further comprising one or more of a binder, a filler, a release modifier, a disintegrant, a lubricant, and a glidant.
4. A pharmaceutical composition according to claim 3, wherein the binder is selected from one or more of polyvinylpyrrolidone, copovidone, starch, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, preferably the binder is present in an amount of 2-10% by weight of the total composition.
5. A pharmaceutical composition according to claim 3, wherein the filler is selected from one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinised starch, sucrose, lactose, preferably one or more of microcrystalline cellulose, dibasic calcium phosphate and pregelatinised starch; preferably, the filler is present in an amount of 5 to 50% by weight of the total composition.
6. A pharmaceutical composition according to claim 3, wherein the release modifier is selected from one or more of ethylcellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, preferably the release modifier is present in an amount of 5-50% by weight of the total composition.
7. A pharmaceutical composition according to claim 3, wherein the disintegrant is selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone, preferably the content of the disintegrant is 0.05-5% of the total weight of the composition.
8. A pharmaceutical composition according to claim 3, wherein the lubricant may be selected from one or more of magnesium stearate, talc, colloidal silica, preferably the lubricant content is 0.05-5% of the total weight of the composition.
9. A pharmaceutical composition according to claim 3, wherein the glidant is selected from one or more of colloidal silicon dioxide, calcium silicate, magnesium silicate, talc, preferably in an amount of 0.1-3% by weight of the total composition.
10. The pharmaceutical composition according to any one of claims 1-9, in the form of a bilayer tablet comprising: a) a slow release layer containing metformin or a pharmaceutically acceptable salt thereof, b) an immediate release layer containing constant gliflozin or a pharmaceutically acceptable salt thereof or a complex thereof, and c) a coating layer covering the slow release layer and the immediate release layer.
11. The pharmaceutical composition of claim 10, wherein the immediate release layer comprises: based on the total weight of the immediate release layer, 1-5% of Henggliflozin or a pharmaceutically acceptable salt or a compound thereof, 30-50% of calcium hydrophosphate, 30-50% of microcrystalline cellulose, 2-10% of hydroxypropyl cellulose, 1-10% of croscarmellose sodium and 0.5-3% of magnesium stearate.
12. The pharmaceutical composition according to claim 10 or 11, wherein the slow release layer comprises: 30-60% metformin or a pharmaceutically acceptable salt thereof, 1-10% carboxymethylcellulose sodium, 20-50% hypromellose, 5-20% microcrystalline cellulose, 0.5-3% colloidal silicon dioxide and 0.1-1% magnesium stearate, based on the total weight of the slow release layer.
13. The pharmaceutical composition according to claim 10 or 11, wherein the slow release layer comprises, based on the total weight of the slow release layer, 60-85% metformin or a pharmaceutically acceptable salt thereof, 1-10% sodium carboxymethyl cellulose, 10-30% hypromellose, 0.5-3% colloidal silica and 0.1-1% magnesium stearate.
14. The pharmaceutical composition according to any one of claims 10-13, wherein the coating layer is selected from the group consisting of opadry I or II.
15. A method of preparing the pharmaceutical composition of any one of claims 1-14, comprising: preparing sustained release layer granule containing metformin or its pharmaceutically acceptable salt, preparing immediate release layer granule containing Hengagliflozin or its pharmaceutically acceptable salt or its compound, tabletting and coating.
16. The method of making according to claim 15, wherein the method of making particles comprises: wet granulating, fluidized bed drying, and mixing.
17. Use of a pharmaceutical composition according to any one of claims 1-14 in the manufacture of a medicament for the treatment of SGLT-2 related diseases.
18. Use of a pharmaceutical composition according to any one of claims 1-14 for the manufacture of a medicament for the treatment of a metabolic disorder, preferably diabetes, more preferably type II diabetes.
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| CN2022116541242 | 2022-12-22 | ||
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