CN117942309A - Preparation method of Sha Kuba triclosartan sodium and dapagliflozin double-layer tablet - Google Patents
Preparation method of Sha Kuba triclosartan sodium and dapagliflozin double-layer tablet Download PDFInfo
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- CN117942309A CN117942309A CN202211286337.4A CN202211286337A CN117942309A CN 117942309 A CN117942309 A CN 117942309A CN 202211286337 A CN202211286337 A CN 202211286337A CN 117942309 A CN117942309 A CN 117942309A
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- sodium
- magnesium stearate
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- silicon dioxide
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- 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 title claims abstract description 44
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 43
- 239000011734 sodium Substances 0.000 title claims abstract description 40
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 31
- 239000000314 lubricant Substances 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 229920000881 Modified starch Polymers 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 12
- 239000003381 stabilizer Substances 0.000 claims abstract description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 88
- 239000000203 mixture Substances 0.000 claims description 67
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 60
- 235000019359 magnesium stearate Nutrition 0.000 claims description 44
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 38
- 239000008187 granular material Substances 0.000 claims description 38
- 235000015424 sodium Nutrition 0.000 claims description 34
- 238000002156 mixing Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 26
- 239000000377 silicon dioxide Substances 0.000 claims description 25
- 235000012239 silicon dioxide Nutrition 0.000 claims description 25
- 229960000913 crospovidone Drugs 0.000 claims description 22
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 22
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 20
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- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 17
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 16
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- 238000005096 rolling process Methods 0.000 claims description 14
- 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 13
- 239000008101 lactose Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
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- 235000021355 Stearic acid Nutrition 0.000 claims description 8
- 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 8
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 8
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 8
- 229940083542 sodium Drugs 0.000 claims description 8
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 8
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- 239000008117 stearic acid Substances 0.000 claims description 8
- NQRAWXHLZGWKRS-FTBISJDPSA-N [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 Chemical compound [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 NQRAWXHLZGWKRS-FTBISJDPSA-N 0.000 claims description 7
- 238000003825 pressing Methods 0.000 claims description 7
- 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
- 229930195725 Mannitol Natural products 0.000 claims description 4
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- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 claims description 3
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- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 abstract description 12
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- 239000004072 C09CA03 - Valsartan Substances 0.000 description 6
- 206010007558 Cardiac failure chronic Diseases 0.000 description 6
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 6
- 229960004699 valsartan Drugs 0.000 description 6
- 229940057948 magnesium stearate Drugs 0.000 description 5
- 229960002117 triamcinolone acetonide Drugs 0.000 description 5
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
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- RFZVORNKUWIYLO-UHFFFAOYSA-N sodium;(4-tert-butylphenyl)sulfonyl-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]azanide Chemical compound [Na+].COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1[N-]S(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 RFZVORNKUWIYLO-UHFFFAOYSA-N 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 1
- DOBNVUFHFMVMDB-BEFAXECRSA-N (2r,4s)-4-(3-carboxypropanoylamino)-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@@H](C)C(O)=O)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 DOBNVUFHFMVMDB-BEFAXECRSA-N 0.000 description 1
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- 208000019505 Deglutition disease Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
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- 102000003673 Symporters Human genes 0.000 description 1
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- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 1
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- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a preparation method of a double-layer tablet of sarcandesartan sodium and dapagliflozin, which comprises Sha Kuba triptan sodium preparation with reduced quality as a first layer, comprises Sha Kuba triptan sodium, a filler, a stabilizer, a disintegrating agent and a lubricant, wherein the stabilizer is pregelatinized starch; the dapagliflozin preparation as the second layer comprises dapagliflozin, a filling agent, a disintegrating agent and a lubricant. The double-layer tablet obtained by the method has good stability, simple process and low production cost, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical preparations, and particularly relates to a preparation method of a double-layer tablet of sarcandesartan sodium and dapagliflozin.
Background
Heart failure is a common clinical disease with higher incidence and continuously rising trend, and the disease is a complex clinical syndrome caused by factors such as heart structure, functional abnormality and the like, and is divided into acute heart failure and chronic heart failure. Wherein, chronic heart failure is the end-stage manifestation of clinical cardiovascular diseases, seriously affecting the physical health of patients and reducing the quality of life. The main method for treating chronic heart failure is the medicine in clinic, wherein the common medicine is an angiotensin II receptor antagonist.
Sha Kuba triptan sodium is a co-crystal formed by valsartan and the Neutral Endopeptidase (NEP) inhibitor Sha Kuba koji (sacubiril) of two different pharmacological chemicals angiotensin ii receptor antagonists/blockers (ARB). The product is developed by Norhua pharmacy, and Sha Kuba trovaptan sodium tablets are approved by FDA in 7 months of 2015 to be marketed under the trade name of Norhuintal, and are used for adult patients with chronic heart failure with reduced ejection fraction (NYHA II-IV grade, LVEF is less than or equal to 40 percent), and the risks of cardiovascular death and heart failure hospitalization are reduced.
Dapagliflozin is an effective, highly selective and orally active human kidney type 2 sodium-glucose co-transporter (SGLT 2) inhibitor that is effective in reducing the reduction in ejection fraction caused by heart failure at low risk of inducing hypoglycemia. Dapagliflozin tablet is developed by Bai-Shi Guibao and Alpre company in combination, and is approved by CFDA in 2017 in month 3, and is the first SGLT2 inhibitor marketed in China for treating type 2 diabetes, and the Chinese trade name is Anda Tang. Month 5 of 2020, FDA approved it for the treatment of adult patients with heart failure with reduced ejection fraction (with/without diabetes) and month 10 of 2020, FDA approved it for reducing the risk of hospitalization for heart failure in adults with type 2 diabetes and other cardiovascular diseases.
The nuo xin tall developed by the nowa company at present is a common quick release preparation, needs to be taken 2 times a day, and has the following disadvantages: 1. the medicine taking times are relatively more, and the medicine taking difficulty of people, especially old people and dysphagia people, is increased; 2. symptomatic hypotension may result, clinically starting with lower doses, slowly doubling the dose according to patient tolerance; 3. sha Kuba the sodium of the triptan is easy to absorb moisture and deliquesce, so that the components of the Sha Kuba triptan and the valsartan are separated, and the preparation and the storage of the pharmaceutical preparation are affected.
Therefore, the compound preparation of Sha Kuba valsartan sodium and other anti-heart failure medicines can be developed, the medicine effect can be enhanced, the administration dosage can be reduced, the administration frequency can be reduced, and the preparation has higher clinical value. However, the method for preparing the double-layer tablet has high requirement on auxiliary materials, high pressing difficulty, special equipment and adverse industrialization.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a double-layer tablet of sodium sarcandesartan and dapagliflozin. The first layer of the double-layer tablet is Sha Kuba-Trivalsartan sodium preparation with reduced mass, and the second layer is dapagliflozin preparation. The double-layer tablet aims at solving the problems that Sha Kuba trovatam sodium is easy to absorb moisture, the administration times are more, and the clinical administration needs slow multiplication of dosage. The double-layer tablet prepared by the invention can well solve the problem that Sha Kuba triptan sodium active ingredient is easy to absorb moisture, and ensures the process smoothness of the preparation in the preparation process; meanwhile, the anti-heart failure drug effect of the drug is obviously improved, the administration frequency is reduced, and the administration dosage is reduced; in addition, the safety risk brought by high-dose administration can be reduced on the premise of ensuring the effectiveness of the medicine. The preparation method has the advantages of simple process, low cost and easy obtainment of auxiliary materials, and easy mass production.
The technical scheme is as follows: the preparation method of the double-layer tablet of the sarcandesartan valsartan sodium and dapagliflozin comprises the following steps:
blending Sha Kuba a zolpidem sodium bulk drug with a filler, a stabilizer, a disintegrating agent and a lubricant;
step (2), granulating the mixture obtained in the step (1) by a dry granulator, setting the rolling pressure of the dry granulator to be 30-60bar, and setting the rotating speed of a roller to be 2-10rpm and the gap between the rollers to be 1.0-3.0mm;
Step (3), after the granules obtained in the step (2) are granulated by a granulator, uniformly mixing the granules with a disintegrating agent and a lubricant;
And (4) blending the dapagliflozin bulk drug with a filler, a disintegrating agent and a lubricant.
Step (5), granulating the mixture obtained in the step (4) by a dry granulator, setting the rolling pressure of the dry granulator to be 30-55bar, and setting the rotating speed of a roller to be 1-5rpm and the clearance of the roller to be 1.0-3.0mm;
Step (6), after the granules obtained in the step (5) are granulated by a granulator, uniformly mixing the granules with a disintegrating agent and a lubricant;
and (7) placing the mixture obtained in the step (3) in a first charging hopper of a tablet press, and placing the mixture obtained in the step (6) in a second charging hopper for double-layer compression.
Wherein the ratio of Sha Kuba troxartan sodium in the step (1) is preferably 10-20%, and the ratio of dapagliflozin in the step (4) is 0.5-2.0%.
The filler in the step (1) is selected from one or more of lactose, mannitol, microcrystalline cellulose and pregelatinized starch, preferably microcrystalline cellulose, and the proportion is preferably 2-10%.
The stabilizer in step (1) is preferably pregelatinized starch, and the proportion is preferably 2-10%.
The disintegrating agent in the step (1) is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably a mixture of crospovidone and low-substituted hydroxypropyl cellulose, wherein the proportion of the crospovidone is preferably 1-5%, and the proportion of the low-substituted hydroxypropyl cellulose is preferably 2-10%.
The lubricant in the step (1) is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder, preferably a mixture of silicon dioxide, magnesium stearate and talcum powder, wherein the silicon dioxide accounts for preferably 0.1-0.4%, the magnesium stearate accounts for preferably 0.5-1.0%, and the talcum powder accounts for preferably 0.2-0.5%.
The disintegrating agent in the step (3) is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone, and the proportion is preferably 1.5-2.0%.
The lubricant in the step (3) is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder, preferably a mixture of magnesium stearate and talcum powder, wherein the magnesium stearate accounts for preferably 0.5-1.0%, and the talcum powder accounts for preferably 0.1-0.3%.
The filler in the step (4) is selected from one or more of lactose, mannitol, microcrystalline cellulose and pregelatinized starch, preferably a mixture of microcrystalline cellulose and lactose, wherein the microcrystalline cellulose accounts for preferably 35-50%, and the lactose accounts for preferably 7-10%.
The disintegrating agent in the step (4) is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone, and the proportion is preferably 1.0-1.5%.
The lubricant in the step (4) is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder, preferably a mixture of silicon dioxide and magnesium stearate, wherein the silicon dioxide accounts for preferably 0.5-1.0%, and the magnesium stearate accounts for preferably 0.3-0.7%.
The disintegrating agent in the step (6) is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone, and the proportion is preferably 1.0-1.5%.
The lubricant in the step (6) is one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder, preferably a mixture of magnesium stearate and silicon dioxide, wherein the proportion of magnesium stearate is preferably 0.1-0.5%, and the proportion of silicon dioxide is preferably 0.2-0.5%.
Compared with the prior art, the invention has the following remarkable advantages:
(1) The pregelatinized starch is introduced as a stabilizer, so that the problem that Sha Kuba troxartan sodium active ingredient is easy to absorb moisture is solved, and the process smoothness of the preparation in the preparation process is ensured.
(2) Sha Kuba the boscalid sodium and dapagliflozin are prepared into double-layer tablets, so that the heart failure resistance effect of the medicine is improved, the administration frequency is reduced, and the administration dosage is reduced.
(3) The preparation process has the advantages of low price, easy obtainment of auxiliary materials, simple process and easy mass production.
Detailed description of the preferred embodiments
The invention will be further illustrated with reference to specific examples.
Example 1 preparation of formulation 1
(1) Sha Kuba A Trifloxed, sartan sodium tablet
(2) Dapagliflozin tablet layer
The Sha Kuba trovaptan sodium and dapagliflozin double-layer tablet is prepared according to the formula in the table, and the preparation method comprises the following steps:
(1) Sieving and mixing Sha Kuba of the raw material medicine of the bosentan sodium and the low-substituted hydroxypropyl cellulose, adding microcrystalline cellulose, pregelatinized starch, crosslinked povidone, colloidal silicon dioxide, talcum powder and magnesium stearate into a conical mixer for premixing;
(2) Granulating the mixture obtained in the step (1) by a dry granulator, and setting the rolling pressure of the dry granulator to be 35bar, the rotating speed of a roller to be 3rpm and the clearance of the roller to be 1.5+/-0.3 mm;
(3) After the granules obtained in the step (2) are granulated by a granulator, adding the granules and externally added crosslinked povidone, talcum powder and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(4) Sieving and mixing dapagliflozin raw material medicine and lactose, adding microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate into a conical mixer for premixing;
(5) Granulating the mixture obtained in the step (4) by a dry granulator, and setting the rolling pressure of the dry granulator to be 45bar, the rotating speed of a roller to be 3rpm and the clearance of the roller to be 2.5+/-0.3 mm;
(6) After the granules obtained in the step (5) are granulated by a granulator, adding the granules and externally added crosslinked povidone, silicon dioxide and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(7) And (3) placing the total mixed particles obtained in the step (3) in a first charging hopper of a tablet press, and placing the total mixed particles obtained in the step (6) in a second charging hopper for double-layer pressing.
Example 2 preparation of formulation 2 (1) Sha Kuba valsartan sodium platelet
(2) Dapagliflozin tablet layer
The Sha Kuba trovaptan sodium and dapagliflozin double-layer tablet is prepared according to the formula in the table, and the preparation method comprises the following steps:
(1) Sieving and mixing Sha Kuba of the raw material medicine of the bosentan sodium and the low-substituted hydroxypropyl cellulose, adding microcrystalline cellulose, pregelatinized starch, crosslinked povidone, colloidal silicon dioxide, talcum powder and magnesium stearate into a conical mixer for premixing;
(2) Granulating the mixture obtained in the step (1) by a dry granulator, and setting the rolling pressure of the dry granulator to be 45bar, the rotating speed of a roller to be 2rpm, and the clearance of the roller to be 2.0+/-0.3 mm;
(3) After the granules obtained in the step (2) are granulated by a granulator, adding the granules and externally added crosslinked povidone, talcum powder and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(4) Sieving and mixing dapagliflozin raw material medicine and lactose, adding microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate into a conical mixer for premixing;
(5) Granulating the mixture obtained in the step (4) by a dry granulator, and setting the rolling pressure of the dry granulator to be 40bar, the rotating speed of a roller to be 2rpm and the clearance of the roller to be 2.0+/-0.3 mm;
(6) After the granules obtained in the step (5) are granulated by a granulator, adding the granules and externally added crosslinked povidone, silicon dioxide and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(7) And (3) placing the total mixed particles obtained in the step (3) in a first charging hopper of a tablet press, and placing the total mixed particles obtained in the step (6) in a second charging hopper for double-layer pressing.
Example 3 preparation of formulation 3
(1) Sha Kuba A Trifloxed, sartan sodium tablet
(2) Dapagliflozin tablet layer
The Sha Kuba trovaptan sodium and dapagliflozin double-layer tablet is prepared according to the formula in the table, and the preparation method comprises the following steps:
(1) Sieving and mixing Sha Kuba of the raw material medicine of the eletriptan sodium and the low-substituted hydroxypropyl cellulose, adding microcrystalline cellulose, crosslinked povidone, colloidal silicon dioxide, talcum powder and magnesium stearate into a conical mixer for premixing;
(2) Granulating the mixture obtained in the step (1) by a dry granulator, and setting the rolling pressure of the dry granulator to be 55bar, the rotating speed of a roller to be 2rpm, and the clearance of the roller to be 2.5+/-0.3 mm;
(3) After the granules obtained in the step (2) are granulated by a granulator, adding the granules and externally added crosslinked povidone, talcum powder and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(4) Sieving and mixing dapagliflozin raw material medicine and lactose, adding microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate into a conical mixer for premixing;
(5) Granulating the mixture obtained in the step (4) by a dry granulator, and setting the rolling pressure of the dry granulator to be 35bar, the rotating speed of a roller to be 2rpm and the clearance of the roller to be 1.5+/-0.3 mm;
(6) After the granules obtained in the step (5) are granulated by a granulator, adding the granules and externally added crosslinked povidone, silicon dioxide and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(7) And (3) placing the total mixed particles obtained in the step (3) in a first charging hopper of a tablet press, and placing the total mixed particles obtained in the step (6) in a second charging hopper for double-layer pressing.
Example 4 preparation of formulation 4
(1) Sha Kuba A Trifloxed, sartan sodium tablet
(2) Dapagliflozin tablet layer
The Sha Kuba trovaptan sodium and dapagliflozin double-layer tablet is prepared according to the formula in the table, and the preparation method comprises the following steps:
(1) Sieving and mixing Sha Kuba of the raw material medicine of the bosentan sodium and the low-substituted hydroxypropyl cellulose, adding microcrystalline cellulose, pregelatinized starch, crosslinked povidone, colloidal silicon dioxide, talcum powder and magnesium stearate into a conical mixer for premixing;
(2) Granulating the mixture obtained in the step (1) by a dry granulator, and setting the rolling pressure of the dry granulator to be 55bar, the rotating speed of a roller to be 2rpm, and the clearance of the roller to be 2.5+/-0.3 mm;
(3) After the granules obtained in the step (2) are granulated by a granulator, adding the granules and externally added crosslinked povidone, talcum powder and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(4) Sieving and mixing dapagliflozin raw material medicine and lactose, adding microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate into a conical mixer for premixing;
(5) Granulating the mixture obtained in the step (4) by a dry granulator, and setting the rolling pressure of the dry granulator to be 35bar, the rotating speed of a roller to be 2rpm and the clearance of the roller to be 1.5+/-0.3 mm;
(6) After the granules obtained in the step (5) are granulated by a granulator, adding the granules and externally added crosslinked povidone, silicon dioxide and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(7) And (3) placing the total mixed particles obtained in the step (3) in a first charging hopper of a tablet press, and placing the total mixed particles obtained in the step (6) in a second charging hopper for double-layer pressing.
Example 5 preparation of formulation 5 (1) Sha Kuba valsartan sodium platelet
(2) Dapagliflozin tablet layer
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The Sha Kuba trovaptan sodium and dapagliflozin double-layer tablet is prepared according to the formula in the table, and the preparation method comprises the following steps:
(1) Sieving and mixing Sha Kuba of the raw material medicine of the bosentan sodium and the low-substituted hydroxypropyl cellulose, adding microcrystalline cellulose, pregelatinized starch, crosslinked povidone, colloidal silicon dioxide, talcum powder and magnesium stearate into a conical mixer for premixing;
(2) Granulating the mixture obtained in the step (1) by a dry granulator, and setting the rolling pressure of the dry granulator to be 55bar, the rotating speed of a roller to be 2rpm, and the clearance of the roller to be 2.5+/-0.3 mm;
(3) After the granules obtained in the step (2) are granulated by a granulator, adding the granules and externally added crosslinked povidone, talcum powder and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(4) Sieving and mixing dapagliflozin raw material medicine and lactose, adding microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate into a conical mixer for premixing;
(5) Granulating the mixture obtained in the step (4) by a dry granulator, and setting the rolling pressure of the dry granulator to be 35bar, the rotating speed of a roller to be 2rpm and the clearance of the roller to be 1.5+/-0.3 mm;
(6) After the granules obtained in the step (5) are granulated by a granulator, adding the granules and externally added crosslinked povidone, silicon dioxide and magnesium stearate into a conical mixer for total mixing to obtain total mixed granules;
(7) And (3) placing the total mixed particles obtained in the step (3) in a first charging hopper of a tablet press, and placing the total mixed particles obtained in the step (6) in a second charging hopper for double-layer pressing.
EXAMPLE 6 stability Studies
Stability study experiments were performed on the formulations 1 to 3 obtained in examples 1 to 3, that is, the formulations were allowed to stand for 30 days at 40.+ -. 2 ℃ and 75.+ -. 5% RH to examine the changes of the related substances, and the HPLC detection results are shown in Table 1.
Table 1 stability study data
Impurity 1 is the degradation impurity of sabatier, impurity 2 is the degradation impurity of valsartan, and impurity 3 is the degradation impurity of dapagliflozin, all are the internal control impurity that lists the quality standard. The stability data show that indexes of related substances of the Sha Kuba-valsartan sodium and dapagliflozin double-layer tablet are not changed obviously, and the quality of a sample is stable.
EXAMPLE 7 hygroscopicity study
The formulations 1 to 3 obtained in examples 1 to 3 were subjected to a hygroscopicity study, the formulations were placed in a constant temperature and humidity cabinet with an open mouth, the temperature was controlled at 25.+ -. 2 ℃ and the humidity was controlled at RH60% and RH50%, respectively, and after 24 hours, the appearance of the tablets was observed, and the results are shown in Table 2.
TABLE 2 study of hygroscopicity
| Formulation 1 | Formulation 2 | Formulation 3 | Formulation 4 | Formulation 5 | |
| RH50％ | Normal state | Normal state | Normal state | Normal state | Normal state |
| RH60％ | Normal state | Normal state | Cracking of | Normal state | Normal state |
As shown in the table above, the preparation 3 does not contain stabilizer auxiliary materials, the tablet absorbs moisture and cracks after being placed for 24 hours under the condition of RH60%, and the samples prepared from the preparations 1,2,4 and 5 all contain stabilizer pregelatinized starch, the tablet has normal appearance after being placed for 24 hours under the conditions of RH60% and RH50%, which indicates that the pregelatinized starch can effectively solve the problem that Sha Kuba troxatan sodium absorbs moisture easily, and the humidity condition of the tablet storage is improved.
EXAMPLE 8 dissolution study
Sha Kuba determination of the dissolution rate of the sodium salt of the triclosan: according to the dissolution and release measurement method (second method of the fourth edition of China pharmacopoeia 2015, ministry of China, general rule 0931), 900ml of pH6.8 phosphate buffer solution is taken as a dissolution medium, and the rotating speed is 50 revolutions per minute.
Dapagliflozin dissolution assay: according to the dissolution and release measurement method (the first method of the fourth edition of China pharmacopoeia 2015, the fourth edition general rule 0931), 1000ml of phosphate buffer solution with pH of 6.8 is taken as a dissolution medium, and the rotating speed is 100 revolutions per minute.
The results are shown in tables 3-5.
TABLE 3 dissolution data for Sha Kuba koji in samples
| 5min | 10min | 15min | 20min | 30min | 45min | |
| Formulation 1 | 24 | 53 | 74 | 86 | 92 | 94 |
| Formulation 2 | 27 | 56 | 75 | 87 | 93 | 94 |
| Formulation 3 | 28 | 57 | 78 | 87 | 92 | 95 |
| Formulation 4 | 32 | 68 | 84 | 89 | 93 | 96 |
| Formulation 5 | 28 | 57 | 77 | 88 | 93 | 94 |
| Norxin tuo | 30 | 59 | 81 | 91 | 96 | 98 |
Table 4 dissolution data of valsartan in samples
| 5min | 10min | 15min | 20min | 30min | 45min | |
| Formulation 1 | 25 | 53 | 75 | 87 | 94 | 95 |
| Formulation 2 | 28 | 57 | 77 | 89 | 95 | 97 |
| Formulation 3 | 28 | 58 | 79 | 88 | 93 | 96 |
| Formulation 4 | 30 | 66 | 82 | 88 | 92 | 95 |
| Formulation 5 | 27 | 56 | 77 | 88 | 94 | 97 |
| Norxin tuo | 30 | 60 | 82 | 92 | 96 | 99 |
TABLE 5 dissolution data for dapagliflozin in samples
| 5min | 10min | 15min | 20min | 30min | 45min | |
| Formulation 1 | 79 | 90 | 93 | 94 | 95 | 96 |
| Formulation 2 | 78 | 90 | 93 | 93 | 94 | 94 |
| Formulation 3 | 73 | 88 | 91 | 92 | 93 | 94 |
| Formulation 4 | 82 | 92 | 95 | 95 | 96 | 96 |
| Formulation 5 | 84 | 93 | 95 | 96 | 96 | 97 |
| Tang Dynasty (Anda) | 64 | 88 | 93 | 94 | 96 | 96 |
As can be seen from the above table, formulations 1-5 substantially match the dissolution profile of the commercial formulations of Northcell and Anda within 45min at pH 6.8.
Example 9 bioavailability evaluation
Beagle dogs were used as test animals and the dosing conditions were as follows:
Fasted period: the animals were not fed at night prior to dosing. Water and conventional feed (SSNIFFHDH) were administered at 1 hour and 4 hours after administration, respectively.
Feeding period: at 10 minutes prior to dosing, the animals received 50g of a high fat diet (SSNIFFEF DogFDA high fat model) (the diet has an energy value of 100kcal and is composed of 15% protein, 25% carbohydrate and 50-60% fat). Water and conventional feed were then administered (SSNIFFHDH) at 1 hour and 4 hours after administration, respectively.
The treatment is as follows:
Treatment 1: formulation 2 tablet, fasted condition, oral route.
Comparative treatment 1: norXintuo (100 mg specification), fasted condition, oral route.
Comparative treatment 2: tang Dynasty (10 mg specification), fasted condition, oral route
Treatment 2: formulation 2 tablet, fed condition, oral route.
Comparative treatment 3: norXintuo (100 mg format), fed condition, oral route.
Comparative treatment 4: anderson (10 mg gauge), fed condition, oral route.
Sampling and analysis:
Blood samples were collected in plastic tubes containing heparin lithium as anticoagulant at the following sample collection times: 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8 and 24 hours before treatment and after administration of each treatment.
Plasma concentrations of Sha Kuba g, valsartan, LBQ657 (active metabolite of Sha Kuba g), dapagliflozin were determined by liquid chromatography mass spectrometry coupling (LC-MS/MS) using exploratory analysis methods.
The following pharmacokinetic parameters were measured for each treatment:
C max (ng/mL): corresponding to the maximum plasma concentration observed,
T max (h): corresponding to the observation time for obtaining the maximum concentration,
AUC last: the time from t 0 to the final quantifiable concentration is calculated by the trapezoidal method, corresponding to the area under the curve or integral of the plasma concentration as a function of time t.
AUC: corresponding to the area under the curve or integral of plasma concentration as a function of time extrapolated to infinity.
T 1/2z: final elimination half life
The results are shown in tables 6-9.
Table 6 Sha Kuba pharmacokinetic parameters of the curve (mean ± SD, n=6 for each formulation)
Table 7 pharmacokinetic parameters of valsartan (mean ± SD, n=6 for each formulation)
Pharmacokinetic parameters of table 8LBQ657 (mean ± SD, n=6 for each formulation)
Table 9 pharmacokinetic parameters of dapagliflozin (mean ± SD, n=6 for each formulation)
In the fasted and fed state, the observed C max and AUC of the double-layer tablet of sabafaxitan and dapagliflozin provided by the invention are similar to the calculated C max and AUC of commercially available norubicin and anderson.
EXAMPLE 10 pharmacodynamic evaluation
Establishment of a chronic heart failure dog model: the method of percutaneous femoral artery puncture is adopted, the remote end in the coronary artery of the beagle is repeatedly micro-embolized, hemodynamic and echocardiographic examination is carried out for 1 time per week until the total Ejection Fraction (EF) of the left ventricle and the maximum rising rate (dP/dt max) of the pressure in the left ventricle are respectively reduced by 20% -25%, the end diastolic pressure (LVEDP) of the left ventricle is more than 14mmHg, and no obvious change is caused in 7-10 days, thus a stable chronic heart failure canine model is established.
For the dose of Sha Kuba triamcinolone acetonide, reference was made to a low dose of 100mg (about 1.5mg/kg based on a standard weight of 70 kg) administered to humans, corresponding to a low dose of 30mg (about 2.5mg/kg based on a standard weight of 12 kg) administered to dogs on the equivalent dose conversion basis; similarly, the high dose of 200mg administered to humans corresponds to the low dose of 60mg administered to dogs. Similarly, for the dose of dapagliflozin, reference was made to a dose of 10mg administered to humans, corresponding to a dose of 3mg administered to dogs.
After successful micro-embolism modeling, heart failure beagle dogs were randomly divided into the following groups:
model group: an equal volume of physiological saline was administered by gavage once daily.
Sha Kuba triamcinolone acetonide sodium high dose group: the gastric administration was carried out twice daily with 60mg Sha Kuba% of valsartan sodium.
Sha Kuba triamcinolone acetonide sodium low dose group: the gastric administration was carried out twice daily with 30mg Sha Kuba% of valsartan sodium.
Dapagliflozin group: the stomach was irrigated with 3mg dapagliflozin once daily.
Sha Kuba. Trifloxatan sodium+dapagliflozin group: gastric administration was performed once daily with 30mg Sha Kuba% of fasciated sodium plus 3mg of dapagliflozin.
Each group was given the corresponding drug daily by intragastric administration and blood pressure, echocardiography, and hemodynamic measurements were performed on each group of beagle dogs after 7 weeks, and the results are shown in tables 10, 11.
Table 10 changes in blood pressure (mean ± SD, n=6) for each group of test dogs
Table 11 changes in various indices related to heart failure of each group of test dogs (mean ± SD, n=6)
From the data in the table, the combination of dapagliflozin and Sha Kuba triamcinolone acetonide can improve the heart failure resistance, reduce the administration frequency, reduce the risk of lowering blood pressure caused by high-dose administration on the premise of ensuring the effectiveness of the medicine, and effectively solve the problem that the clinical administration of Sha Kuba triamcinolone acetonide needs to slowly multiply the dosage.
Claims (10)
1. The preparation method of the double-layer tablet of the sarcandesartan valsartan sodium and dapagliflozin comprises the following steps:
blending Sha Kuba a zolpidem sodium bulk drug with a filler, a stabilizer, a disintegrating agent and a lubricant;
step (2), granulating the mixture obtained in the step (1) by a dry granulator, setting the rolling pressure of the dry granulator to be 30-60bar, and setting the rotating speed of a roller to be 2-10rpm and the gap between the rollers to be 1.0-3.0mm;
Step (3), after the granules obtained in the step (2) are granulated by a granulator, uniformly mixing the granules with a disintegrating agent and a lubricant;
step (4), blending dapagliflozin bulk drug with filler, disintegrating agent and lubricant;
Step (5), granulating the mixture obtained in the step (4) by a dry granulator, setting the rolling pressure of the dry granulator to be 30-55bar, and setting the rotating speed of a roller to be 1-5rpm and the clearance of the roller to be 1.0-3.0mm;
Step (6), after the granules obtained in the step (5) are granulated by a granulator, uniformly mixing the granules with a disintegrating agent and a lubricant;
Step (7), placing the mixture obtained in the step (3) in a first charging hopper of a tablet press, and placing the mixture obtained in the step (6) in a second charging hopper for double-layer pressing;
Wherein the stabilizer in the step (1) is pregelatinized starch, the proportion of Sha Kuba% of the sodium bulk drug of the zolpidem is 10-20%, and the proportion of the dapagliflozin bulk drug in the step (4) is 0.5-2.0%.
2. The preparation method according to claim 1, wherein the filler in the step (1) is one or more selected from lactose, mannitol and microcrystalline cellulose; the disintegrating agent is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder.
3. The method according to claim 2, wherein the filler in the step (1) is microcrystalline cellulose in a proportion of 2 to 16%; the disintegrating agent is a mixture of crospovidone and low-substituted hydroxypropyl cellulose, wherein the cross-linked povidone accounts for 1-5%, and the low-substituted hydroxypropyl cellulose accounts for 2-10%; the lubricant is a mixture of silicon dioxide, magnesium stearate and talcum powder, the silicon dioxide accounts for 0.1-0.4%, the magnesium stearate accounts for 0.5-1.0%, and the talcum powder accounts for 0.2-0.5%.
4. The method of claim 1, wherein the pregelatinized starch in step (1) comprises 2-10%.
5. The preparation method according to claim 1, wherein the disintegrating agent in the step (3) is one or more selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder.
6. The method according to claim 5, wherein the disintegrant in step (3) is crospovidone in an amount of 1.0 to 2.0%. The lubricant is a mixture of magnesium stearate and talcum powder, wherein the magnesium stearate accounts for 0.5-1.0%, and the talcum powder accounts for 0.1-0.3%.
7. The preparation method according to claim 1, wherein the filler in the step (4) is one or more selected from lactose, mannitol and microcrystalline cellulose; the disintegrating agent is one or more selected from crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder.
8. The method according to claim 7, wherein the filler in the step (4) is a mixture of microcrystalline cellulose and lactose, the microcrystalline cellulose accounts for 35-50% and the lactose accounts for 7-15%; the disintegrating agent is crospovidone, and the proportion is 1.0-1.5%; the lubricant is a mixture of silicon dioxide and magnesium stearate, the silicon dioxide accounts for 0.5-1.0%, and the magnesium stearate accounts for 0.3-0.7%.
9. The preparation method according to claim 1, wherein the disintegrating agent in the step (6) is one or more selected from the group consisting of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate and talcum powder.
10. The method of claim 9, wherein the disintegrant in step (6) is crospovidone in a ratio of 1.0 to 2.0%; the lubricant is a mixture of magnesium stearate and silicon dioxide, wherein the magnesium stearate accounts for 0.1-0.6%, and the silicon dioxide accounts for 0.2-0.5%.
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