CN105935358B - One seed sand library is than bent Valsartan sustained release agent and preparation method thereof - Google Patents
One seed sand library is than bent Valsartan sustained release agent and preparation method thereof Download PDFInfo
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- CN105935358B CN105935358B CN201510958324.0A CN201510958324A CN105935358B CN 105935358 B CN105935358 B CN 105935358B CN 201510958324 A CN201510958324 A CN 201510958324A CN 105935358 B CN105935358 B CN 105935358B
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- valsartan
- sustained release
- sacubitril
- release
- lubricant
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 80
- 229960004699 valsartan Drugs 0.000 title claims abstract description 77
- 238000013268 sustained release Methods 0.000 title claims abstract description 37
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 37
- 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 title claims abstract 10
- 239000003795 chemical substances by application Substances 0.000 title abstract description 3
- 239000004576 sand Substances 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 title description 17
- 239000000314 lubricant Substances 0.000 claims abstract description 22
- 239000003085 diluting agent Substances 0.000 claims abstract description 14
- 230000005496 eutectics Effects 0.000 claims abstract description 4
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 claims description 57
- 229960003953 sacubitril Drugs 0.000 claims description 57
- 239000003405 delayed action preparation Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 34
- 238000009472 formulation Methods 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000000463 material Substances 0.000 claims description 18
- 239000011248 coating agent Substances 0.000 claims description 15
- 238000000576 coating method Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 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 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 11
- 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 9
- 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 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
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- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
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- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims 1
- 239000007939 sustained release tablet Substances 0.000 abstract description 13
- 238000012360 testing method Methods 0.000 abstract description 11
- 238000000338 in vitro Methods 0.000 abstract description 10
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- 230000002459 sustained effect Effects 0.000 abstract 1
- ACWBQPMHZXGDFX-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=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 58
- 239000003826 tablet Substances 0.000 description 37
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- 239000012729 immediate-release (IR) formulation Substances 0.000 description 14
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- 206010019280 Heart failures Diseases 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
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- 230000002829 reductive effect Effects 0.000 description 9
- 229940100321 entresto Drugs 0.000 description 8
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 8
- 239000008384 inner phase Substances 0.000 description 6
- 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 5
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- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- 108010061435 Enalapril Proteins 0.000 description 2
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 2
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- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 2
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
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- PYNXFZCZUAOOQC-UHFFFAOYSA-N 4-[[5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid Chemical compound C1=CC(CC(CC(C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 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 description 1
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- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 description 1
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- 239000000692 natriuretic peptide Substances 0.000 description 1
- 210000000607 neurosecretory system Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 231100000572 poisoning Toxicity 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a seed sand libraries than bent Valsartan sustained release agent, comprising: Sha Ku is than bent Valsartan eutectic 10wt%~70wt%；Hydrophilic gel matrix material 10wt%~50wt%；0~80wt% of diluent；Lubricant 0.1wt%~10wt%；Above-mentioned each component total content is 100%.Sand library prepared by the present invention is in vitro than bent Valsartan sustained release tablets in the release research of simulated intestinal fluid, and to release about 80% in 8 hours, the equal slow release of two active constituents, in vitro test showed sustained releasing character for Sha Ku release about 80% in than bent to 12 hours, Valsartan.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a Sacubitril valsartan sustained release preparation and a preparation method thereof.
Background
Sacubitril/valsartan (formerly LCZ696) was developed by Nowa pharmaceutical, Switzerland, marketed in the United states under the trade designation "Entresto" 7 months in 2015 as a non-moisture-resistant coated immediate release tablet.
Entresto is used in heart failure patients with reduced ejection fraction (heart failure), reducing the risk of cardiovascular death and hospitalization for heart failure. Heart failure is a life-threatening heart disease in which the heart of a patient is unable to pump enough blood to face high risk of death, repeated hospitalizations, and other symptoms (e.g., dyspnea, fatigue, fluid retention), which can severely affect the life span and quality of life of the patient. Statistically, approximately 600 million heart failure patients in the United states are associated with a decrease in ejection fraction, of which about 220 million patients are classified as NYHA grades II-IV. The human population suitable for Entresto is patients with moderate to severe heart failure with heart function grade II-IV (NYHA class II-IV), which is usually combined with other heart failure drugs to replace Angiotensin Converting Enzyme (ACE) inhibitors or other Angiotensin Receptor Blockers (ARB). Entresto is a first-created dual-effect angiotensin receptor-enkephalinase inhibitor (ARNI), has a unique mode of action, can enhance the protective neuroendocrine system (NP system, natriuretic peptide system) of the heart, and simultaneously inhibits the harmful system (RAAS system, renin-angiotensin-aldosterone system), and is thought to reduce the strain of failing heart. LCZ696 combines the hypertension drug profile of Norwalk (Diovan, common name: valsartan, valsartan) and the experimental drug AHU-377 (Sacubitril). AHU377 is an enkephalinase inhibitor that blocks the mechanism of action threatening the 2 polypeptides responsible for lowering blood pressure, and valsartan is an angiotensin II receptor antagonist that improves vasodilation and stimulates the body to excrete sodium and water. Entresto's approval was based on the positive top line data of the milestone stage III PARADIGM-HF study, which was the ever largest-scale study conducted in the heart failure patient population. The data show that Entresto is significantly superior to enalapril (enalapril), a standard therapeutic drug for heart failure, ACE inhibitor, at multiple key endpoints, with highly statistically significant differences and clinical importance. Across treatment groups, Entresto showed sustainable therapeutic benefit from early treatment: (1) the risk of cardiovascular disease death is reduced by 20% (p ═ 0.00004); (2) the hospitalization rate for heart failure decreased by 21% (p ═ 0.00004); (3) the risk of all-cause death is reduced by 16% (p ═ 0.0005); overall, the risk is reduced by 20% (p 0.0000002) when measured as a combination of cardiovascular death or major cardiac failure hospitalization endpoints. In terms of safety, Entresto shows higher safety than conventional drugs.
CN201310154064.2 discloses a sacubitril valsartan cocrystal pharmaceutical composition and a preparation method thereof, which is a non-moisture-proof coated immediate release tablet, using a twice-daily administration mode. Immediate release tablets require two or more daily administrations, which often result in missed dose, and some patients may even be adept at changing the administration regimen, thereby failing to achieve the intended therapeutic objectives; and the administration mode of multiple daily administration is easy to generate larger peak-valley fluctuation phenomenon of the blood concentration, adverse reaction and even poisoning are easy to generate when the blood concentration is at the peak value, and the blood concentration is probably lower than the treatment concentration when the blood concentration is at the valley, so that the curative effect can not be exerted.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a Sacubitril valsartan sustained release preparation and a preparation method thereof, wherein in the prepared Sacubitril valsartan sustained release preparation, both components can be slowly released.
The invention provides a Sacubitril valsartan sustained release preparation, which comprises the following components:
the total content of the components is 100 percent.
Preferably, the hydrophilic gel matrix material is hydroxypropyl methyl cellulose.
Preferably, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose K15M or hydroxypropyl methylcellulose K100M.
Preferably, the content of the Sacubitril-valsartan co-crystal is 30-65 wt%.
Preferably, the content of the hydrophilic gel skeleton material is 20 wt% -40 wt%.
Preferably, the diluent is any one or more of lactose, starch, dextrin, calcium phosphate, calcium hydrogen phosphate, microcrystalline cellulose and polyethylene glycol.
Preferably, the lubricant is any one or more of magnesium stearate, talc and silica.
Preferably, the sabotabivalsartan sustained release preparation further comprises a coating.
The invention also provides a preparation method of the Sacubitril valsartan sustained release preparation, which comprises the following steps:
mixing the sacubitril valsartan co-crystal, the hydrophilic gel framework material, the diluent and the first lubricant, performing dry granulation, adding the second lubricant, mixing and tabletting to obtain the sacubitril valsartan sustained release preparation;
the weight ratio of the Sacubitril-valsartan co-crystal, the framework material and the diluent to the total weight of the first lubricant and the second lubricant is (10-70): (10-50): (0-80): (0.1-10).
Compared with the prior art, the invention provides a Sacubitril valsartan sustained release preparation, which comprises the following components: 10-70 wt% of Sacubitril-valsartan eutectic; 10-50 wt% of hydrophilic gel framework material; 0-80 wt% of a diluent; 0.1 wt% -10 wt% of lubricant; the total content of the components is 100 percent.
In the research of the release degree of the in-vitro simulated intestinal juice, the sabotaltrex valsartan sustained release tablet prepared by the invention releases about 80% in 12 hours and releases about 80% in 8 hours, and the two active ingredients are slowly released, so that the sustained release characteristic is shown in an in-vitro test.
The results of pharmacokinetic experiments in animals show that C of each active ingredient in the Sacubitril valsartan sustained release tablets prepared by the inventionmaxAre all obviously reduced, TmaxThe time of the sustained release preparation in vivo drug effect is obviously prolonged, and the sustained release characteristic of the preparation is obvious. The sustained release preparation reduces the peak-valley fluctuation of the blood concentration, reduces toxicity and adverse reaction, and maintains constant blood solubility of the treatment. The medicine is released through diffusion and/or gel skeleton erosion, the skeleton can be completely dissolved at last, the medicine is completely released, the bioavailability is equivalent to that of a quick release tablet, the administration frequency is reduced to once a day, the medicine is convenient to use, and the compliance of a patient is improved.
Drawings
Fig. 1 is a release profile of a sabotabivalsartan sustained release formulation prepared in example 1 of the present invention;
FIG. 2 is a release profile of Sacubitril valsartan sustained release formulation prepared in example 4 of the present invention;
FIG. 3 is a release profile of Sacubitril valsartan sustained release formulation prepared in comparative example 1 of the present invention;
FIG. 4 is a release profile of Sacubitril valsartan sustained release formulation prepared in comparative example 2 of the present invention;
FIG. 5 is a time course of a commercial immediate release tablet of Sacubitril valsartan;
FIG. 6 is a chronograph of the Sacubitril valsartan sustained release formulation prepared in example 1 of the present invention;
FIG. 7 is a chronograph of the Sacubitril valsartan sustained release formulation prepared in example 4 of the present invention;
FIG. 8 is a bar graph of the blood peak concentrations of the Sacubitril valsartan sustained release formulation prepared in accordance with an embodiment of the present invention and commercially available quick release tablets of Sacubitril valsartan;
fig. 9 is a blood peak time bar graph of the sabotabivalsartan sustained release preparation prepared by the example of the invention and the commercial immediate release tablet of sabotabivalsartan.
Detailed Description
The invention provides a Sacubitril valsartan sustained release preparation, which comprises the following components:
the total content of the components is 100 percent.
In the research of the release degree of the in-vitro simulated intestinal juice, the sabotaltrex valsartan sustained release tablet prepared by the invention releases about 80% in 12 hours and releases about 80% in 8 hours, and the two active ingredients are slowly released, so that the sustained release characteristic is shown in an in-vitro test.
The results of pharmacokinetic experiments in animals show that C of each active ingredient in the Sacubitril valsartan sustained release tablets prepared by the inventionmaxAre all obviously reduced, TmaxThe time of the sustained release preparation in vivo drug effect is obviously prolonged, and the sustained release characteristic of the preparation is obvious. The sustained release preparation reduces the peak-valley fluctuation of the blood concentration, reduces toxicity and adverse reaction, and maintains constant blood solubility of the treatment. The medicine is released through diffusion and/or gel skeleton erosion, the skeleton can be completely dissolved at last, the medicine is completely released, the bioavailability is equivalent to that of a quick release tablet, the administration frequency is reduced to once a day, the medicine is convenient to use, and the compliance of a patient is improved.
In the invention, the content of the Sacubitril-valsartan co-crystal is preferably 10-70 wt%, and more preferably 30-65 wt%.
The hydrophilic gel framework material is preferably hydroxypropyl methyl cellulose, and more preferably hydroxypropyl methyl cellulose K15M or hydroxypropyl methyl cellulose K100M.
The content of the framework material is preferably 10 wt% to 50 wt%, and more preferably 20 wt% to 40 wt%. In certain embodiments of the invention, the amount is 29 wt% or 36 wt%.
The diluent is preferably any one or more of lactose, starch, dextrin, calcium phosphate, calcium hydrogen phosphate, microcrystalline cellulose and polyethylene glycol, more preferably lactose.
The content of the diluent is preferably 0 to 80 wt%, and more preferably 0 to 30 wt%.
The lubricant is preferably any one or more of magnesium stearate, talc and silica, more preferably magnesium stearate and talc.
The content of the lubricant is preferably 0.1 wt% to 10 wt%, more preferably 3 wt% to 8 wt%.
Preferably, the sabotabivalsartan sustained release preparation further comprises a coating.
The material of the coating is preferably a moisture-proof film coating premix.
The content of the coating is preferably 3 wt% -6 wt% of the total amount of the tablet core.
Most preferably, in the Sacubitril valsartan sustained release preparation, a skeleton material is hydroxypropyl methyl cellulose K15M or K100M; the diluent is lactose; the lubricant is magnesium stearate and pulvis Talci; the material of the coating is opadry AMB. At the moment, the Sacubitril valsartan sustained release preparation has optimal sustained release performance.
The invention also provides a preparation method of the Sacubitril valsartan sustained release preparation, which comprises the following steps:
mixing the sacubitril valsartan co-crystal, the hydrophilic gel framework material, the diluent and the first lubricant, performing dry granulation, adding the second lubricant, mixing and tabletting to obtain the sacubitril valsartan sustained release preparation;
the weight ratio of the Sacubitril-valsartan co-crystal, the framework material and the diluent to the total weight of the first lubricant and the second lubricant is (10-70): (10-50): (0-80): (0.1-10).
The obtained Sacubitril valsartan sustained release preparation core material is provided.
The first lubricant and the second lubricant are added in portions, and the proportion thereof is not particularly limited in the present invention, and may be added according to actual conditions.
When the Sacubitril valsartan sustained release formulation has a coating, the steps further comprise:
uniformly dispersing the coating material in water to prepare 8-20% of suspension to obtain a coating solution;
and spraying the coating solution on the surface of the tablet core material of the Sacubitril valsartan sustained-release preparation, and drying to obtain the Sacubitril valsartan sustained-release preparation.
In order to further illustrate the present invention, the Sacubitril valsartan sustained release formulation and the preparation method thereof provided by the present invention are described in detail below with reference to examples.
Examples 1 to 3
According to the mixture ratio of table 1, the Sacubitril valsartan sustained release preparation is prepared:
table 1 examples 1-3 raw material ratios
Wherein,
49/51 mg/tablet: the content of the Sacubitril in the sustained release preparation of the Sacubitril and the valsartan is 49 mg/tablet and 51 mg/tablet. The rest is analogized in the same way.
The preparation method comprises the following steps:
uniformly mixing the Sacubitril-valsartan co-crystal, hydroxypropyl methylcellulose K15M, lactose and talcum powder in a three-dimensional motion mixer, adding magnesium stearate for mixing, rolling the obtained mixed powder into strips by a dry-method granulator under the pressure of about 30KN, and crushing and granulating by a granulator to obtain inner-phase particles; the granules of the inner phase are mixed with an additional part of talcum powder and magnesium stearate in a three-dimensional motion mixer uniformly, and then the final mixture is compressed into tablets by using a high-speed rotary tablet press. Coating with Opadry AMB type moisture-proof coating material to obtain the moisture-proof coated sustained-release tablet.
Examples 4 to 6
According to the mixture ratio of table 2, the sacubitril valsartan sustained release preparation is prepared:
table 2 examples 4 to 6 raw material ratios
The preparation method comprises the following steps:
uniformly mixing the Sacubitril-valsartan co-crystal, hydroxypropyl methylcellulose K100M and talcum powder in a three-dimensional motion mixer, adding magnesium stearate for mixing, rolling the obtained mixed powder into strips by a dry-method granulator under the pressure of about 30KN, and crushing and granulating by a granulator to obtain inner-phase particles; the granules of the inner phase are mixed with an additional part of talcum powder and magnesium stearate in a three-dimensional motion mixer uniformly, and then the final mixture is compressed into tablets by using a high-speed rotary tablet press. Coating with Opadry AMB type moisture-proof coating material to obtain the moisture-proof coated sustained-release tablet.
Comparative example 1
According to the mixture ratio of table 3, the sacubitril valsartan sustained release preparation is prepared:
TABLE 3 raw material compounding ratio of comparative example 1
The preparation method comprises the following steps:
uniformly mixing the Sacubitril-valsartan eutectic, ethyl cellulose and talcum powder in a three-dimensional motion mixer, adding magnesium stearate for mixing, rolling the obtained mixed powder into strips by a dry-process granulator under the pressure of about 30KN, and crushing and granulating by a granulator to obtain inner-phase particles; the granules of the inner phase are mixed with an additional part of talcum powder and magnesium stearate in a three-dimensional motion mixer uniformly, and then the final mixture is compressed into tablets by using a high-speed rotary tablet press.
Comparative example 2
According to the mixture ratio of table 4, the sacubitril valsartan sustained release preparation is prepared:
TABLE 4 raw material ratio of comparative example 2
The preparation method comprises the following steps:
adding the Sacubitril valsartan co-crystal into molten octadecanol in a water bath, stirring uniformly while the mixture is hot, cooling slowly under continuous stirring, then sieving with a 18-mesh sieve for granulation, then placing the granules, talcum powder and magnesium stearate into a three-dimensional motion mixer for uniform mixing, and then pressing the final mixture into tablets by using a high-speed rotary tablet press.
Example 7
In vitro release test
The results of in vitro release tests on the sacubitril valsartan sustained release formulations prepared in examples 1, 4, comparative examples 1 and 2 are shown in table 5 and fig. 1 to 4, and table 5 is a summary of the results of in vitro release tests in example 7 of the present invention.
Fig. 1 is a release profile of a sabotabivalsartan sustained release formulation prepared in example 1 of the present invention;
FIG. 2 is a release profile of Sacubitril valsartan sustained release formulation prepared in example 4 of the present invention;
FIG. 3 is a release profile of Sacubitril valsartan sustained release formulation prepared in comparative example 1 of the present invention;
FIG. 4 is a release profile of Sacubitril valsartan sustained release formulation prepared in comparative example 2 of the present invention;
TABLE 5 summary of the results of the in vitro Release test of example 7 of the invention
As can be seen from table 5, the sabotabivalsartan sustained release formulations prepared in examples 1 and 4 of the present invention have excellent sustained release characteristics, and are superior to the sabotabivalsartan sustained release formulations prepared in comparative examples 1 and 2.
Example 8
Moisture resistance test
The moisture resistance of the quick-release tablets (called original grinding tablets for short) of the salbutamol in example 1 and example 4 and the commercial salbutamol is tested, the results are shown in table 6, and the results of the moisture resistance test in example 8 of the invention are summarized in table 6.
Table 6 summary of moisture resistance test results of example 8 of the present invention
As can be seen from table 6, the samples prepared in examples 1 and 4 with the moisture-proof coating have significantly lower moisture absorption and weight gain than the original ground tablet under high humidity, so that the moisture absorption of the product is reduced, and the stability and the service life are effectively improved.
Example 9
In vivo Release assay
In order to determine whether the in vivo drug release of the sustained-release tablet prepared by the invention has sustained-release effect, animal in vivo experiments are carried out. Specifically, the method comprises the following steps: using 6 beagle dogs, 2 dogs each, a commercial sabotabivalisartan immediate-release tablet group was designated as group a (1A, 2A), a sabotabivalisartan sustained-release preparation prepared in example 1 was designated as group B (3B, 4B), and a sabotabivalisartan sustained-release preparation prepared in example 4 was designated as group C (5C, 6C), and each of group a (original 49/51mg standard, designated as F) of a single oral administration of sabotabivalisartan immediate-release tablet was measured (original 49/51mg standard, designated as F)0) And extended release tablet group B (sample 49/51mg size from example 1, noted F1) Group C (sample 49/51mg size from example 4, noted F2)。
Referring to the clinical pharmacokinetics test of the original tablet, the non-clinical pharmacokinetics blood sampling time point of the beagle dog is designed by adopting a drug administration mode of 1 tablet/tablet and oral drenching: blood samples were taken at the saphenous vein of the forelimb 0h before administration and 1h, 1.5h, 2h, 4h, 6h, 8h, 12h after administration of the immediate release tablet, 1h, 2h, 4h, 6h, 8h, 12h, 14h after administration of the sustained release formulation, and 2mL of whole blood was taken at each time point. After related treatment, plasma drug concentration of valsartan and LBQ657 (rapidly metabolically converted into active substance LBQ657 after absorption of Sacubitril) is determined, and corresponding pharmacokinetic parameter AUC is calculated0-t、AUC0-∞、Tmax、Cmax。
The results are shown in tables 7 to 11, and FIGS. 5 to 9.
FIG. 5 is a time course of a commercial immediate release tablet of Sacubitril valsartan;
FIG. 6 is a chronograph of the Sacubitril valsartan sustained release formulation prepared in example 1 of the present invention;
FIG. 7 is a chronograph of the Sacubitril valsartan sustained release formulation prepared in example 4 of the present invention;
fig. 8 is a histogram of blood peak concentrations of sabotabivalsartan sustained release formulations and commercially available immediate release tablets of sabotabivalsartan prepared according to an example of the present invention, wherein group a is the commercially available immediate release tablet of sabotabivalsartan, group B is the sustained release formulation of sabotabivalsartan prepared according to example 1, and group C is the sustained release formulation of sabotabivalsartan prepared according to example 4;
fig. 9 is a blood peak time bar graph of the sabotabivalsartan sustained release preparation prepared in the example of the present invention and the commercial sabotabivalsartan fast release tablet, wherein group a is the commercial sabotabivalsartan fast release tablet, group B is the sabotabivalsartan sustained release preparation prepared in example 1, and group C is the sabotabivalsartan sustained release preparation prepared in example 4;
in fig. 5 to 9, LBQ657 is an active substance obtained by rapid metabolic conversion of sabotara after absorption.
Table 7 shows the blood concentration data of the commercial sabotabivalsartan immediate release tablets; table 8 is the blood concentration data of the sabotabivalisartan sustained release tablets prepared in example 1; table 9 is the blood concentration data for the sabotabivalisartan sustained release tablets prepared in example 4; table 10 is the non-compartmental model pharmacokinetic parameters for each group; table 11 is the area under the time curve of blood concentration for each group of unit doses.
TABLE 7 blood concentration data for commercial Sacubitril immediate release tablets of valsartan
Table 8 blood concentration data of sabotabivalsartan sustained release tablets prepared in example 1
Table 9 blood concentration data of sabotabivalsartan sustained release tablets prepared in example 4
TABLE 10 sets of non-compartmental model pharmacokinetic parameters
TABLE 11 area under time curve of blood concentration for each group of unit dose
The experimental data show that F is orally taken by experimental animals under the condition of the same dosage1、F2AUC of (1)(0-∞)And F0AUC of (immediate Release preparation)(0-∞)The values are similar, which shows that the bioavailability of the Sacubitril valsartan sustained-release tablets prepared in examples 1 and 4 in vivo is bioequivalent to that of the original quick-release preparation.
From each pharmacokinetic parameter-peak blood concentration (C)max) It can be seen that Sacubitril valsartan crude grinding quick release tablet valsartan Cmax386.50ng/L, LBQ657 (in vivo transformation of Sacubitril) Cmax1159.49ng/L, sustained release preparation F1C of valsartanmax217.48ng/L, LBQ 657Cmax610.90ng/L, sustained release preparation F2C of valsartanmax226.78ng/L, LBQ 657Cmax637.15ng/L, sustained release preparation F1、F2C of (A)maxObviously reduces the blood concentration, is more stable and durable, avoids the peak-valley effect and has the slow release characteristic.
From each pharmacokinetic parameter-time to peak (T)max) It is known that F0、F1、F2The peak reaching times of valsartan are about 1.51h, 4.41h and 4.92h respectively, and the peak reaching times of LBQ657 are about 1.50h, 4.40h and 4.99h respectively, so that it can be seen that the valsartan in the sustained release preparations obtained in examples 1 and 4 and the T of LBQ657maxThe time of the drug effect of the sustained release preparations prepared in examples 1 and 4 in vivo is remarkably prolonged, and the sustained release characteristics of the preparations are remarkable.
According to the embodiment and the comparative example, the invention adopts hydroxypropyl methyl cellulose as a slow release material to prepare the Sacubitril valsartan sustained release preparation, and both medicaments can be slowly released and have the in vivo sustained release characteristic.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (3)
1. A Sacubitril valsartan sustained release formulation comprising:
the Sacubitril-Valsartan eutectic is 30-65 wt%;
hydroxypropyl methyl cellulose K15M or K100M 20 as hydrophilic gel skeleton material in 20-40 wt%;
0-80 wt% of a diluent;
0.1 wt% -10 wt% of lubricant;
the total content of the components is 100 percent;
the diluent is any one or more of lactose, starch, dextrin, calcium phosphate, calcium hydrogen phosphate, microcrystalline cellulose and polyethylene glycol;
the lubricant is any one or more of magnesium stearate, talcum powder and silicon dioxide.
2. The sacubitril valsartan sustained release formulation of claim 1, further comprising a coating.
3. A method of preparing a Sacubitril valsartan sustained release formulation according to any one of claims 1-2, comprising:
mixing the sacubitril valsartan co-crystal, the hydrophilic gel framework material, the diluent and the first lubricant, performing dry granulation, adding the second lubricant, mixing and tabletting to obtain the sacubitril valsartan sustained release preparation;
the weight ratio of the Sacubitril-valsartan co-crystal, the framework material and the diluent to the total weight of the first lubricant and the second lubricant is (30-65): (20-40): (0-80): (0.1-10).
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| KR102545274B1 (en) | 2020-02-26 | 2023-06-20 | 에리슨제약(주) | Sustained-release formulation comprising sacubitril and valsartan for treating heart failure, and multiple-release composite formulation comprising the same and method for preparation thereof |
| KR20210138510A (en) | 2020-05-12 | 2021-11-19 | 에리슨제약(주) | Pharmaceutical composition comprising sacubitril, valsartan and nebivolol for prevention or treatment of heart failure and ischemic heart disease, and pharmaceutical composite formulation including the same |
| CN112641742B (en) * | 2020-12-30 | 2022-12-20 | 南京康川济医药科技有限公司 | Sacubitril valsartan sodium sustained-release tablet and preparation method thereof |
| EP4371558A4 (en) * | 2021-07-12 | 2025-01-01 | Shanghai Aurora Biotechnology Co., Ltd. | COMPOSITION OF SACUBITRIL-VALSARTAN SODIUM WITH SUSTAINED RELEASE, MANUFACTURE PROCESS AND USE THEREOF |
| CN115444829B (en) * | 2022-10-25 | 2023-08-22 | 南京康川济医药科技有限公司 | Sakuba/valsartan sodium gastric retention sustained release tablet and preparation method thereof |
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