CN115429765B - Sustained release preparation of sotalol hydrochloride and preparation method thereof - Google Patents
Sustained release preparation of sotalol hydrochloride and preparation method thereof Download PDFInfo
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- CN115429765B CN115429765B CN202110610166.5A CN202110610166A CN115429765B CN 115429765 B CN115429765 B CN 115429765B CN 202110610166 A CN202110610166 A CN 202110610166A CN 115429765 B CN115429765 B CN 115429765B
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- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960003579 sotalol hydrochloride Drugs 0.000 title claims abstract description 65
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 50
- 238000013268 sustained release Methods 0.000 claims abstract description 39
- 239000012730 sustained-release form Substances 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 27
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 24
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 23
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 17
- 229920003156 Eudragit® RL PO Polymers 0.000 claims abstract description 16
- 239000002245 particle Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000000853 adhesive Substances 0.000 claims abstract description 6
- 230000001070 adhesive effect Effects 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 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
- 238000001035 drying Methods 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
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- 230000008569 process Effects 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 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 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 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 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 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 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 229960001681 croscarmellose sodium Drugs 0.000 claims 1
- 229960000913 crospovidone Drugs 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 1
- 238000010298 pulverizing process Methods 0.000 claims 1
- 229940083542 sodium Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 229960003943 hypromellose Drugs 0.000 abstract description 7
- 230000032683 aging Effects 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000005550 wet granulation Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 9
- 230000001186 cumulative effect Effects 0.000 description 8
- 238000011049 filling Methods 0.000 description 7
- 206010067484 Adverse reaction Diseases 0.000 description 6
- 229920003160 Eudragit® RS PO Polymers 0.000 description 6
- 230000006838 adverse reaction Effects 0.000 description 6
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- 238000000338 in vitro Methods 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
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- 239000013558 reference substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010003662 Atrial flutter Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- 206010047302 ventricular tachycardia Diseases 0.000 description 1
Classifications
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the new technical field of pharmaceutical preparations, and provides a sustained-release preparation of sotalol hydrochloride and a preparation method thereof. The sustained release preparation of sotalol hydrochloride provided by the invention is prepared by adopting a wet granulation technology, and is obtained by mixing drug-loaded sustained release particles and a lubricant and tabletting. The drug-loaded slow-release particles consist of sotalol hydrochloride, a filler, a disintegrating agent, an adhesive, a glidant and a slow-release framework material, wherein the framework material is a composition of hypromellose K15M and Eudragit RL-PO. The skeleton type sustained release preparation is difficult to leak, has a good sustained release effect, improves the problem of release reduction or the effect of dose burst caused by aging of a film control agent, and ensures the safety of clinical medication. And the preparation process is simple, the technical difficulty is low, the cost is low, and the like, and the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and provides a sotalol hydrochloride sustained-release preparation and a preparation method thereof.
Background
Sotalol hydrochloride, 4' - (1-hydroxy-2-isopropylamino ethyl) methanesulfonamide hydrochloride, is a non-selective beta adrenergic receptor blocker, with beta 1 And beta 2 The receptor blocking effect, the prolongation effect of III class action potential (ADP) and the inhibition of various antiarrhythmic drugs related to sympathetic nerve excitation. The beta-receptor blocker developed by Squibb is synthesized for the first time in 1960, and is approved by FDA in 1992 to be marketed as a first-line drug for treating sinus rhythm and atrial fibrillation.
Sotalol hydrochloride is easily soluble in water or methanol, soluble in ethanol, and hardly soluble in chloroform. The traditional Chinese medicine composition is a common preparation such as a preparation, an injection, a freeze-dried powder injection and the like, and is mainly used for treating various ventricular arrhythmias, atrial flutter, tremor, prevention of ventricular tachycardia, complications of acute myocardial infarction and serious arrhythmia and the like. The specifications of the common oral preparation which is marketed at home and abroad at present are 80mg, 120mg, 160mg and 240mg. The sotalol hydrochloride tablet needs to be administrated twice a day, 1-2 tablets at a time and the administration dosage is 80-160 mg/time, and has great significance for preparing slow release preparations from medicines with large administration dosage, higher peak concentration and dosage needing to be regulated at any time. The sustained release preparation can achieve the therapeutic effect with the common tablet by taking the sustained release preparation once a day, has more stable blood concentration and reduces the incidence rate of adverse reaction.
The sustained release preparation is a preparation which can continuously release the drug for a long time after administration and has long-acting effect. Compared with the common preparation, the administration frequency is reduced by half, or the administration frequency is reduced, adverse reaction is reduced, and the compliance of patients is improved. According to the different mechanism and composition of the drug release, the sustained release preparation comprises a framework type and a membrane controlled type release framework and a membrane controlled combination type. The skeleton slow release material mainly comprises a hydrophilic gel skeleton material, an insoluble skeleton material and a biodegradable skeleton material. The skeleton type and the dosage of the skeleton material are regulated to reach the slow release effect, and the film controlled tablet is coated with the film thickness, the film pore size and the coating material composition to regulate the release of the medicine. Compared with the membrane controlled slow release preparation, the skeleton type slow release preparation has the advantages of simple production process, difficult leakage, low cost and the like.
The sotalol hydrochloride is a high-solubility high-dose medicine, and can be prepared into a skeleton type slow-release preparation, so that the curative effect can be continuously exerted for a long time, the burst release danger possibly occurring in the common preparation is improved, and the occurrence rate of adverse reactions such as bradycardia, hypotension, bronchospasm and the like can be reduced. The method has huge market potential, can obtain certain economic benefit and social benefit, and has good application prospect.
Disclosure of Invention
The invention aims to provide a novel sustained-release drug delivery system sotalol hydrochloride skeleton type sustained-release preparation and a preparation method thereof, wherein the sustained-release preparation mainly achieves the sustained-release effect through methylcellulose propylene K15M and Eudragit RL-PO. The skeleton type slow release preparation prepared by the invention is not easy to leak, has better slow release effect, more stable blood concentration, reduces the incidence rate of adverse reaction, improves the effect of release reduction or dosage burst release caused by easy aging of a film control film, ensures the safety of clinical medication, and has the advantages of simple production process, low technical difficulty, low cost and the like, thereby being suitable for amplified production.
The invention provides a sustained release preparation of sotalol hydrochloride and a preparation process thereof, wherein the preparation process is as follows: the method comprises the steps of uniformly mixing the raw material of the sotalol hydrochloride with a preferable slow-release framework material, an adhesive, a disintegrating agent, a filler and a glidant, granulating by a wet method, uniformly mixing the prepared granules with a lubricant, and tabletting.
Further, the sustained release preparation of sotalol hydrochloride disclosed by the invention comprises the following components in percentage by mass: 1. prescription:
furthermore, the prescription comprises the following components in percentage by mass:
the filler is one or more selected from microcrystalline cellulose, starch, pre-crosslinked starch, lactose, sucrose, mannitol, sorbitol, dextrin and calcium hydrophosphate. Preferably microcrystalline cellulose, pre-cross-linked starch, lactose, preferably microcrystalline cellulose is microcrystalline cellulose pH113.
The binder is selected from one of polyvinylpyrrolidone (PVP K30), ethanol solution, hypromellose (HPMC E5) or preferable. Preferably 60% ethanol solution.
The disintegrating agent is one of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose or crosslinked povidone. Low substituted hydroxypropyl cellulose is preferred.
The glidant is one of colloidal silicon dioxide, silicon dioxide or talcum powder, preferably silicon dioxide.
The lubricant is one of magnesium stearate or sodium stearyl fumarate, and magnesium stearate is preferable in view of production cost.
The slow-release framework material is one or more of hypromellose K4M, K, M, K M, eudragit RL-PO, or Eudragit RS-PO. The weight ratio of HPMC to Eudragit RL-PO is (1-3): (1-2), preferably HPMC: the ratio of Eudragit RL-PO is 2:1. the sustained release effect is better through the preferable proportion.
The invention provides a preparation method of a sustained release preparation of sotalol hydrochloride, which comprises the following steps:
(1) The method comprises the steps of crushing and sieving the raw material of sotalol hydrochloride, and controlling the mesh number of a sieve to be 100.
(2) Taking the sotalol hydrochloride, the filling agent, the disintegrating agent, the glidant, the slow-release framework material and the like, uniformly mixing, adding the adhesive, granulating, and controlling the particle size distribution of the granules.
(3) And (3) drying by a fluidized bed, setting the drying temperature to 60 ℃, and drying for 30-45 minutes to obtain the sustained-release sotalol hydrochloride particles.
(4) Tabletting, namely uniformly mixing the drug-carrying particles with a lubricant, and controlling the hardness of the tablet to be 50N-80N.
The technical scheme of the invention has the following advantages:
1) The skeleton-type sustained-release preparation of the sotalol hydrochloride has good content uniformity, difficult leakage and better sustained-release effect through controlling the granularity of particles,
2) The obtained preparation has stable blood concentration, reduces the incidence rate of adverse reaction, improves the phenomenon of release reduction or abrupt dosage release caused by easy aging of the membrane control tablet, ensures the safety of clinical medication,
3) Simple production process, low technical difficulty, low cost and the like, and is suitable for large-scale production.
Drawings
FIG. 1 is a graph of in vitro cumulative release profiles for examples 1, 2, 3, 4, 5;
FIG. 2 is a graph of in vitro cumulative release profiles for examples 6, 7, 8, 9, 10, 11;
in the figure, the abscissa represents time (h), and the ordinate represents the cumulative dissolution (%).
Detailed Description
Example 1: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method comprises the steps of crushing and sieving the raw material of sotalol hydrochloride, and sieving the raw material of sotalol hydrochloride with a 100-mesh sieve. 160g of sotalol hydrochloride, 120g of microcrystalline cellulose pH-113, 32g of lactose, 8g of low-substituted hydroxypropyl cellulose, 4M 64g of hydroxypropyl methylcellulose K and 2.8g of hydroxypropyl methylcellulose K are weighed and uniformly mixed, and a proper amount of 60% ethanol solution is added for wet granulation. The wet granules were dried in a fluidized bed at 60℃for 40 minutes and sieved. Collecting particles with the particle size distribution of 24-120 meshes, and tabletting. Mixing the drug-carrying particles with magnesium stearate uniformly, tabletting, controlling the hardness to be 50-80N, and detecting the cumulative release degree of the sotalol hydrochloride sustained-release preparation according to a high-efficiency liquid phase method.
Example 2: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, and other auxiliary materials and the dosage are the same as those of example 1. The difference is that the ingredients and the dosage of the auxiliary materials are correspondingly changed, and the slow-release framework material is hydroxypropyl methylcellulose K15M.
Example 3: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, and other auxiliary materials and the dosage are the same as those of example 1, except that the sustained release framework material is hypromellose K100M.
Example 4: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, and the difference is that the ingredients and the dosage of auxiliary materials are correspondingly changed, and the sustained release framework material is Eudragit RL-PO.
Example 5: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, except that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, and the sustained release framework material is Eudragit S-PO.
Example 6: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K4M and Eudragit RS-PO, and the weight ratio is 2:1.
example 7: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K4M and Eudragit RL-PO, and the weight ratio is 2:1
Example 8: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K15M and Eudragit RS-PO, and the weight ratio is 2:1.
example 9: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K15M and Eudragit RL-PO, and the weight ratio is 2:1
Example 10: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K15M and Eudragit RL-PO, and the weight ratio is 3:2.
example 11: sustained release sotalol hydrochloride tablet and preparation process (1000 tablets) thereof
The method of the example 1 is adopted to prepare the sustained release preparation of the sotalol hydrochloride, the difference is that the ingredients and the dosage of the filling auxiliary materials are correspondingly changed, the sustained release framework material is composed of hydroxypropyl methylcellulose K15M and Eudragit RL-PO, and the weight ratio is 1:1. the release degree of the sustained release preparation of sotalol hydrochloride obtained in examples 1 to 11 is tested by the following specific test method:
the release degree is measured by dissolution and release degree measurement (first method of the fourth edition of China pharmacopoeia 2015, rule of four years 0931). Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler, sodium octanesulfonate solution-acetonitrile (70:30) is used as a mobile phase, and the flow rate is as follows: 1.0ml/min, sample injection amount: 20 μl, detection wavelength: 228nm, theoretical plate number: calculated as the peak of sotalol hydrochloride, should be no less than 2000. Taking 900ml of 0.1mol/L hydrochloric acid solution as a dissolution medium, taking a proper amount of solution in 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 20 hours and 24 hours of lofting, centrifuging, and taking supernatant as a sample solution according to a law, wherein the rotating speed is 50 rpm; and timely replenishing the dissolution medium with the same temperature and volume; in addition, the appropriate amount of the sotalol hydrochloride reference substance is precisely weighed, and the solution containing about 0.1mg of the reference substance per 1mL of the reference substance is prepared by adding hydrochloric acid solution for dissolution and quantitative dilution. Precisely measuring 20 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, recording the chromatograms, and calculating the cumulative release of each tablet according to the external standard method by using the peak area.
Test examples 1 to 5 curves of cumulative release degree of the sustained release preparation of sotalol hydrochloride over time, the specific release data are:
TABLE 1 relationship between time and Release of the formulations obtained in examples 1-5
According to the drawing results of table 1, as shown in fig. 1, the drug release characteristics of different framework materials when the framework materials occupy the same mass fraction are compared, in the dosage range of the invention, the drug release of the example 1 is faster, the slow release effect cannot be achieved in the earlier stage, the drug release of the example 3 and the example 4 is slow, the release of the active drug is retarded, the release effects of the examples 2 and 5 are better, the stable release can be realized, and the drug release requirement can be met. It can be seen from example 1.2.3 that the blocking effect of the hypromellose with different viscosity grades on the release of the active drug is different, and the strength of the gel formed after water absorption is also different due to the different viscosity of the hypromellose, so that the release of the drug is affected, and the release speed is regulated by regulating the dosage and the viscosity grade of the hypromellose. Eudragit RL-PO and Eudragit RS-PO are novel acrylic resin auxiliary materials developed in recent years, and are widely used for sustained-release framework materials, sustained-release coating materials, enteric coating materials, protective isolation coating materials and the like. The blocking effect of Eudragit RS-PO is stronger than that of Eudragit RL-PO, and the Eudragit RL-PO is not suitable to be used as a skeleton slow release material alone, has good control effect on drug release, and is a good skeleton slow release material.
Test examples 6 to 11 curves of cumulative release degree of the sustained release formulations of sotalol hydrochloride with time,
TABLE 2 relationship between time and Release of the formulations obtained in examples 6-11
The results are shown in FIG. 2. As can be seen from fig. 2. The active drug release effect of the preferable framework material is better than that of the single framework material, the framework material can be slowly released, the release is almost complete at 20 hours, one tablet is taken in one day, the drug effect in one day can be exerted, and the taking times are reduced. Illustrating that the selection of the framework material of the present invention is somewhat inventive. The invention compares the compressibility of the slow-release material, and the compressibility of HPMC is better than that of Eudragit RS-PO and Eudragit RL-PO.
2. Process reproducibility
Three consecutive batches of the sustained release formulations of sotalol hydrochloride were prepared according to the formulation and process of example 9 and examined for process reproducibility and uniformity of in vitro release. Fitting the in-vitro release of the sustained release preparation of the sotalol hydrochloride, taking the average value of the cumulative release of three batches of medicines, and fitting by using a zero-order equation, a first-order equation and a Higuchi equation. The results are shown in table 1, the in-vitro release of the sotalol hydrochloride sustained release preparation provided by the invention is closer to the first-order release, and accords with the release characteristics of skeleton type medicines, and the release is probably the result of the combination of medicine diffusion and skeleton erosion. The sustained release preparation of the sotalol hydrochloride provided by the invention has the advantages that the release is stable, the blood concentration is stable, the fluctuation of the blood concentration in the body is reduced, the occurrence rate of adverse reaction is reduced, and a better treatment effect is further achieved.
TABLE 1 in vitro Release model fitting results for sustained release formulations of sotalol hydrochloride
| Model | Fang Cheng | Correlation coefficient (r) 2 ) |
| Zero order | M t ＝4.50t-18.82 | 0.9217 |
| First level | M t ＝110.49(1-e 0.11t ) | 0.9967 |
| Higuchi | M t ＝25.76t 1/2 -12.10 | 0.9895 |
The above technical solution only represents the preferred technical solution of the present invention, and some changes may be made to some parts of the technical solution by those skilled in the art without exceeding the scope of protection of the claims, and the technical solution is within the scope of protection of the present invention.
Claims (6)
1. The sustained-release preparation of the sotalol hydrochloride is characterized by comprising drug-loaded sustained-release particles and a lubricant, wherein the drug-loaded sustained-release particles comprise the sotalol hydrochloride and a sustained-release framework material, the sustained-release framework material consists of HPMC and Eudragit RL-PO, the HPMC is hydroxypropyl methylcellulose K15M, the weight ratio of the HPMC K15M to the Eudragit RL-PO is 2:1 or 3:2 or 1:1, the drug-loaded sustained-release particles also comprise a filler, a disintegrating agent, an adhesive and a glidant, and the mass percentage of the components of the sustained-release preparation of the sotalol hydrochloride is as follows: 40% of sotalol hydrochloride, 38% of filler, 2.5% of disintegrating agent, 16% of slow-release framework material, 0.7% of glidant, 0.8% of lubricant and 60% of ethanol solution as an adhesive.
2. The sustained release preparation of sotalol hydrochloride according to claim 1, wherein the filler is one or more selected from microcrystalline cellulose, starch, pre-cross-linked starch, lactose, sucrose, mannitol, sorbitol, dextrin and calcium hydrogen phosphate.
3. The sustained release preparation of sotalol hydrochloride according to claim 1, wherein the disintegrating agent is one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone; the glidant is one or more of silicon dioxide or talcum powder; the lubricant is one or more of magnesium stearate or sodium stearyl fumarate.
4. The sustained release formulation of sotalol hydrochloride in accordance with claim 1, wherein the glidant is colloidal silicon dioxide.
5. A process for the preparation of a sustained release formulation of sotalol hydrochloride according to claim 1, characterized in that it comprises the steps of:
1) Pulverizing and sieving the raw material of sotalol hydrochloride;
2) Taking the sotalol hydrochloride, a filler, a disintegrating agent, a glidant and a slow-release framework material, uniformly mixing, adding an adhesive and granulating by a wet method;
3) Drying the mixture in a fluidized bed to obtain the sotalol hydrochloride slow-release particles;
4) Mixing the drug-carrying particles with lubricant, and tabletting.
6. The method for preparing a sustained release preparation of sotalol hydrochloride according to claim 5, wherein the fluidized bed is dried at a temperature of 60 ℃ for 30-45 minutes.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107982237A (en) * | 2018-01-17 | 2018-05-04 | 宁波蒙曼生物科技有限公司 | A kind of Betapace and preparation method thereof |
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| CN107982237A (en) * | 2018-01-17 | 2018-05-04 | 宁波蒙曼生物科技有限公司 | A kind of Betapace and preparation method thereof |
Non-Patent Citations (4)
| Title |
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| Formulation and Evaluation of Controlled Release Matrix Tablets of Sotalol;Mufeeda Kathija等;《Research Journal of Pharmaceutical Dosage Forms and Technology》;第7卷(第2期);第134-142页 * |
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