CN117442628A - Quick-release aspirin coated capsule containing slow-release dipyridamole Mo Weipian and preparation method thereof - Google Patents
Quick-release aspirin coated capsule containing slow-release dipyridamole Mo Weipian and preparation method thereof Download PDFInfo
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- CN117442628A CN117442628A CN202311411524.5A CN202311411524A CN117442628A CN 117442628 A CN117442628 A CN 117442628A CN 202311411524 A CN202311411524 A CN 202311411524A CN 117442628 A CN117442628 A CN 117442628A
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- China
- Prior art keywords
- capsule
- coated
- aspirin
- dipyridamole
- microchip
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- 239000002775 capsule Substances 0.000 title claims abstract description 96
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 67
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960002768 dipyridamole Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 38
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 38
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 37
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 31
- 230000002378 acidificating effect Effects 0.000 claims abstract description 29
- 239000002702 enteric coating Substances 0.000 claims abstract description 27
- 238000009505 enteric coating Methods 0.000 claims abstract description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 26
- 239000011248 coating agent Substances 0.000 claims abstract description 25
- 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 abstract description 22
- 229920000642 polymer Polymers 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 18
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- 239000011253 protective coating Substances 0.000 claims abstract description 12
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 16
- 235000002906 tartaric acid Nutrition 0.000 claims description 16
- 239000011975 tartaric acid Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 6
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- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 3
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
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- 239000000049 pigment Substances 0.000 claims description 3
- 239000004014 plasticizer Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000001384 succinic acid Substances 0.000 claims description 3
- 235000011044 succinic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 19
- 230000015556 catabolic process Effects 0.000 abstract description 10
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- 210000000936 intestine Anatomy 0.000 abstract description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
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- 238000013268 sustained release Methods 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
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- 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 description 1
- 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 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- 239000000600 sorbitol Substances 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a hydroxypropyl methyl cellulose capsule containing microplates, which comprises the following components: the tablet comprises a microchip core, wherein the microchip core comprises dipyridamole, an acidic auxiliary material and at least one pharmaceutically acceptable auxiliary material; and an enteric coating coated on the core of the microtablet, the enteric coating comprising an enteric polymer and an acidic excipient; and the capsule has an immediate release coating comprising aspirin. The coated capsules are optionally coated with an immediate release protective coating. Dipyridamole minitablets contain acidic excipients in the tablet core and enteric coating, which aim to create a slightly acidic environment in the intestine before and when dipyridamole is released in the intestine, resulting in a rapid but controlled continuous dissolution of dipyridamole and solving the problem of poor dissolution profile. In addition, the present invention provides an aspirin coating on hypromellose capsules that completely separates dipyridamole from aspirin, thereby preventing dipyridamole degradation. The invention also relates to a process for preparing said capsules.
Description
Technical Field
The invention relates to the technical field of HPMC capsules containing microplates, in particular to a quick-release aspirin coated capsule containing slow-release dipyridamole Mo Weipian and a preparation method thereof
Background
Dipyridamole has antithrombotic and antiplatelet aggregation activities. Dipyridamole is known by the chemical name (2, 6-bis- (diethanolamino) -4, 8-dipiperidino- (5, 4-d) -pyrimidine). Dipyridamole is a weakly basic drug with a relatively low solubility under neutral conditions (e.g. in the intestinal tract) compared to the solubility under acidic conditions. Thus, it is desirable to prepare formulations that provide a slightly acidic environment in the intestinal tract to increase the dissolution of dipyridamole. Aspirin, known as acetylsalicylic acid, inhibits human platelet aggregation. It is well known that dipyridamole in combination with aspirin has a synergistic effect in controlling aggregation of human platelets.
Combination of dipyridamole and aspirin as a pharmaceutical agent since 1999Oral capsules are available in the united states and are useful for reducing the risk of stroke in patients with transient cerebral ischemia or total ischemic stroke due to thrombosis. Every particle->Hard gelatin capsules contain 200mg of dipyridamole in sustained release form and 25mg of aspirin quick-release coated tablets.
As disclosed in US 6015577, dipyridamole Mo Weili/granule/tablet core contains acidic excipients. Furthermore, US 6015577 discloses granules/particles of dipyridamole + acid adjuvant and aspirin tablets alone, both enclosed in gelatin capsules. According to US 6015577 dipyridamole and aspirin are separated with an inert layer, as acetylsalicylic acid is cleaved during storage to form traces of acetic acid. Free acetic acid reacts with dipyridamole to form hygroscopic salts and dipyridamole-acetate, resulting in deterioration of dipyridamole. Thus, dipyridamole was separated from aspirin to prevent deterioration of dipyridamole. However, US 6015577 discloses that dipyridamole and aspirin are located very close together, both within the capsule. Since both dipyridamole Mo Weili and aspirin tablets are in capsules, dipyridamole degradation may result from improper coating or particle damage during production/transport, which may contact each other.
In addition, dipyridamole Mo Weili/granule cores containing acidic excipients release the acidic excipients at the same time as the microparticles/granules dissolve out, potentially delaying the formation of a suitable acidic microenvironment required for dipyridamole dissolution in the intestinal tract. Thus, the creation of an acidic microenvironment in the intestinal tract in advance and simultaneously facilitates the rapid but controlled continuous dissolution of dipyridamole. Furthermore, US 6015577 discloses gelatin capsules. It is well known that gelatin capsules have a relatively high moisture content and may lead to degradation of the moisture sensitive ingredient.
Thus, there is a need to prepare capsules in which aspirin is completely separated from dipyridamole to avoid degradation of dipyridamole, capsules in which premature and concurrent release of acidic excipients in the intestine results in rapid but controlled continuous dissolution of dipyridamole, and capsules of compositions having low moisture content.
Disclosure of Invention
The invention provides a hydroxypropyl methyl cellulose capsule containing microplates, which is provided with a slightly acidic environment created in the intestinal tract before and parallel to the release of dipyridamole in the intestinal tract, so that the dipyridamole is dissolved out rapidly and continuously in a controlled manner, and the problem of poor dissolution curve is solved. Meanwhile, the invention also provides a preparation method of the hydroxypropyl methyl cellulose capsule containing the microchip.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a hydroxypropyl methylcellulose capsule comprising a microchip core comprising dipyridamole, an acidic excipient and at least one pharmaceutically acceptable excipient, and an enteric coating coated on the microchip core, said enteric coating comprising an enteric polymer and an acidic excipient; and the capsule is coated with an immediate release coating comprising aspirin, the capsule optionally being coated with an immediate release protective coating.
Optionally, the capsule is an aspirin coated capsule.
Optionally, wherein the acidic auxiliary material is selected from tartaric acid, fumaric acid, citric acid, succinic acid and malic acid.
Optionally, the dosage of the acid auxiliary material is 20 to 30 percent of the total weight of the aspirin coated capsule.
Optionally, wherein the enteric polymer is selected fromS-100 (methacrylic acid copolymer, type B NF), -, and->L-100 (methacrylic acid copolymer, type A NF), hypromellose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hypromellose succinate, cellulose acetate succinate or mixtures thereof.
Optionally, wherein the enteric polymer is used in an amount of 5% to 15% of the total weight of the aspirin coated capsule.
Optionally, wherein the enteric polymer is used in an amount of 5% to 15% of the total weight of the aspirin coated capsule.
Optionally, the microchip core comprises 20% to 30% dipyridamole, 20% to 27% tartaric acid and at least one pharmaceutically acceptable excipient; the enteric coating coated on the microchip core, the enteric coating comprising 5% to 15% enteric polymer and 1% to 3% tartaric acid; and the capsule is coated with an immediate release coating comprising 2.5% to 5% aspirin, the capsule is optionally coated with an immediate release protective coating, and the percentages are based on the total weight of the aspirin coated capsule.
Optionally, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, glidants, anti-sticking agents, polymers, immediate release coating excipients, opacifiers, plasticizers and pigments.
The invention provides a preparation method for preparing an aspirin coated capsule, which comprises the following steps:
firstly, preparing a microchip core containing dipyridamole, tartaric acid and at least one pharmaceutically acceptable auxiliary material;
secondly, coating enteric coating containing enteric polymer and acid auxiliary materials on the microchip core;
thirdly, encapsulating the coated microplatelets in HPMC capsules;
fourth, the HPMC capsule is coated with an immediate release coating containing aspirin.
Preferably, the quick release protective coating is coated on the coated capsule obtained in the step four.
Drawings
Fig. 1 is a structure of an aspirin coated capsule of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1, the present invention provides a technical solution: sustained release dipyridamole and immediate release aspirin, wherein dipyridamole is in the form of enteric microtablets in hydroxypropyl methylcellulose capsules, and the capsules are coated with immediate release aspirin. The dipyridamole micro-tablet comprises acidic auxiliary materials in a tablet core and an enteric coating, and aims to create a slightly acidic environment in the intestinal tract before and parallel to the release of dipyridamole in the intestinal tract, thereby leading to rapid but controlled continuous dissolution of the dipyridamole and solving the problem of poor dissolution curve. In addition, the present invention provides an aspirin coating on HPMC capsules that completely separates dipyridamole from aspirin, thereby preventing dipyridamole degradation. In addition, the use of low moisture content capsules, i.e., HPMC capsules, reduces the chance of moisture degradation of the moisture sensitive ingredient.
The structure of the aspirin coated capsule shown in fig. 1 of the present invention provides a unique and novel method that allows for: aspirin is completely separated from dipyridamole, thereby avoiding degradation of dipyridamole, releasing acidic excipients in the intestine in advance and in parallel, thereby resulting in rapid but controlled continuous dissolution of dipyridamole, and use of low moisture content capsules (HPMC capsules) that reduce the chance of wet degradation of moisture sensitive ingredients.
The term "capsule" as used in this document in connection with the present invention refers to a capsule consisting of hydroxypropyl methylcellulose, i.e. HPMC capsule.
The term "aspirin coated capsule/coated capsule" as used in the present invention means that the HPMC capsule is coated with immediate release aspirin, which is optionally further coated with an immediate release protective coating.
The term "microtablet" as used in the present invention refers to pellets, granules or microparticles.
The term "enteric coating" as used in the present invention refers to a coating that resists dissolution of the active ingredient in gastric juice of the stomach and is more soluble at the pH typically found in the intestinal tract. These polymers are generally used to prevent dissolution of the active substance before reaching the intestine.
The term immediate release coating as used in the present invention refers to such a coating that allows for immediate release of the active ingredient in the stomach.
The terms "dipyridamole" and "aspirin" as used in the present invention include their base forms or their pharmaceutically acceptable salt forms.
The term "%" as used in mass standards refers to the percentage by weight of the total weight of the aspirin coated capsule, unless otherwise specified.
In one aspect, the invention provides a hydroxypropyl methylcellulose capsule comprising a microchip core comprising dipyridamole, an acidic excipient and at least one pharmaceutically acceptable excipient, and an enteric coating coated on the microchip core, said enteric coating comprising an enteric polymer and an acidic excipient; and the capsule is coated with an immediate release coating comprising aspirin, the capsule optionally being coated with an immediate release protective coating.
In the present invention, dipyridamole is present in an amount of 20% to 30% of the total weight of the aspirin coated capsule, preferably 24% to 25% of the total weight, and aspirin is present in an amount of 2.5% to 5% of the total weight, preferably 2.5% to 3% of the total weight of the aspirin coated capsule.
The acidic adjuvant is selected from tartaric acid, fumaric acid, citric acid, succinic acid and malic acid. The amount of the acidic auxiliary material is 20 to 30 percent of the total weight, and most preferably 25 to 30 percent of the total weight of the coated capsule. Specifically, the microtablet core comprises 20% to 27% of an acidic excipient and the enteric coating comprises 1% to 3% of an acidic excipient, based on the total weight of the aspirin coated capsule.
Pharmaceutically acceptable excipients useful in the present invention are well known for preparing pharmaceutical compositions. The pharmaceutically acceptable excipients most preferably used in the solid composition may be selected from, but are not limited to, diluents, binders, disintegrants, lubricants, glidants/anti-adherents, polymers, enteric coating excipients, immediate release coating excipients and solvents.
The diluent is selected from microcrystalline cellulose (MCC), powdered cellulose, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, mannitol, maltodextrin, modified starches such as pregelatinized starch, corn flour, corn starch and mixtures thereof. The amount of diluent in the present invention is from about 5% to about 25% by weight, and from 5% to 10% by weight of the total weight of the aspirin coated capsule.
The binder is selected from the group consisting of povidone (polyvinylpyrrolidone), copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, propylene glycol, polyvinyl alcohol, and mixtures thereof. The amount of binder in the present invention is from about 1% to about 10% by weight of the total weight, most preferably from 1% to 5% by weight of the total weight of the aspirin coated capsule.
The glidant is selected from talc, colloidal silicon dioxide, magnesium stearate and mixtures thereof. The glidant is present in the present invention in an amount of about 1% to about 15% by weight, preferably 7% to 12% by weight of the total weight of the aspirin coated capsule.
Pharmaceutically acceptable solvents may include, but are not limited to, water, ethanol, isopropanol, and the like, or mixtures thereof. Solvents or solvent mixtures may be used for wet granulation and enteric or immediate release coatings.
The quick-release coating/quick-release protective coating comprises polyvinyl alcohol/polyethylene glycol graft copolymerHypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, or mixtures thereof. The immediate release coating polymer is used in an amount of about 2% to 5% by weight of the total aspirin coated capsule. Suitable coating excipients may also include opacifiers, such as titanium dioxide, in amounts of about 0.5% to 2% by weight of the total aspirin coated capsule, glidants, such as talc and pigments, such as iron oxide yellow.
Enteric coatings include, but are not limited to, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer @, ands), hypromellose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hypromellose succinate or cellulose acetate succinate or mixtures thereof. The preferred slow release coating comprises->S-100 (methacrylic acid copolymer, type B NF) and +.>L-100 (methacrylic acid copolymer, NF type A). The enteric coating polymer is present in the present invention in an amount of about 5% to about 15% by weight, and most preferably in an amount of 7% to 12% by weight of the total aspirin coated capsule. The immediate release or enteric coating may also contain a plasticizer, such as triethyl citrate, in an amount of about 2% to about 2% by weight of the total aspirin coated capsuleAbout 5%.
Optionally, a hydroxypropyl methylcellulose capsule containing microplatelets comprising: a microchip core comprising 20% to 30% dipyridamole, 20% to 27% tartaric acid and at least one pharmaceutically acceptable excipient; an enteric coating over the core of the microtablet, the enteric coating comprising 5% to 15% enteric polymer and 1% to 3% tartaric acid; and the capsule is coated with an immediate release coating comprising 2.5% to 5% aspirin, the capsule is optionally coated with an immediate release protective coating, and the percentages are based on the total weight of the aspirin coated capsule. The microchip cores may be prepared by methods known in the pharmaceutical arts, such as direct compression, dry granulation or wet granulation (e.g., fluid bed granulation or flash mixed granulation, with fluid bed granulation being preferred). Drying of the particles may be carried out at suitable temperatures, including 50±15 ℃.
The following table gives a data comparison of the inventive examples with comparative example 1 without tartaric acid and comparative example 2 without tartaric acid in the enteric coating:
TABLE-1
X = no present, q.s = moderate amount
Tables 2 and 3 show the comparison of the dissolution data of the inventive examples with comparative example 1 without tartaric acid and comparative example 2 without tartaric acid in the enteric coating:
the capsules of the examples of the present invention and comparative examples 1 and 2 were taken and analyzed using the following methods:
step 1 (both dipyridamole and acetylsalicylic acid): using USP apparatus I (basket method), the mixing speed was 100rpm at 37℃and 1 hour in 900mL of 0.1N HCl (Medium I) dissolution medium. As shown in table-2, samples of dissolution medium were collected over 45 minutes and analyzed by HPLC.
Step 2 (related to dipyridamole only): the medium I was removed from the vessel and 900mL of NaH2P04 buffer (medium II) at pH 5.5 was added for 1 to 12 hours at a mixing speed of 100rpm and a temperature of 37 ℃. A sample of dissolution medium was collected over 700 minutes as shown in table-3 and analyzed by HPLC.
TABLE-2
Percent = cumulative dissolution percentage
TABLE-3
Percent = cumulative dissolution percentage
From the results given in tables 2 and 3, it is apparent that the dissolution rates of aspirin and dipyridamole of example 1 are superior to those of comparative examples 1 and 2. In addition, the dissolution rate and the dissolution rate of example 1Equivalent or slightly better than->
In addition, the aspirin coated capsule of the present invention contains slow release dipyridamole Mo Weipian, which provides the following advantages over the prior art: 1. aspirin is completely separated from dipyridamole to avoid degradation of dipyridamole. 2. The release of the acidic excipients in the intestine in advance and in parallel results in a rapid but controlled continuous dissolution of dipyridamole. 3. The use of low moisture content capsules (HPMC capsules) reduces the chance of moisture degradation of the moisture sensitive ingredient.
In another aspect, the present invention provides a method for preparing an aspirin coated capsule, comprising the steps of:
firstly, preparing a microchip core containing dipyridamole, tartaric acid and at least one pharmaceutically acceptable auxiliary material;
secondly, coating enteric coating containing enteric polymer and acid auxiliary materials on the microchip core;
thirdly, encapsulating the coated microplatelets in HPMC capsules;
fourth, the HPMC capsule is coated with an immediate release coating containing aspirin.
Further, the quick-release protective coating is coated on the coated capsule obtained in the step four.
The present inventors have discovered a unique and novel method for preparing immediate release aspirin coated capsules containing sustained release dipyridamole, as shown in figure 1, which overcomes the problems of the prior art.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A hydroxypropyl methylcellulose capsule comprising microplatelets, characterized by: comprises a microchip tablet core, which comprises dipyridamole, an acidic auxiliary material and at least one pharmaceutically acceptable auxiliary material, and an enteric coating coated on the microchip tablet core, wherein the enteric coating comprises an enteric polymer and the acidic auxiliary material; and the capsule is coated with an immediate release coating comprising aspirin, the capsule optionally being coated with an immediate release protective coating.
2. The microchip-containing hypromellose capsule according to claim 1, wherein: the capsule is an aspirin coated capsule.
3. The microchip-containing hypromellose capsule according to claim 1, wherein: wherein the acidic auxiliary material is selected from tartaric acid, fumaric acid, citric acid, succinic acid and malic acid.
4. The microchip-containing hypromellose capsule according to claim 1, wherein: the dosage of the acid auxiliary material is 20 to 30 percent of the total weight of the aspirin coated capsule.
5. The microchip-containing hypromellose capsule according to claim 1, wherein: wherein the enteric polymer is selected fromS-100 (methacrylic acid copolymer, type B NF), -, and->L-100 (methacrylic acid copolymer, type A NF), hypromellose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hypromellose succinate, cellulose acetate succinate or mixtures thereof.
6. The microchip-containing hypromellose capsule according to claim 5, wherein: wherein the enteric polymer is used in an amount of 5% to 15% of the total weight of the aspirin coated capsule.
7. The microchip-containing hypromellose capsule according to claim 1, wherein: the microchip core comprises 20 to 30% dipyridamole, 20 to 27% tartaric acid and at least one pharmaceutically acceptable auxiliary material; the enteric coating coated on the microchip core, the enteric coating comprising 5% to 15% enteric polymer and 1% to 3% tartaric acid; and the capsule is coated with an immediate release coating comprising 2.5% to 5% aspirin, the capsule is optionally coated with an immediate release protective coating, and the percentages are based on the total weight of the aspirin coated capsule.
8. The microchip-containing hypromellose capsule according to any one of claims 1 to 7, wherein: wherein the pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, glidants, anti-sticking agents, polymers, immediate release coating excipients, opacifiers, plasticizers and pigments.
9. A method of preparing the aspirin coated capsule of claim 1, comprising the steps of:
firstly, preparing a microchip core containing dipyridamole, tartaric acid and at least one pharmaceutically acceptable auxiliary material;
secondly, coating enteric coating containing enteric polymer and acid auxiliary materials on the microchip core;
thirdly, encapsulating the coated microplatelets in HPMC capsules;
fourth, the HPMC capsule is coated with an immediate release coating containing aspirin.
10. The method for preparing an aspirin coated capsule according to claim 9, wherein an immediate release protective coating is applied to the coated capsule obtained in the fourth step.
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| CN202311411524.5A CN117442628A (en) | 2023-10-27 | 2023-10-27 | Quick-release aspirin coated capsule containing slow-release dipyridamole Mo Weipian and preparation method thereof |
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