CN117679381A - Dipyridamole osmotic pump controlled release tablet and preparation method thereof - Google Patents
Dipyridamole osmotic pump controlled release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN117679381A CN117679381A CN202311499400.7A CN202311499400A CN117679381A CN 117679381 A CN117679381 A CN 117679381A CN 202311499400 A CN202311499400 A CN 202311499400A CN 117679381 A CN117679381 A CN 117679381A
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- Prior art keywords
- dipyridamole
- parts
- controlled release
- tablet
- pump controlled
- Prior art date
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- 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 207
- 229960002768 dipyridamole Drugs 0.000 title claims abstract description 207
- 230000003204 osmotic effect Effects 0.000 title claims abstract description 139
- 238000013270 controlled release Methods 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000011247 coating layer Substances 0.000 claims abstract description 56
- 239000003085 diluting agent Substances 0.000 claims abstract description 42
- 239000000463 material Substances 0.000 claims abstract description 35
- 239000004014 plasticizer Substances 0.000 claims abstract description 23
- 239000000314 lubricant Substances 0.000 claims abstract description 17
- 239000007884 disintegrant Substances 0.000 claims abstract description 15
- 239000000853 adhesive Substances 0.000 claims abstract description 11
- 230000001070 adhesive effect Effects 0.000 claims abstract description 11
- 239000011248 coating agent Substances 0.000 claims description 86
- 238000000576 coating method Methods 0.000 claims description 85
- 239000007788 liquid Substances 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000012046 mixed solvent Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
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- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 claims description 11
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Abstract
The application discloses dipyridamole osmotic pump controlled release tablet and a preparation method thereof. The dipyridamole osmotic pump controlled release tablet comprises a tablet core and a coating layer coated on the surface of the tablet core; wherein, the tablet core comprises the following components by weight: 20-60 parts of first dipyridamole, 40-80 parts of diluent, 1.0-2.0 parts of adhesive, 5-15 parts of osmotic pressure promoter, 5-15 parts of disintegrant and 0.5-1.0 part of lubricant; the coating layer comprises the following components in parts by weight: 3-6 parts of second dipyridamole, 3-6 parts of film forming material and 1-3 parts of plasticizer. According to the dipyridamole osmotic pump controlled release tablet, the components of the tablet core and the coating layer are synergistic, and the osmotic pressure principle is utilized to enable dipyridamole release to accord with zero-order release pharmacokinetics, so that the burst effect of dipyridamole drug can be reduced, the fluctuation range of the release rate of the dipyridamole drug can be reduced, the acting time of the dipyridamole can be prolonged, and the bioavailability of the dipyridamole can be improved.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a dipyridamole osmotic pump controlled release tablet and a preparation method thereof.
Background
Dipyridamole, also known as dipyridamole, has a chemical name of 2,2',2", 2'" - [ (4, 8-dipiperidinylpyrimido [5,4-d ] pyrimidine-2, 6-diyl) bisazo ] -tetraethanol, and has the following structural formula.
Dipyridamole has long been used clinically successfully for preventing and treating angina pectoris, and is also used for preventing recurrence of myocardial infarction and thrombosis due to its platelet aggregation-inhibiting function. In recent years, research has found that: dipyridamole has broad-spectrum antiviral effect, and has inhibitory effect on picornaviruses, orthomyxoviruses and certain DNA viruses. The traditional Chinese medicine composition is also clinically used for treating diseases such as infant diarrhea, acute upper respiratory tract infection, chronic renal failure and the like.
The dipyridamole dosage forms presently disclosed are typically conventional tablets. Because dipyridamole has strong lipophilicity, quick absorption and poor dissolution, the oral bioavailability is only about 50%. For the above reasons, it is necessary to use a pharmaceutical means to prolong the duration of action of dipyridamole drug, reduce the fluctuation range of drug release, and improve bioavailability.
Disclosure of Invention
The invention aims to provide a dipyridamole osmotic pump controlled release tablet and a preparation method thereof, and aims to solve the technical problems of how to reduce the fluctuation range of the release rate of dipyridamole drugs, prolong the acting time of the dipyridamole and improve the bioavailability of the drugs.
In order to achieve the purposes of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides a dipyridamole osmotic pump controlled release tablet comprising a tablet core and a coating layer coated on the surface of the tablet core; wherein,
The tablet core comprises the following components in parts by weight: 20-60 parts of first dipyridamole, 40-80 parts of diluent, 1.0-2.0 parts of adhesive, 5-15 parts of osmotic pressure promoter, 5-15 parts of disintegrant and 0.5-1.0 part of lubricant;
the coating layer comprises the following components in parts by weight: 3-6 parts of second dipyridamole, 3-6 parts of film forming material and 1-3 parts of plasticizer.
The dipyridamole osmotic pump controlled release tablet provided by the application comprises a tablet core and a coating layer, wherein the tablet core is added with first dipyridamole, and the coating layer is added with second dipyridamole. The second dipyridamole can play a role of a pore-forming agent in the coating layer, and can be used as a quick-release part in the dipyridamole osmotic pump controlled release tablet, and the second dipyridamole can be dissolved in gastric acid for the first time after being taken into the stomach and then absorbed into blood by a human body, so that the initial blood concentration is formed quickly, and the therapeutic effect is played quickly; after the second dipyridamole is dissolved, the micropores formed in the coating layer can adjust the permeation rate of the coating layer, and can also enable gastric acid to rapidly enter the coating layer to disintegrate the tablet core, so that gastric acid enters the film to promote the tablet core to disintegrate and dissolve the first dipyridamole, the osmotic pressure promoter and the water-soluble diluent, and simultaneously serve as a channel for the first dipyridamole in the tablet core to diffuse into the gastrointestinal tract under the action of osmotic pressure after being dissolved. In this way, the dipyridamole release in the dosage form of the application accords with zero-order release pharmacokinetics by the synergistic effect of the components of the tablet core and the coating layer by utilizing an osmotic pressure principle, so that the burst effect of the dipyridamole drug can be reduced, the fluctuation range of the release rate of the dipyridamole drug can be reduced, the acting time of the dipyridamole can be prolonged, and the bioavailability of the dipyridamole can be improved.
In a second aspect, the present application provides a method for preparing a dipyridamole osmotic pump controlled release tablet, comprising the steps of:
providing raw materials of all components in the dipyridamole osmotic pump controlled release tablet;
and preparing the tablet core, and then coating the tablet core to form the coating layer to obtain the dipyridamole osmotic pump controlled release tablet.
The dipyridamole osmotic pump controlled release tablet provided in the second aspect of the application is prepared by firstly preparing a tablet core containing first dipyridamole, and then coating the tablet core to form a coating layer containing second dipyridamole, so as to obtain the dipyridamole osmotic pump controlled release tablet. The preparation method is simple in preparation process and mild in condition, is suitable for industrial mass production and application, and simultaneously the prepared dipyridamole osmotic pump controlled release tablet has the drug release conforming to zero-order release pharmacokinetics, so that the burst effect of dipyridamole drug can be reduced, the fluctuation range of the release rate of the dipyridamole drug can be reduced, the acting time of the dipyridamole can be prolonged, and the bioavailability of the dipyridamole can be improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic flow chart of a process for preparing dipyridamole osmotic pump controlled release tablets according to an embodiment of the present application;
fig. 2 is a graph of cumulative release profiles for dipyridamole osmotic pump controlled release tablets of examples and comparative examples of the present application.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present application more clear, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of an association object, which means that there may be three relationships, for example, a and/or B may mean: a alone, a and B together, and B alone. Wherein A, B may be singular or plural. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the present application, "at least one" means one or more, and "a plurality" means two or more. "at least one of" or the like means any combination of these items, including any combination of single item(s) or plural items(s).
It should be understood that, in various embodiments of the present application, the sequence number of each process does not mean that the sequence of execution is sequential, and some or all of the steps may be executed in parallel or sequentially, where the execution sequence of each process should be determined by its functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weights of the relevant components mentioned in the embodiments of the present application may refer not only to specific contents of the components, but also to the proportional relationship between the weights of the components, and thus, any ratio of the contents of the relevant components according to the embodiments of the present application may be enlarged or reduced within the scope disclosed in the embodiments of the present application. Specifically, the mass described in the specification of the examples of the present application may be a mass unit known in the chemical industry such as μ g, mg, g, kg.
The terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated for distinguishing between objects such as substances from each other. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the present application. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature.
Since the end of the 50 s of the 20 th century, the theory and technology of oral controlled release formulations has matured with the development of modern pharmaceutical formulation technology. Among the controlled release technologies, the osmotic pump technology is considered as the most ideal oral controlled release preparation at present, which uses osmotic pressure as the release power of active drugs, controls the release of the drugs by zero order kinetics, controls the release time of the drugs, and has good in vivo and in vitro correlation without being affected by gastric emptying and gastrointestinal peristalsis. In addition, the osmotic pump preparation can realize the sustained release of the medicine and reduce the fluctuation of blood concentration, thereby reducing the toxic and side effects and the drug resistance of the medicine.
The existing dipyridamole Mo Changgui tablet has more adverse reactions, which are mainly caused by the excessive peak concentration of the drug existing in the burst release effect of the dipyridamole common oral preparation. Therefore, the dipyridamole osmotic pump controlled release tablet provided by the application solves the problems that the prior dipyridamole Mo Pianji has more adverse reactions to a certain extent, and the blood concentration can be relatively stable when the osmotic pump controlled release tablet is manufactured, so that the defects of the phenomenon of wave crest and wave trough of the blood concentration caused by single administration in the clinical use process are overcome, the bioavailability is improved, the clinical curative effect is improved, the adverse reactions caused by overhigh wave crest stage of the blood concentration are reduced, and the drug resistance phenomenon is reduced. The specific scheme is as follows.
In a first aspect, embodiments of the present application provide a dipyridamole osmotic pump controlled release tablet, including a tablet core and a coating layer coated on the surface of the tablet core; wherein, the tablet core comprises the following components by weight: 20-60 parts of first dipyridamole, 40-80 parts of diluent, 1.0-2.0 parts of adhesive, 5-15 parts of osmotic pressure promoter, 5-15 parts of disintegrant and 0.5-1.0 part of lubricant; the coating layer comprises the following components in parts by weight: 3-6 parts of second dipyridamole, 3-6 parts of film forming material and 1-3 parts of plasticizer.
Wherein the active ingredients are as follows: the first dipyridamole is prepared into a constant-release part of the tablet core, and the second dipyridamole is prepared into an immediate-release part of the coating layer and simultaneously serves as a coating semipermeable membrane pore-forming agent.
In order to shorten the acting time of the drug, the dipyridamole osmotic pump controlled release tablet provided by the embodiment of the application comprises a tablet core and a coating layer, wherein the second dipyridamole in the coating layer is taken as a quick release part in the dipyridamole osmotic pump controlled release tablet when the effect of a pore-forming agent is exerted, and is dissolved in gastric acid for the first time after being taken into the stomach, absorbed into blood, so that the initial blood concentration is quickly improved, the therapeutic effect is quickly exerted, micropores are formed in the coating layer after the second dipyridamole is dissolved, the micropores are mainly used for controlling the release rate, and the dipyridamole osmotic pressure promoter is also taken as a channel for enabling gastric acid to quickly enter the inner side of the coating layer to disintegrate the tablet core, and the first dipyridamole, the osmotic pressure promoter and the water-soluble diluent in the tablet core are dissolved. The tablet core is added with the disintegrating agent to enable the tablet core to be rapidly disintegrated under the action of gastric acid, the osmotic pressure and the release rate of the first dipyridamole formed in the solution are increased by adding the diluent and the osmotic pressure promoter into the tablet core, and the fluctuation range of the release rate of the dipyridamole is reduced or even eliminated under the condition of fully ensuring the drug concentration, so that the zero-order release of the dipyridamole in the body is realized, the safety of the drug is improved, and the occurrence rate of adverse reactions is reduced.
The film forming material in the coating layer is a main material for constructing an osmotic pump controlled release system, is a barrier of the osmotic controlled release system, prevents free release in a runaway state in the drug release process, takes the second dipyridamole as an active ingredient, and has the solubility of 32.6mg/ml in 0.1mol/L hydrochloric acid, therefore, the second dipyridamole is added into the coating layer as a pore-forming agent to prepare the dipyridamole osmotic pump controlled release tablet, and the dipyridamole can directly contact and dissolve with gastric acid after being orally taken into the stomach, and can be absorbed into blood while forming micropores of the coating film, thereby forming the initial blood concentration rapidly and exerting the curative effect.
Therefore, the oral osmotic pump controlled release tablet prepared by using the osmotic pressure principle has the advantages that the release accords with zero-order release pharmacokinetics, the initial blood concentration is formed rapidly, the maintenance time of the drug in blood is prolonged, the larger fluctuation of the blood concentration is avoided, the sudden release effect of the drug is eliminated to the maximum extent, the occurrence of adverse reaction is avoided or the occurrence probability of the adverse reaction is reduced, the blood concentration can reach the curative effect concentration rapidly, and the drug onset time is shortened obviously. Meanwhile, in consideration of the limitation of production conditions and operability, a microporous osmotic pump controlled release tablet capable of avoiding laser perforation is selected as a dipyridamole osmotic pump controlled release dosage form. The release medium can dissolve the second dipyridamole to form micropores, gastric juice quickly enters the inner side of the membrane through the micropores, the tablet core is quickly disintegrated under the action of the disintegrating agent added into the tablet core, the first dipyridamole, the osmotic pressure promoter and the water-soluble diluent in the tablet core are dissolved, the hypertonic saturated solution is continuously formed under the action of the diluent and the osmotic pressure promoter, the saturation of the hypertonic solution can be further maintained, the higher osmotic pressure is continuously formed, and the solute is pushed to permeate to the low-permeability end outside the membrane through the micropores at the same time, so that zero-order release is realized.
In some embodiments, the tablet core comprises the following weight components: 20 to 60 parts of first dipyridamole, 40 to 80 parts of diluent, 1.0 to 2.0 parts of adhesive, 5 to 15 parts of osmotic pressure promoter, 5 to 15 parts of disintegrant and 0.5 to 1.0 part of lubricant. Wherein the first dipyridamole may be 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 55 parts, 60 parts, etc.; the diluent may be 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, etc.; the binder may be 1.0 part, 1.2 parts, 1.4 parts, 1.6 parts, 1.8 parts, 2.0 parts, etc.; the osmotic pressure promoter can be 5 parts, 8 parts, 10 parts, 15 parts, etc.; the disintegrating agent can be 5 parts, 8 parts, 10 parts, 15 parts, etc.; the lubricant may be 0.5 parts, 0.8 parts, 1.0 parts, etc.
Specifically, the diluent in the tablet core comprises at least one of dextrates, xylitol, povidone K30, maltodextrin, lactose, sucrose powder, sorbitol, dextrin and starch; maltodextrin may be specifically selected. These diluents serve both the primary diluent and the filler as well as the shaping function. The use amount of 20-60 parts of the diluent in the tablet core of the dipyridamole osmotic pump controlled release tablet ensures the molding effect of the tablet core, the maltodextrin is used as the diluent for directly tabletting powder, the fluidity and the compressibility are better, and the use amount is not limited. In some preferred embodiments, the diluent is selected from maltodextrin, is a diluent for direct powder tabletting and wet granulation tabletting, has stable properties, has good fluidity, can avoid the use of a glidant, can improve the fluidity and compressibility of materials, can make the surface smooth and clean, particularly the maltodextrin is dissolved in water, can also be used as an osmotic pressure promoter, can improve the osmotic pressure of a solution in a coating film, and can promote the constant-speed release of dipyridamole through micropores in the coating film. The maltodextrin is selected as a diluent, and has important positive significance for the preparation of dipyridamole osmotic pump controlled release tablets.
The binder comprises at least one of alginic acid, acacia, hydroxypropyl cellulose, hypromellose, povidone K30, low-substituted hydroxypropyl cellulose, crospovidone, hydroxyethyl cellulose, ethyl cellulose, hypromellose phthalate and dextrin; the adhesive can be prepared into aqueous solution or alcohol solution, and after the aqueous solution or alcohol solution is prepared into liquid adhesive, each auxiliary material and the main medicine are adhered together, so that the tablet core can be pressed, and the structural stability of the tablet core can be improved. The dipyridamole osmotic pump controlled release tablet has good adhesion effect by using 1.0-2.0 parts of adhesive in the tablet core, ensures the molding effect of the tablet core and does not influence the disintegration time limit of the tablet core. In some preferred embodiments, the binder is low-substituted hydroxypropyl cellulose, which can be used for wet granulation and direct powder tabletting, and is flexible and convenient to apply. The low-substituted hydroxypropylcellulose may be a low-substituted hydroxypropylcellulose having a degree of substitution of 5% to 16%, such as low-substituted hydroxypropylcellulose L-11, L-31.
The osmotic pressure promoter comprises at least one of sodium sulfate, mannitol, xylitol, sorbitol, sodium chloride, lactose, sodium phosphate and sucrose; the digestive juice outside the membrane enters the membrane and is dissolved in the digestive juice together with dipyridamole and water-soluble diluent to form higher osmotic pressure of the solution, and the constant high osmotic pressure relative to the outside of the membrane is maintained for a certain time, so that dipyridamole Mo Hengsu is pushed to be released through micropores generated on the coating membrane after the second dipyridamole serving as a pore-forming agent in the coating layer is dissolved in gastric acid. The osmotic pressure promoter in the tablet core of the dipyridamole osmotic pump controlled release tablet is added in an amount of 5-15 parts, so that the promotion effect on the osmotic release stability of the dipyridamole drug in the tablet core is fully ensured. In some preferred embodiments, mannitol is selected as the osmotic pressure promoter, so that the osmotic pressure in the membrane of the dipyridamole osmotic pump controlled release tablet can be better improved and maintained, and the dipyridamole is promoted to realize constant-speed release.
The disintegrating agent comprises at least one of alginic acid, croscarmellose sodium, croscarmellose calcium, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and sodium carboxymethyl starch; the disintegrating agents can promote the tablet core to be rapidly disintegrated into fragments on the inner side of the semipermeable membrane of the coating layer, so that gastric juice entering the inner side of the membrane through the pores of the coating membrane rapidly dissolves the primary drug first dipyridamole, the osmotic pressure promoter and the water-soluble diluent to continuously form a hypertonic saturated solution. The addition of 5-15 parts of disintegrating agent in the tablet core of the dipyridamole osmotic pump controlled release tablet is beneficial to promoting the dipyridamole in the tablet core to be disintegrated and released and also beneficial to maintaining the stability of drug release. In some preferred embodiments, the disintegrant is preferably sodium carboxymethyl starch or sodium carboxymethyl cellulose.
The lubricant comprises at least one of sodium stearate, magnesium stearate, zinc stearate, and sodium stearyl fumarate. The lubricants can avoid the phenomenon that the tablet core quality is damaged by sticky impact caused by material during tabletting, so that coating cannot be performed, and the fluidity of dry particles can be increased, so that uniform filling in the tabletting process is realized, and the tablet weight difference is controlled in a smaller range. In some preferred embodiments, the lubricant is selected from zinc stearate.
In some embodiments, the coating layer comprises the following weight components: 3-6 parts of second dipyridamole, 3-6 parts of film forming material and 1-3 parts of plasticizer. Wherein the second dipyridamole may be 3 parts, 4 parts, 5 parts, 6 parts, etc.; the film forming material can be 3 parts, 4 parts, 5 parts, 6 parts and the like; the plasticizer may be 1 part, 2 parts, 3 parts, etc. The coating layer is understood to be a coating film which is coated on the surface of the tablet core and which is a semipermeable film; thus, the coating layer, coating film/coating film, semipermeable film in the present specification refer to the same material structure unless otherwise specified.
The second dipyridamole and the first dipyridamole are pharmaceutically active ingredients in a dipyridamole osmotic pump controlled release tablet (Active pharmaceutical ingredient). After the second dipyridamole in the coating layer is contacted and dissolved with gastric acid, loose spongy micropores are formed in the coating layer, so that the tablet core is disintegrated for digestion liquid to enter the coating film quickly, the first dipyridamole, osmotic pressure promoter and water-soluble diluent in the tablet core are dissolved, an initial osmotic pressure channel for providing controlled release is formed, and the controlled release effect of the medicine is improved. Meanwhile, the second dipyridamole is used as an immediate release active ingredient, and the first dipyridamole is used as a constant release active ingredient.
The dipyridamole is dissolved in 0.1mol/L hydrochloric acid to reach 32.6mg/ml, and the dipyridamole is added into a coating layer as a pore-forming agent to prepare dipyridamole osmotic pump controlled release tablet, and the dipyridamole can be directly contacted with gastric acid and dissolved in stomach after being orally taken, and absorbed into blood to quickly form initial blood concentration while forming coating film micropores to quickly exert curative effect.
Specifically, the film-forming material comprises at least one of cellulose acetate, ethyl cellulose, methyl cellulose, ethyl cellulose acetate, ethylene-vinyl acetate copolymer, ethylene acrylic acid copolymer, polyvinyl alcohol, polyethyl acetate and ethylene-cellulose acetate copolymer; the film-forming materials have the characteristics of no toxicity, stable property, no dissolution in acid, alkali and aqueous solution and the like, and can coat the tablet cores to form stable semipermeable coating layers with enough toughness. In some specific embodiments, ethylene-cellulose acetate copolymer is selected as a film forming material, the tablet core is coated, and a tablet is prepared, and a coating layer made of the film forming material is used as a main raw material for establishing an osmotic pump controlled release system and mainly serves as a barrier for establishing the controlled release system, so that release of the active pharmaceutical ingredient is controlled, free release of the active pharmaceutical ingredient is avoided, and release of the active pharmaceutical ingredient only through micropores formed in the coating film after dissolution of the second dipyridamole is ensured. The ethylene-cellulose acetate copolymer has better film forming property, can be used as a semipermeable film coating for preparing film agents, in particular to be used for preparing osmotic pump controlled release preparations and implantation preparations, controls and delays the release of medicaments, can be used with other substances to realize the purpose of controlled release, does not need to make a hole on a film like a common osmotic pump controlled release system, and more importantly, the ethylene-cellulose acetate copolymer is insoluble in artificial gastric juice and intestinal juice, and can keep good stability in digestive juice, thereby realizing better controlled release effect.
The plasticizer is at least one selected from triethyl citrate, tripropyl citrate, trimethyl citrate, dimethyl phthalate, triethyl glycerol, dibutyl sebacate, dibutyl phthalate, tributyl acetylcitrate, triethyl acetylcitrate, diethyl phthalate and polyethylene glycol; specifically, tributyl acetylcitrate can be selected. The plasticizer can improve the film forming property of the film forming material, strengthen the flexibility and the mechanical strength of the film forming material, so as to obtain a coating layer with excellent toughness, keep the coating layer continuously intact, ensure that the medicine is released at a constant speed through micropores in the coating film, and ensure that the release curve of the medicine shows a good zero-order release pharmacokinetics state. When the film forming material is singly applied to the coating film, most of the formed coating film has poor toughness, is brittle and is easy to crack, and in order to improve the performance of the coating film, the plasticizer is added into the coating liquid to improve the ductility and the elasticity of the coating material and strengthen the flexibility and the mechanical strength of the coating material so as to obtain the coating film with excellent controlled release performance. The plasticizer is added into the coating material, so that the elastic deformation performance of the coating layer can be improved, the coating film is prevented from being broken, and the dipyridamole can not realize uniform constant-speed zero-order release. In some embodiments, the plasticizer is selected from tributyl acetyl citrate, has good compatibility with film forming materials such as ethylene-cellulose acetate copolymer, ensures that the coating is in a complete state continuously, and provides necessary conditions for the drug release curve to exhibit zero-order release pharmacokinetic characteristics.
In some embodiments, the mass ratio of the tablet core to the coating layer in the dipyridamole osmotic pump controlled release tablet is (95-97): (3-5); the proportion ensures the isolation effect of the coating layer on the tablet core, maintains the stable structure of the coating film, is favorable for realizing stable constant-speed zero-order release of dipyridamole through micropores in the coating film, ensures that the quantity of the dipyridamole released in unit time tends to be constant, and particularly, the second dipyridamole serving as a pore-forming agent enters the stomach after the drug is taken, is dissolved in gastric acid, is released, is rapidly absorbed into blood, becomes a quick-release part of the dipyridamole, rapidly forms initial blood concentration and plays a role in curative effect. In some embodiments, the mass percent of the coating layer in the dipyridamole osmotic pump controlled release tablet includes, but is not limited to, 5%, 6%, 7%, 8%, 9%, 10%, etc.
In a second aspect, an embodiment of the present application provides a method for preparing a dipyridamole osmotic pump controlled release tablet, as shown in fig. 1, including the following steps:
s01: providing raw materials of each component in the dipyridamole osmotic pump controlled release tablet provided by the embodiment of the application;
s02: firstly preparing a tablet core, and then coating the tablet core to form a coating layer to obtain the dipyridamole osmotic pump controlled release tablet.
According to the preparation method of the embodiment of the application, a part of dipyridamole raw material medicine (namely first dipyridamole) is added with a diluent, an adhesive, an osmotic pressure promoter, a disintegrating agent and a lubricant for mixing treatment, so that a tablet core is prepared; dissolving another part of dipyridamole raw material (namely second dipyridamole) as a pore-forming agent, a film-forming material and a plasticizer into a solvent to prepare coating liquid, coating the prepared tablet core coating to prepare an osmotic pump controlled release tablet, orally taking the osmotic pump controlled release tablet, rapidly dissolving the dipyridamole which is caused to Kong Jidi in the coating film into gastric juice, absorbing the gastric juice into blood to rapidly form initial blood concentration, exerting curative effect, further enabling acid gastric juice to enter the inner side of the coating film through dense micropores formed after dissolving the second dipyridamole in the coating film, promoting the tablet core to disintegrate under the action of a disintegrating agent, and dissolving the water-soluble diluent, the osmotic pressure promoter and the first dipyridamole in the coating liquid, wherein the gastric juice just has the characteristic of dissolving the dipyridamole, so that the dipyridamole can be rapidly dissolved into a saturated solution with a certain initial osmotic pressure, and simultaneously, the gastric juice is continuously dissolved in the gastric juice through the micropores of the coating film, and the osmotic pressure promoter continuously dissolving the tablet in the water-soluble core to continuously form a saturated solution; because of the rigid structure of the coating film, osmotic pressure difference between the inside and the outside of the tablet core as drug release power can maintain gastric juice to continuously enter the tablet core to continuously dissolve osmotic pressure promoter, water-soluble diluent and first dipyridamole in the tablet core until all the first dipyridamole in the tablet core is dissolved in the release medium, so that the saturated aqueous solution of the drug and the permeation promoter is continuously released from drug release pores generated after the second dipyridamole in the coating film is dissolved in the release medium, and the effect of constant drug release is achieved under the high osmotic pressure maintained by the osmotic pressure promoter. This constant release process will continue until the drug in the tablet core is completely dissolved in the semipermeable membrane. The remaining drug is released at a gradually decreasing rate until the osmotic pressure within and outside the tablet is equalized.
In the dipyridamole osmotic pump controlled release tablet prepared by the embodiment of the application, the size and the number of micropores on the coating film have a decisive effect on the release speed and the total amount of the drug, the micropores are dissolved when gastric juice contacts with the dipyridamole on the coating film, loose spongy micropores are formed in the film, so that gastric juice can quickly enter the coating film through the micropores to measure, the tablet core is promoted to disintegrate, the first dipyridamole, an osmotic pressure promoter and a water-soluble diluent are dissolved, then a hypertonic saturated solution is continuously formed, the active component of the drug is passively diffused from the high osmotic end of the inner side of the coating film to the low osmotic end of the outer side of the coating film at a constant speed until osmotic pressure of two sides is equal, the second dipyridamole is taken as the micropores formed on the semipermeable film by the pore-forming agent, and is taken as a channel for osmotic release of the first dipyridamole, and the release speed can be controlled until the peak of the blood concentration is maintained.
In the step S01, raw materials of each component are as follows: dipyridamole (including first dipyridamole and second dipyridamole), diluent, binder, osmotic pressure promoter, disintegrant, lubricant, film forming material and plasticizer for specific parts by weight, see above; these materials are commercially available.
In the step S02, 20 to 60 parts of first dipyridamole, 40 to 80 parts of diluent, 1.0 to 2.0 parts of adhesive, 5 to 15 parts of osmotic pressure accelerator, 5 to 15 parts of disintegrant and 0.5 to 1.0 part of lubricant are mixed to prepare a tablet core, 3 to 6 parts of film forming material, 3 to 6 parts of second dipyridamole and 1 to 3 parts of plasticizer are dissolved in 30 to 70 parts of solvent to prepare coating liquid, and the coating treatment is carried out.
In some embodiments, the step of making the tablet core comprises: sieving first dipyridamole, diluent, osmotic pressure promoter and disintegrating agent respectively, mixing well, mixing with aqueous solution of binder to obtain wet granule, drying, mixing with lubricant, and tabletting to obtain tablet core. In some embodiments, the first dipyridamole, the diluent, the osmotic pressure promoter and the disintegrant are respectively sieved by a 100-mesh sieve, the components are uniformly mixed, then an aqueous solution with the concentration of 6.0wt% of the binder is added to prepare 18-mesh wet granules, the wet granules are dried at the temperature of 60-65 ℃ until the water content is 4.0-4.3%, cooled to room temperature, 14-mesh granules are finished, the lubricant is added, and the mixture is uniformly mixed and pressed into a shallow arc-shaped tablet with the thickness of 10.0mm to obtain a tablet core.
In some embodiments, the step of coating the tablet core to form a coating layer comprises:
Mixing the second dipyridamole, a film-forming material, a plasticizer and a solvent to obtain a coating liquid; spraying the coating liquid on the surface of the tablet core, and then drying to form a coating layer.
The solvent is selected from any one of mixed solvent of dichloroethane and ethanol, mixed solvent of dichloroethane and methanol, mixed solvent of dichloromethane and propanol, mixed solvent of acetone and water, mixed solvent of acetone and methanol, mixed solvent of ethyl acetate and ethanol, mixed solvent of ethyl acetate and methanol, mixed solvent of chloroform and ethanol, and mixed solvent of chloroform and acetone. In some embodiments, a mixed solution of chloroform-ethanol is selected, wherein the volume ratio of the chloroform-ethanol is 95:5.
specifically, the coating liquid is sprayed on the surface of the tablet core in a coating machine, and the conditions for spraying the coating liquid on the surface of the tablet core include: the rotating speed is 7-9 rpm, and the air inlet temperature is 50-70 ℃.
In some embodiments, the step of coating treatment comprises: placing the tablet core into a coating machine, controlling the rotating speed of the coating machine to be 3-4 r/min, the air inlet temperature to be 75-85 ℃, preheating to the air outlet temperature to be 50-55 ℃ for 30 min, and starting coating by a coating liquid; specifically, the rotating speed of the coating machine is regulated to 8-9 revolutions per minute, the air inlet temperature is 50-70 ℃, coating liquid is sprayed into the tablet core to carry out coating treatment, so that the coating liquid is uniformly distributed on the tablet core, the air inlet temperature and the spraying amount are regulated, the layer-by-layer drying is ensured, the coating liquid is ensured to be fully covered on the surface of the tablet core, and the dosage shortage caused by the loss of the second dipyridamole is avoided. And (5) fully drying to obtain the dipyridamole osmotic pump controlled release tablet.
In sum, the dipyridamole osmotic pump controlled release tablet of the formula can increase the osmotic pressure of a solution formed by mixing gastric juice with a drug active ingredient, an osmotic pressure promoter and a water-soluble diluent through coating film micropores by adding the water-soluble diluent and the osmotic pressure promoter into a tablet core, promote the coating film to expand to the limit, form continuous limit high permeability, ensure that dipyridamole is pushed to realize zero-order release into the stomach through the micropores in the film at a constant speed, improve the safety of the drug, and reduce the severity degree, incidence rate and drug resistance of adverse reactions. The dipyridamole osmotic pump controlled release tablet can improve the great fluctuation of the blood concentration of the medicinal active ingredient caused by the burst release effect necessarily caused by the conventional oral preparation, so that the blood concentration of the dipyridamole is more stable. The second dipyridamole in the coating film is dissolved in gastric acid in the stomach first, rapidly absorbs blood, rapidly forms initial blood concentration, and plays a therapeutic role in the first time. Gastric juice rapidly enters the membrane to meet the tablet core through uniformly dispersed and densely distributed holes generated by dissolving the second dipyridamole in gastric acid, so that the tablet core is rapidly disintegrated by virtue of the disintegrating agent added into the tablet core, the gastric juice is rapidly dissolved when meeting the first dipyridamole, the osmotic pressure promoter and the water-soluble diluent in the tablet core, a hypertonic saturated solution is continuously formed under the action of the water-soluble diluent and the osmotic pressure promoter, and the hypertonic solution is permeated and diffused into the stomach with low osmotic pressure through the micropores of the coating membrane at the inner side of the membrane under the pushing of osmotic pressure, so that blood is absorbed, the in vivo zero-order release of the dipyridamole is realized, and the amount of the dipyridamole released per unit time tends to be constant. The dipyridamole Mo Junyun is released at a constant rate, so that a stable blood concentration can be maintained under the condition of reducing the administration frequency of dipyridamole.
In order that the implementation details and operations described above in the present application can be clearly understood by those skilled in the art, and that the advanced performance of the dipyridamole osmotic pump controlled release tablet and the preparation method thereof according to the embodiments of the present application are significantly reflected, the above technical solutions are exemplified by a plurality of embodiments below.
Example 1
Dipyridamole osmotic pump controlled release tablet, its preparation raw material formulation is shown in table 1 below.
TABLE 1
Making 10000 tablets.
Wherein the dipyridamole comprises 900g of a first dipyridamole and 100g of a second dipyridamole; maltodextrin as a diluent, mannitol as an osmotic pressure promoter, low-substituted hydroxypropylcellulose as a binder, sodium carboxymethyl starch as a disintegrant, zinc stearate as a lubricant, ethylene-cellulose acetate copolymer as a film forming material, tributyl acetylcitrate as a plasticizer, and chloroform-ethanol (volume ratio 95:5) as a solvent. The first dipyridamole, maltodextrin, mannitol, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and zinc stearate are used as raw materials for preparing tablet cores, and the second dipyridamole, ethylene-cellulose acetate copolymer, tributyl acetylcitrate and methylene dichloride-ethanol are used as raw materials for preparing coating layers.
The preparation method comprises the following steps:
1. preparation of tablet cores
1.1 preparation of adhesive: adding water into the prescription amount of low-substituted hydroxypropyl cellulose to dissolve the prescription amount of low-substituted hydroxypropyl cellulose to prepare a low-substituted hydroxypropyl cellulose aqueous solution with the mass concentration of 6.0 percent;
1.2 granulating: firstly, respectively crushing the prescription dose of maltodextrin, mannitol, first dipyridamole and carboxymethyl starch sodium, sieving with a 100-mesh sieve, mixing for 10 minutes, adding 6.0% low-substituted hydroxypropyl cellulose aqueous solution, mixing for 2 minutes, preparing into 18-mesh wet granules, drying at 60-65 ℃ until the water content is 4.0-4.3%, cooling to room temperature, finishing the granules with 14 meshes, adding the prescription dose of zinc stearate, and mixing for 30 minutes;
1.3 tabletting: the granules are pressed into shallow arc-shaped tablets with the thickness of 10.0mm, namely tablet cores of dipyridamole osmotic pump controlled release tablets, and each tablet weighs 0.32g.
2. Coating layer
2.1 preparation of coating liquid: and (3) dissolving the tributyl acetylcitrate with the prescription amount in a chloroform-ethanol (volume ratio of 95:5) solution, sequentially adding the second dipyridamole and the ethylene-cellulose acetate copolymer, stirring and mixing for 30 minutes, and preparing the coating liquid.
2.2 coating: the dipyridamole osmotic pump controlled release tablet core is placed in a high-efficiency coating machine, the rotating speed of the coating machine is controlled to be 3-4 revolutions per minute, the air inlet temperature is controlled to be 75-85 ℃, and the tablet core is preheated to the air outlet temperature of 50-55 ℃ for 30 minutes; and then adjusting the rotating speed of a coating machine to 8-9 revolutions per minute, spraying coating liquid at the air inlet temperature of 50-70 ℃ to uniformly distribute the coating liquid on the tablet core, adjusting the air inlet temperature and the spraying amount to ensure that the coating liquid is fully covered on the surface of the tablet core, and after the coating liquid is fully dried, increasing the weight of the coating by 7.85%, thus obtaining the dipyridamole osmotic pump controlled release tablet.
Example 2
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the osmotic pressure promoter mannitol amount was reduced to 200g and the diluent maltodextrin amount was increased to 1800g. The other components and preparation steps were the same as in example 1. The specific formulation is shown in table 2 below.
TABLE 2
Making 10000 tablets.
Example 3
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the amount of disintegrant sodium carboxymethylcellulose was reduced to 200g and the amount of diluent maltodextrin was increased to 1750g. The other components and preparation steps were the same as in example 1. The specific formulation is shown in table 3 below.
TABLE 3 Table 3
Making 10000 tablets.
Example 4
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the amount of the plasticizer tributyl acetylcitrate is reduced to 35g, and the amount of the film-forming material ethylene-cellulose acetate copolymer is increased to 115g. The other components and preparation steps were the same as in example 1. The specific formulation is shown in table 5 below.
TABLE 4 Table 4
Making 10000 tablets.
Example 5
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the osmotic pressure promoter mannitol was replaced with sodium chloride and the other components and preparation steps were the same as in example 1. The specific formulation is shown in table 5 below.
TABLE 5
Making 10000 tablets.
Comparative example 1
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the osmotic pressure promoter mannitol was deleted and the diluent dextrates amount was increased to 2000g. The other components and preparation steps were the same as in example 1. The specific formulation is shown in table 6 below.
TABLE 6
Making 10000 tablets.
Comparative example 2
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the second dipyridamole as a porogen in the coating layer was replaced with xylitol and a total of 1000g of the second dipyridamole and the first dipyridamole was used for granulating and tabletting the tablet cores, the amount of maltodextrin as a diluent was reduced to 1600g, and other components and preparation steps were similar to those of example 1. The specific formulation is shown in table 7 below.
TABLE 7
Making 10000 tablets.
Comparative example 3
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the plasticizer tributyl acetylcitrate is deleted, and the amount of the film forming material ethylene-cellulose acetate copolymer is increased to 150g. The other components and preparation steps were the same as in example 1. The specific formulation is shown in table 8 below.
TABLE 8
Making into 1000 pieces.
Comparative example 4
Dipyridamole osmotic pump controlled release tablet, which differs from example 1 in that: the second dipyridamole serving as a pore-forming agent is combined with the first dipyridamole in the tablet core and then used for granulating and tabletting the tablet core, the amount of the plasticizer acetyl tributyl citrate is increased to 100g, the amount of the coating agent ethylene-cellulose acetate copolymer is increased to 150g, and the amount of the diluent maltodextrin is reduced to 1600g. Other components and preparation steps were similar to those of example 1. The specific formulation is shown in table 9 below.
TABLE 9
Making into 1000 pieces.
Performance testing
To verify the advancement of the examples of the present application, the following performance tests were performed for each example and comparative example, respectively:
1. method for measuring accumulated release amount of dipyridamole osmotic pump controlled release tablet
1.1 taking a proper amount of a sample solution, adopting a first method for measuring dissolution and release of Chinese pharmacopoeia (four parts) of 2020 edition, taking 900mL of hydrochloric acid solution (9-1000) as a dissolution medium, rotating at 100 revolutions per minute, rotating at 75r/min, operating at 37+/-5 ℃ according to the law, taking 10mL of dissolution liquid at 0, 2, 5, 15, 30, 60, 90, 120, 180, 240, 300, 360, 420 and 480 minutes, immediately supplementing the dissolution medium with the same temperature and the same volume, filtering the taken dissolution liquid, precisely measuring the subsequent filtrate, and respectively adding the dissolution medium to quantitatively dilute the dissolution medium into a solution containing about 10 mug in each 1 mL.
1.1.2 accurate weighing of dipyridamole reference substance, accurate weighing, dissolving in dissolution medium, and quantitatively diluting to obtain solution containing 10 μg per 1 ml.
1.1.3 measurement method the sample solution and the control solution were taken, absorbance was measured at 283nm wavelength, respectively, according to C, by ultraviolet-visible spectrophotometry (generally 0401) 24 H 40 N 8 O 4 Absorption coefficient (E) 1％ 1cm ) Calculate the accumulated release amount of each piece at different time for 625
The cumulative release and curves of the dipyridamole examples and comparative examples are shown in Table 10 and FIG. 2.
TABLE 10 cumulative release of dipyridamole (%)
From the above test results, it can be seen that: examples 1, 2, 3, 4 and 5 all have release rates of more than 5% in 2 minutes and release rates of more than 6% in 5 minutes; while comparative examples 2, 4, which did not use the second dipyridamole as a porogen, had a release of zero at 2 minutes, the prodrug release rate was lower than in the examples of the present application even with comparative example 2, which used xylitol as a porogen. It was thus demonstrated that the second dipyridamole as a coating layer porogen exhibited a rapid release effect, and that the immediate release portion of the formulation obtained as examples herein practically exhibited a sufficient release rate, providing a sufficient initial basal concentration for rapid onset of the formulation of examples herein.
The cumulative release of dipyridamole from example 1 had a very good linear correlation, the linear correlation coefficients were 0.9991, it was confirmed that the zero-order release was extremely high, the release rate was 0.1988, which was higher than that of examples 2, 3, 4, 5 and comparative examples 1, 2, 4, and that of example 4, which was lower than that of examples 1, 2 and 3, 5, although the release rate was lower than that of examples 1, 2, 3, 5, but the release profile correlation coefficient was lower than that of examples 1, 2, 3, 5, probably due to the uneven release of dipyridamole, an active ingredient having lower plasticity in the coating layer, caused by the fact that the release was irregular. The release rate of example 2 was higher than that of example 5, whereas the release rate of example 5 was higher than that of example 3, and the release rate of example 3 was higher than that of comparative example 1, and it was seen that the effect of the disintegrant on the release rate in the formulation exceeded that of the osmotic pressure promoter, but was less linear-dependent. The coating layers of comparative examples 2 and 4 did not incorporate the portion Mo Sushi of the second dipyridamole as a porogen, and comparative example 4 did not incorporate other porogens whose release was completely dependent on semipermeable membrane permeation diffusion, and whose release rate was lower than that of comparative example 2 in which xylitol was used as a porogen, but its linear correlation was slightly worse than that of comparative example 2, but not significant. The release rate of comparative example 2 was much lower than that of example 1, and it was seen that the release rate of the controlled release tablet made with xylitol as the porogen was lower than that of the second dipyridamole as the porogen. Example 3 is an example in which the amount of disintegrant is reduced, comparative example 2 changes the second dipyridamole porogen of the coating layer to xylitol so that there is no immediate release portion of the second dipyridamole, and the porogen of xylitol acts similarly to dipyridamole so that the release behavior is significantly different from example 3 except that there is no immediate release portion, i.e., the release rate using xylitol as porogen is slightly lower than that of example 3 in which a smaller amount of disintegrant is used.
The release rate and the linear correlation evaluation are combined, and the linear correlation is a direct characterization parameter of the zero-order release degree, so that the comparative example 3 is poor in linearity of the release curve because the coating layer is not provided with the plasticizer, so that the coating film cannot be kept complete continuously, a control system is crashed and the coating film is broken, and the release rate of the drug is high but the release curve is irregular; while other examples showed better immediate and controlled release effects than the comparative examples, and the zero order release degree and release rate of the immediate and controlled release portions of example 1 were better than those of the other examples and comparative examples.
The foregoing description of the preferred embodiments of the present application is not intended to be limiting, but is intended to cover any and all modifications, equivalents, and alternatives falling within the spirit and principles of the present application.
Claims (10)
1. The dipyridamole osmotic pump controlled release tablet is characterized by comprising a tablet core and a coating layer coated on the surface of the tablet core; wherein,
the tablet core comprises the following components in parts by weight: 20-60 parts of first dipyridamole, 40-80 parts of diluent, 1.0-2.0 parts of adhesive, 5-15 parts of osmotic pressure promoter, 5-15 parts of disintegrant and 0.5-1.0 part of lubricant;
The coating layer comprises the following components in parts by weight: 3-6 parts of second dipyridamole, 3-6 parts of film forming material and 1-3 parts of plasticizer.
2. The dipyridamole osmotic pump controlled release tablet according to claim 1, wherein the mass ratio of the tablet core to the coating layer is 95-97: 3 to 5.
3. A dipyridamole osmotic pump controlled release tablet according to claim 1 or 2,
the diluent comprises at least one of dextrates, xylitol, povidone K30, maltodextrin, lactose, sucrose powder, starch, dextrin and sorbitol;
and/or the binder comprises at least one of alginic acid, acacia, hydroxypropyl cellulose, hypromellose, povidone K30, low-substituted hydroxypropyl cellulose, crospovidone, hydroxyethyl cellulose, ethylcellulose, hypromellose phthalate, dextrin, lactose;
and/or the osmotic pressure promoter comprises at least one of sodium sulfate, mannitol, sodium chloride, lactose, sodium phosphate, sucrose, xylitol and sorbitol;
and/or the disintegrating agent comprises at least one of alginic acid, croscarmellose sodium, croscarmellose calcium, microcrystalline cellulose, carmellose sodium, carmellose calcium and carmellose sodium;
And/or the lubricant comprises at least one of sodium stearate, magnesium stearate, zinc stearate and sodium stearyl fumarate.
4. A dipyridamole osmotic pump controlled release tablet according to claim 3, wherein the diluent is maltodextrin, the binder is low substituted hydroxypropylcellulose, the osmotic pressure enhancer is mannitol, the disintegrant is sodium carboxymethyl starch or sodium carboxymethyl cellulose, and the lubricant is zinc stearate.
5. A dipyridamole osmotic pump controlled release tablet according to claim 1 or 2,
the film forming material comprises at least one of cellulose acetate, ethyl cellulose, methyl cellulose, ethylene-vinyl acetate copolymer, ethylene acrylic acid copolymer, polyvinyl alcohol, polyethyl acetate and ethylene-cellulose acetate copolymer;
and/or the plasticizer is at least one selected from triethyl citrate, tripropyl citrate, trimethyl citrate, dimethyl phthalate, triethyl glycerol, dibutyl sebacate, dibutyl phthalate, tributyl acetylcitrate, triethyl acetylcitrate, diethyl phthalate and polyethylene glycol.
6. The dipyridamole osmotic pump controlled release tablet according to claim 5, wherein said film-forming material is an ethylene-cellulose acetate copolymer and said plasticizer is tributyl acetylcitrate.
7. The preparation method of the dipyridamole osmotic pump controlled release tablet is characterized by comprising the following steps:
providing the component materials in the dipyridamole osmotic pump controlled release tablet according to any one of claims 1 to 6;
and preparing the tablet core, and then coating the tablet core to form the coating layer to obtain the dipyridamole osmotic pump controlled release tablet.
8. The method of manufacturing of claim 7, comprising the steps of: the step of coating the tablet core to form the coating layer comprises the following steps:
mixing the second dipyridamole, the film-forming material, the plasticizer and a solvent to obtain a coating liquid;
spraying the coating liquid on the surface of the tablet core, and then drying to form the coating layer.
9. The method according to claim 8, wherein the solvent is selected from any one of a mixed solvent of dichloroethane and ethanol, a mixed solvent of dichloroethane and methanol, a mixed solvent of dichloromethane and propanol, a mixed solvent of chloroform and ethanol, a mixed solvent of chloroform and methanol, a mixed solvent of chloroform and acetone, a mixed solvent of acetone and water, a mixed solvent of acetone and methanol, a mixed solvent of ethyl acetate and ethanol, and a mixed solvent of ethyl acetate and methanol.
10. The method of claim 8, wherein spraying the coating solution onto the surface of the tablet core in a coating machine comprises: the rotating speed is 7-9 rpm, and the air inlet temperature is 50-70 ℃.
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