Cilnidipine osmotic pump controlled release tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a cilnidipine osmotic pump controlled release tablet and a preparation method thereof. The preparation method of the cilnidipine osmotic pump controlled release tablet comprises the following steps: mixing cilnidipine and a cyclodextrin derivative to obtain a cilnidipine cyclodextrin inclusion compound; mixing the cilnidipine cyclodextrin inclusion compound with an osmotic pressure accelerant, a cosolvent, a disintegrating agent, an adhesive and a diluent, and granulating to obtain cilnidipine cyclodextrin inclusion compound particles; mixing and tabletting the cilnidipine cyclodextrin inclusion compound particles, a flow aid and a lubricant to obtain a cilnidipine osmotic pump controlled release tablet core; and mixing the cilnidipine osmotic pump controlled release tablet core with a pore-foaming agent, an opacifying agent, a plasticizer and a coating material, and carrying out coating treatment to obtain the cilnidipine osmotic pump controlled release tablet. The cilnidipine osmotic pump controlled release tablet prepared by the invention can prolong the action time of the medicine, improve the bioavailability of the medicine, reduce the peak-valley effect of the blood concentration of the medicine and improve the medication compliance of a patient.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sustained-release nisoldipine osmotic pump tablet and a preparation method thereof. BACKGROUND

[0002] Nisoldipine is a dihydropyridine calcium channel antagonist, and its chemical name is E-racemic-1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridine dicarboxylic acid-2-methoxyethyl-3-phenyl-2-propenyl ester; its molecular formula is C 27 H 28 N2O7; its molecular weight is 492.533; it is slightly soluble in methanol or ethanol, easily soluble in acetone or chloroform, almost insoluble in water, soluble in glacial acetic acid, and has a melting point of 105-109 DEG C. Since nisoldipine is almost insoluble in water, the ordinary tablet made of the raw material has a low dissolution rate.

[0003] Nisoldipine is mainly used for treating hypertension and angina pectoris in clinic, and its white film-coated tablet was marketed in Japan in 1995. Although nisoldipine has a good curative effect, the commercially available tablet of nisoldipine has a significant blood concentration peak-valley phenomenon after being taken orally for two hours, which causes a first-dose effect in clinical use, i.e. the blood pressure of a patient is greatly reduced after the patient takes the tablet for the first time, thereby causing adverse reactions of the cardiovascular system. SUMMARY

[0004] The present application aims to provide a sustained-release nisoldipine osmotic pump tablet and a preparation method thereof, and aims to solve the technical problem of how to control the release of nisoldipine, prolong the drug action time, improve the patient compliance, reduce the blood concentration peak-valley phenomenon, reduce the toxic side effects of the drug, and reduce the probability of drug resistance.

[0005] To achieve the above-mentioned application purposes, the technical scheme adopted by the present application is as follows:

[0006] In a first aspect, the present application provides a preparation method of a sustained-release nisoldipine osmotic pump tablet, which comprises the following steps:

[0007] mixing and treating nisoldipine and a cyclodextrin derivative to obtain a nisoldipine cyclodextrin inclusion compound;

[0008] granulating the nisoldipine cyclodextrin inclusion compound by mixing it with an osmotic pressure promoter, a solubilizer, a disintegrant, a binder and a diluent to obtain nisoldipine cyclodextrin inclusion compound granules;

[0009] mixing the nisoldipine cyclodextrin inclusion compound granules with a glidant and a lubricant to press a tablet to obtain a nisoldipine osmotic pump tablet core;

[0010] The cilnidipine osmotic pump controlled release tablet core is mixed with a pore-forming agent, an opacifying agent, a plasticizer and a coating material to perform coating treatment, thereby obtaining the cilnidipine osmotic pump controlled release tablet.

[0011] The preparation method of the cilnidipine osmotic pump controlled release tablet provided in the first aspect of the present application comprises the following steps: preparing cilnidipine cyclodextrin inclusion compound by using water-insoluble cilnidipine and cyclodextrin derivatives to increase the water solubility of cilnidipine; adding a disintegrant, a cosolvent, an osmotic pressure promoter, a binder and a diluent to granulate; adding a glidant and a lubricant to tablet to prepare a cilnidipine osmotic pump controlled release tablet core; and mixing a pore-forming agent, an opacifying agent, a plasticizer and a coating material to perform coating to obtain the cilnidipine osmotic pump controlled release tablet. The preparation method is simple and easy to implement, and the cilnidipine osmotic pump controlled release tablet obtained by the method can prolong the action time of the drug, provide stable and uniform blood drug concentration for patients, reduce the fluctuation range of blood drug concentration, reduce the probability of adverse reactions of the drug, improve the bioavailability of the drug, and enable the drug to be more effectively released and absorbed in the intestine, thereby having a good application prospect.

[0012] The cilnidipine osmotic pump controlled release tablet provided in the second aspect of the present application is prepared by the specific preparation method. The cilnidipine osmotic pump controlled release tablet can make the active ingredient cilnidipine have suitable water solubility and fat solubility, thereby being able to well control the release, prolong the action time of the drug, improve the bioavailability of the drug, reduce the peak-valley effect of blood drug concentration, and improve the compliance of patients. DETAILED DESCRIPTION

[0013] In order to make the technical problems, technical solutions and beneficial effects of the present application clearer, the present application will be further described in detail below in combination with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0014] In the present application, the term "and / or" describes the association relationship of the associated objects, which means that there can be three kinds of relationships, for example, A and / or B, which can mean that A exists alone, A and B exist together, and B exists alone. Wherein A and B can be singular or plural. The character " / " generally represents an "or" relationship between the front and rear associated objects.

[0015] In the present application, "at least one" means one or more, and "multiple" means two or more. "At least one" or similar expressions mean any combination of these items, including any combination of single item or multiple items.

[0016] It should be understood that the size of the sequence number of the above processes in various embodiments of the present application does not mean the order of execution, and part or all of the steps can be executed in parallel or in sequence, and the execution order of the processes should be determined according to their functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0017] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "said" and "the" used in the embodiments of the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0018] The weight of the related components mentioned in the specification of the embodiments of the present application can not only refer to the specific content of each component, but also represent the weight ratio relationship between each component, therefore, as long as the content of the related components in the specification of the embodiments of the present application is enlarged or reduced in proportion, it is within the scope disclosed in the specification of the embodiments of the present application. Specifically, the mass mentioned in the specification of the embodiments of the present application can be μg, mg, g, kg and other mass units commonly known in the chemical field.

[0019] The terms "first", "second" are only for the purpose of description, used to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the embodiments of the present application, the first XX can also be called the second XX, and similarly, the second XX can also be called the first XX. Therefore, the features limited by "first", "second" can explicitly or implicitly include one or more of the features.

[0020] Although cinnidipine has good efficacy, the marketed tablet of cinnidipine has obvious peak-trough phenomenon of blood drug concentration after oral administration for two hours, which causes the first dose effect in clinical use, that is, the blood pressure of patients decreases greatly at the initial use, the fluctuation range of blood pressure is large, thereby causing discomfort of the cardiovascular system, especially causing the side effects and serious consequences such as organ function limitation or even organ tissue necrosis due to insufficient blood supply of important organs, or causing serious ischemia of heart and brain blood vessels due to local blood vessel rupture caused by too large fluctuation range of blood pressure. Therefore, how to use the preparation means to overcome the peak-trough phenomenon of cinnidipine to improve the safety and effectiveness of the drug, reduce various side effects, achieve long-acting and stable antihypertensive effect, and improve patient compliance is a problem to be solved. Based on this, the embodiments of the present application provide the following specific solutions.

[0021] First aspect. The embodiments of the present application provide a preparation method of a cinnidipine osmotic pump controlled release tablet, specifically comprising the following steps:

[0022] S01: mixing and treating cinnidipine and cyclodextrin derivatives to obtain a cinnidipine cyclodextrin inclusion compound;

[0023] S02: granulating the cinnidipine cyclodextrin inclusion compound with an osmotic pressure promoter, a solubilizer, a disintegrant, a binder, and a diluent to obtain cinnidipine cyclodextrin inclusion compound granules;

[0024] S03: tabletting the cinnidipine cyclodextrin inclusion compound granules with a glidant and a lubricant to obtain a cinnidipine osmotic pump controlled-release tablet core;

[0025] S04: coating the cinnidipine osmotic pump controlled-release tablet core with a pore-forming agent, an opacifying agent, a plasticizer, and a coating material to obtain a cinnidipine osmotic pump controlled-release tablet.

[0026] The embodiment of the present application mixes cinnidipine and a cyclodextrin derivative to obtain a cinnidipine cyclodextrin inclusion compound, and then granulates the cinnidipine cyclodextrin inclusion compound with an osmotic pressure promoter, a solubilizer, a disintegrant, a binder, and a diluent to obtain cinnidipine cyclodextrin inclusion compound granules, and then mixes the cinnidipine cyclodextrin inclusion compound granules with a glidant and a lubricant to obtain a cinnidipine osmotic pump controlled-release tablet core, and then coats the cinnidipine osmotic pump controlled-release tablet core with a pore-forming agent, an opacifying agent, a plasticizer, and a coating material to obtain a cinnidipine osmotic pump controlled-release tablet. The cinnidipine osmotic pump controlled-release tablet obtained in this way can improve the solubility and release rate of cinnidipine, prolong the action time of the drug, control the fluctuation range of the blood drug concentration, and enable the drug to be released, absorbed, and utilized more effectively, uniformly, and continuously in the intestine.

[0027] In some embodiments, the mixing and processing of cinnidipine and a cyclodextrin derivative in step S01 includes: (1) dissolving the cyclodextrin derivative in ethanol to obtain a saturated cyclodextrin derivative solution; (2) dissolving the cinnidipine in ethyl acetate to obtain a cinnidipine ethyl acetate solution; (3) mixing the saturated cyclodextrin derivative solution and the cinnidipine ethyl acetate solution and then performing crystallization processing to obtain a crystalline product; and (4) performing vacuum drying processing on the crystalline product to obtain a cinnidipine cyclodextrin inclusion compound. This process can better pack the cinnidipine molecules in the molecular cage of β-cyclodextrin and combine the cinnidipine molecules with the lipophilic carbon-hydrogen bonds and ether bonds on the inner side of the cyclodextrin molecular cage through intermolecular van der Waals forces to form a cinnidipine cyclodextrin inclusion compound.

[0028] In some embodiments, the cyclodextrin derivative is selected from a β-cyclodextrin derivative, the β-cyclodextrin derivative is dissolved in an alcohol solution to fully dissolve the β-cyclodextrin derivative to obtain a β-cyclodextrin derivative ethanol solution, the cilnidipine is dissolved in ethyl acetate to obtain a cilnidipine ethyl acetate solution, the cilnidipine ethyl acetate solution is then added to the β-cyclodextrin derivative ethanol solution, and the cilnidipine molecules are fully introduced into the molecular cage of the β-cyclodextrin derivative and combined with the lipophilic groups containing carbon-hydrogen bonds and ether bonds in the molecular cage of the β-cyclodextrin derivative by Van der Waals force after homogenization at a temperature of 40-80°C and a rotation speed of 4000-12000 r / min for 80-120 min, and then the cilnidipine is gradually crystallized by slow cooling and separated to obtain a cilnidipine cyclodextrin inclusion compound. In some specific embodiments, the separation step includes filtering the crystals by suction filtration or the like, then washing the crystals with anhydrous ethanol, and then vacuum drying the crystals to obtain the cilnidipine cyclodextrin inclusion compound. In some specific embodiments, the β-cyclodextrin derivative is dissolved in an alcohol solution to fully dissolve the β-cyclodextrin derivative to obtain a saturated solution, which is more conducive to the subsequent inclusion of cilnidipine and the crystallization of cilnidipine, that is, the ester-soluble cilnidipine molecules are introduced into the molecular cage of the β-cyclodextrin derivative and combined with the lipophilic carbon-hydrogen bonds and ether bonds in the molecular cage of the β-cyclodextrin derivative by intermolecular Van der Waals force, so that the drug has hydrophilicity through the hydrophilic hydroxyl groups on the outside of the β-cyclodextrin, thereby improving the water solubility of the drug, and the solubility of the β-cyclodextrin derivative and cilnidipine is improved under this temperature condition, thereby improving the preparation efficiency of the β-cyclodextrin derivative inclusion compound.

[0029] In some embodiments, the mixing of the cyclodextrin derivative saturated solution and the cilnidipine ethyl acetate solution is a process of inclusion; specifically, the temperature of the inclusion treatment is 60-80°C, and further optionally 70°C; the rotation speed is optionally 6000-8000 r / min; and the inclusion time is optionally 90-110 min.

[0030] In some embodiments, after the mixing of the cyclodextrin derivative saturated solution and the cilnidipine ethyl acetate solution, the mixture can be placed in a homogenizer for homogenization or in a ball mill for grinding.

[0031] In some embodiments, the cyclodextrin derivative is dissolved in ethanol, and the ethanol is selected from a 60-95% ethanol solution, that is, a solution containing 5-40% water and 60-95% ethanol solvent by volume percentage (all ethanol solutions mentioned in the embodiments of the present application are by volume percentage); the alcohol solution with this concentration ratio has a better solubilization and dispersion effect on the β-cyclodextrin derivative, and is also conducive to the subsequent crystallization and precipitation of the cilnidipine cyclodextrin inclusion compound from the solution system. In some specific embodiments, the β-cyclodextrin derivative is dissolved in an ethanol solution with a volume percentage of 60%, 70%, 80%, 90%, or 95% ethanol.

[0032] In some embodiments, the β-cyclodextrin derivative is selected from at least one of hydroxypropyl-β-cyclodextrin, 2,3,6-trimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 6-deoxy-β-cyclodextrin derivative, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin derivative, maltotriosyl-β-cyclodextrin derivative, 2,6-dimethyl-β-cyclodextrin. β-cyclodextrin (β-CD) is a "endo-lipophilic, exo-hydrophilic" compound with a "cone" shape formed by 7 D-glucopyranose units connected head to tail. This special cavity and the internal hydrophobic environment facilitate the combination of the fat-soluble cinnidipine with intermolecular van der Waals forces to form an inclusion complex, which can better increase the stability of the drug, prevent drug oxidation and decomposition, improve the water solubility of the drug, prolong the transmembrane transport time of the drug, reduce the toxic side effects of the drug, reduce the peak-trough phenomenon of drug absorption, reduce the amplitude of blood concentration fluctuation during drug absorption, and thus achieve the purpose of stable antihypertensive medication.

[0033] In some embodiments, the β-cyclodextrin derivative is selected from 2,3,6 trihydroxypropyl-β-cyclodextrin, which has the advantages of good water solubility, low nephrotoxicity and small hemolysis, is a good excipient, and can form an inclusion complex with cinnidipine that has good structure and performance stability. By making cinnidipine into an inclusion complex, the drug can be protected from destruction by physical and metabolic shielding, especially the water solubility of cinnidipine can be improved, and the drug has a suitable oil-water partition coefficient. Moreover, 2,3,6 trihydroxypropyl-β-cyclodextrin can promote the absorption of cinnidipine through the paracellular pathway from the mucosa, and after the cinnidipine cyclodextrin inclusion complex is absorbed into the blood, plasma proteins competitively bind to cinnidipine, causing cinnidipine to be competitively displaced from the inclusion complex and exert a clinical antihypertensive effect.

[0034] In some embodiments, the temperature for the crystallization treatment is 4-7°C, which can make the cinnidipine cyclodextrin inclusion complex fully analyze the crystalline material, while improving the crystallization rate, especially the cinnidipine can be improved by rapid crystallization to improve the inclusion rate.

[0035] In some embodiments, the vacuum drying treatment of the crystalline material obtained by the above crystallization treatment includes: placing the crystalline material in the vacuum drying oven tray, pushing it into the vacuum drying oven, closing the oven door, starting the vacuum until the vacuum reaches -0.006 MPa to -0.09 MPa, the drying temperature is 55°C to 65°C, under the above conditions, the moisture content of the crystalline material is 3.5% to 3.9%, and the temperature is cooled to room temperature (25-30°C), and the temperature is cooled to room temperature (25-30°C). The powder is crushed to 120 mesh fine powder, and the cinnidipine cyclodextrin inclusion complex is obtained.

[0036] In some embodiments, the cinalium, cyclodextrin derivative is complexed by mixing solvents of ethanol and ethyl acetate, then crystallized, vacuum dried, and pulverized to produce the cinalium cyclodextrin complex. Specifically, the process of preparing the cinalium cyclodextrin complex includes: dissolving cinalium in ethyl acetate to obtain a cinalium ethyl acetate solution; adding cyclodextrin derivatives into ethanol to produce a saturated solution of cyclodextrin derivatives in ethanol, then mixing the solution with the cinalium ethyl acetate solution in a homogenizer at 6000-8000 rpm / min, or in a ball mill, taking out the mixture into a stainless steel container, and storing in a refrigerator at 4-7°C to crystallize, washing with ethanol after suction filtration, vacuum drying, and pulverizing to obtain the cinalium cyclodextrin complex.

[0037] In some embodiments, the cyclodextrin derivative is at least one of hydroxypropyl-β-cyclodextrin, 2,3,6-trimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 6-deoxy-β-cyclodextrin derivative, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin derivative, maltotriosyl-β-cyclodextrin derivative, and 2,6-dimethyl-β-cyclodextrin. The cyclodextrin derivative can be 2,3,6-trihydroxypropyl-β-cyclodextrin. According to the liposolubility characteristics of cinalium, the hydrophilic outer structure and the lipophilic inner structure of 2,3,6-trihydroxypropyl-β-cyclodextrin are used to prepare a water-soluble cyclodextrin complex of cinalium, thereby improving the solubility of cinalium in water, making it have a suitable oil-water partition coefficient, and reducing the rate of passing through the biological membrane.

[0038] In some embodiments, the binder includes a first binder and a second binder, the first binder is a dry powder, and the second binder is prepared into a solution; the mixing granulation in step S02 includes: mixing the cinalium cyclodextrin complex, the diluent, the osmotic pressure promoter, the cosolvent, the disintegrant, and the first binder in a powder state, then adding the second binder solution prepared by the second binder (which can be used as a wetting agent) to mix into a soft material, and then granulating through a 20-mesh sieve and boiling drying at 55-65°C.

[0039] In some embodiments, the binder comprises a first binder and a second binder, the first binder is selected from at least one of low-substituted hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, the first binder can be mixed with the cyclodextrin inclusion compound and other excipients, on the one hand, to ensure that the granules are pressed into tablets, and more importantly, to ensure that the pressed tablets have sufficient mechanical strength, especially hardness, to facilitate the storage and transportation of the tablets, and subsequent coating operations. The second binder is selected from at least one of hypromellose, povidone, dextrin, maltodextrin, pregelatinized starch, lactose, ethyl cellulose, hydroxypropyl cellulose, the second binder can be processed into a second binder solution (which can be used as a wetting agent) by mixing it with purified water and other solvents, and after mixing with the cinitapril cyclodextrin inclusion compound, diluents, disintegrants, osmotic pressure promoters, dissolution agents, the other materials in the prescription, especially the first binder, are wetted to produce sufficient adhesion to facilitate the preparation of suitable soft material, the preparation of granules with a certain particle size level and suitable particle size distribution, to ensure that the tablets have a certain mechanical strength, especially hardness, under the condition of sufficient fluidity. The first binder mainly functions to improve the hardness and other mechanical strength of the tablets, and the second binder mainly functions to bind the excipients together to form soft material for further processing into granules for tablet pressing, and the granules function to improve the strength of the tablets through intergranular bonding, while improving the fluidity of the materials to ensure uniform filling of the materials during tablet pressing and improve the weight uniformity of the tablets. For example, the first binder can be low-substituted hydroxypropyl cellulose (L-HPC, which can be a non-ionic cellulose derivative prepared by etherification of alkaline cellulose with propylene oxide, and the hydroxypropoxy substituent content can be 7.0%-16.0%), and the second binder can be hypromellose.

[0040] The second binder is prepared into a solution, for example, the second binder is added to purified water, stirred to dissolve, mixed uniformly, and made up to volume to prepare a 1-2% hypromellose aqueous solution, which is the second binder solution.

[0041] In some embodiments, the osmotic pressure promoter is selected from at least one of lactose, sodium chloride, sodium carbonate, sodium sulfate, mannitol, sodium chloride, sodium phosphate, sucrose; for example, the osmotic pressure promoter can be mannitol, which can facilitate the drying of the granules, significantly increase the osmotic pressure of the drug dissolved in the digestive medium, and significantly improve the appearance of the tablets after tabletting, with sweetness and good taste, and especially, mannitol is not absorbed by the gastrointestinal tract and can be directly excreted through the large intestine.

[0042] In some embodiments, the solubilizing agent is selected from at least one of sodium dodecyl sulfate, Tween-80; for example, the solubilizing agent can be sodium dodecyl sulfate, which is an anionic hydrophilic surfactant with an HLB value of 40, and can increase the hydrophilicity of the liposoluble drug, cilnidipine. Tween-80 has an HLB value of 15, which is much smaller than that of sodium dodecyl sulfate, and therefore sodium dodecyl sulfate can be selected as the solubilizing agent.

[0043] In some embodiments, the disintegrant is selected from at least one of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, microcrystalline cellulose, sodium carboxymethyl starch, polyethylene glycol, hydroxypropyl methyl cellulose, and povidone; for example, the disintegrant can be povidone, which can increase the disintegration of the core of the cilnidipine osmotic pump controlled-release tablet through its molecular chain, increase the hydrophilicity of the hydrophobic drug, and facilitate the increase in drug dissolution. Povidone also has the function of a dry binder, which can increase the hardness of the tablet and improve the smoothness of the tablet, and is conducive to the coating of the controlled-release film.

[0044] In some embodiments, the diluent is selected from at least one of lactose, dextran, starch, sucrose, dextrin, maltitol, fructose, mannitol, and pregelatinized starch; for example, the diluent can be lactose, which has good compressibility and flowability, and the resulting tablet is smooth and beautiful. Lactose has little effect on the disintegration time of the drug during storage and little effect on the accuracy of the content determination; it can quickly dissolve in a digestive medium with water as the main component, rapidly increase the osmotic pressure of the drug solution, and promote the dissolution of the core in the controlled-release film into the drug solution formed by the micropores in the digestive medium generated by the first time dissolution of the pore-forming agent in the controlled-release film into the digestive medium inside the controlled-release film. The drug solution rapidly reaches the peak osmotic pressure under the control of the controlled-release film, thereby rapidly controlling the constant release.

[0045] In some embodiments, in step S03, the cilnidipine cyclodextrin inclusion complex particles are mixed with the glidant and the lubricant and then pressed into tablets, which includes: adding the cilnidipine cyclodextrin inclusion complex particles to the glidant and the lubricant, placing them in a square cone mixer, controlling the rotation speed for mixing, and then using a rotary tablet press with a Ф10.5mm shallow arc punch to press the tablets, with a tablet weight of 0.4g / tablet.

[0046] In some embodiments, the weight ratio of the above-mentioned process is (25-75):(125-375):(80-160):(80-120):(150-450):(60-140):(30-80):(5-15):(3-8). The specific binder includes a first binder and a second binder, and the mass ratio of the two can be (50-150):(10-30); for example, in an embodiment, the weight ratio of the cinnidipine, cyclodextrin derivative, first binder, disintegrant, cosolvent, osmotic pressure promoter, diluent, second binder, glidant, and lubricant is (25-75):(125-375):(50-150):(80-120):(30-80):(60-140):(150-450):(10-30):(5-15):(3-8).

[0047] In some embodiments, the glidant is selected from at least one of sodium phosphate, magnesium trisilicate, calcium phosphate, dextrates, and microfine silica; for example, the glidant can be dextrates, which can improve the flowability of the prepared granules, improve the filling uniformity during the tabletting process, and ensure the uniformity of the tablet content. In particular, it can also dissolve in the digestive medium, thereby increasing the osmotic pressure of the solution in the control film, thereby achieving constant release under the control of a fixed number of micropores with uniform pore size and uniform distribution generated by the dissolution of the pore-forming agent in the digestive medium, thereby reducing the peak-trough effect of the drug concentration-time curve caused by the absorption of ordinary immediate-release tablets, and thereby reducing drug resistance caused by drug concentrations below the therapeutic window and toxic side effects caused by drug concentrations above the therapeutic window.

[0048] In some embodiments, the lubricant is selected from at least one of magnesium stearate, sodium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, and glycerol monostearate; for example, the lubricant can be sodium stearyl fumarate. The amount of sodium stearyl fumarate can dissolve in the digestive medium, and it can also supplement the intake of stearate and fumarate. Sodium stearyl fumarate is non-toxic, non-irritating, easily absorbed, and the unabsorbed sodium stearyl fumarate can also be quickly excreted in the original form by feces, with good safety.

[0049] For example, the preparation process of the cinnidipine osmotic pump controlled-release tablet core includes: adding the cinnidipine cyclodextrin inclusion compound to the first binder, diluent, cosolvent, disintegrant, and osmotic pressure promoter, mixing uniformly, then adding the second binder solution to make a soft material, passing through a 20-mesh sieve to make wet granules, then drying the wet granules in a fluid bed dryer, and then granulating, adding the glidant and lubricant, and compressing into tablets.

[0050] In some embodiments, the step of mixing the cintidine osmotic pump controlled release tablet core with the light shielding agent, the pore-forming agent, the plasticizer and the coating material in step S04 includes: dissolving and suspending the pore-forming agent, the light shielding agent, the plasticizer and the coating material in ethanol to obtain a coating liquid; and spraying the coating liquid onto the surface of the cintidine osmotic pump controlled release tablet core at 70-90°C to coat, and then drying.

[0051] For example, the coating liquid is prepared from the coating material, the light shielding agent, the pore-forming agent and the plasticizer, and the weight ratio of the coating material, the light shielding agent, the pore-forming agent and the plasticizer is (4-5):(2-3):(0.8-1.2):(4-5). The solvent for coating is ethanol. Specifically, the preparation process of the coating liquid includes: mixing the plasticizer and the light shielding agent thoroughly, dissolving the plasticizer in the ethanol solvent by strong stirring, suspending the light shielding agent in the ethanol solution in which the plasticizer is dissolved, adding the pore-forming agent and stirring to dissolve, and finally adding the coating material, stirring to completely dissolve, and mixing uniformly to obtain the coating liquid.

[0052] Specifically, the coating liquid can be prepared by uniformly mixing the pore-forming agent which is extremely soluble in water, the plasticizer which has good ductility and plastic deformation, the light shielding agent which has light shielding performance, and the coating material which has high strength and flexibility.

[0053] In some embodiments, the coating material is selected from at least one of cellulose acetate, ethyl cellulose, methyl cellulose, acrylic resin, polyvinyl alcohol phthalate, cellulose acetate phthalate, and hypromellose phthalate. For example, the coating material can be ethyl cellulose. The ethyl cellulose has sufficient mechanical strength as the coating film material, and the combination of the hydrophobic water-insoluble coating material and the plasticizer which has good ductility and plastic deformation has high flexibility, and the drug release can be well controlled by the added pore-forming agent.

[0054] In some embodiments, the pore-forming agent is selected from at least one of xylitol, mannitol, sodium chloride, and polyethylene glycol, such as at least one of polyethylene glycol 2000, polyethylene glycol 4000, and polyethylene glycol 6000. For example, the pore-forming agent can be xylitol. The added pore-forming agent is a material which has good water solubility. After the drug enters the digestive juice through the digestive tract, the pore-forming agent is first dissolved in the digestive juice, thereby forming uniformly distributed pores on the coating film, becoming a channel for the active pharmaceutical ingredient to enter the digestive juice under the driving force of osmotic pressure, and also becoming a channel for the digestive juice to enter the inside of the controlled release film to dissolve the active pharmaceutical ingredient. The pore-forming agent has no ultraviolet absorption at about 240 nm, does not interfere with the detection of the drug, and does not affect the quantitative detection of cintidine.

[0055] In some embodiments, the plasticizer is selected from at least one of triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, diethyl succinate, propylene glycol and glyceryl triacetate, and the plasticizer can be selected from dibutyl phthalate.

[0056] In some embodiments, the light shielding agent is selected from titanium dioxide. Adding a certain amount of titanium dioxide in the coating agent composition can prevent the degradation of cilnidipine due to light.

[0057] In some embodiments, the weight ratio of the coating material, the light shielding agent, the pore-forming agent and the plasticizer is (4-5):(2-3):(0.8-1.2):(4-5). Further, the total weight of the coating material, the light shielding agent, the pore-forming agent and the plasticizer accounts for 4-6% of the weight of the cilnidipine osmotic pump controlled release tablet core.

[0058] In some embodiments, the step of coating treatment comprises: placing the cilnidipine tablet core obtained in the previous step into a high-efficiency coating machine, controlling the rotation speed of the coating machine to 2-3 revolutions per minute, preheating the inlet air temperature to 60-70°C to an outlet air temperature of 40-45°C for 30 minutes, adjusting the rotation speed of the coating machine to 7-9 revolutions per minute, adjusting the inlet air temperature to 60-70°C, uniformly spraying the coating liquid to make the coating liquid uniformly distributed on the tablet core, adjusting the inlet air temperature and the amount of sprayed slurry to ensure layer-by-layer drying, and fully drying to obtain the cilnidipine osmotic pump controlled release tablet, and the coating weight gain is 4%, thereby obtaining the cilnidipine osmotic pump controlled release tablet.

[0059] The cilnidipine osmotic pump controlled release tablet prepared by the above process can not only improve the water solubility of the water-insoluble cilnidipine, reduce the transmembrane transport rate of the drug, prolong the drug absorption time, and further prolong the drug action time; at the same time, the zero-order release of the drug is realized through the control of the coating film containing the pore-forming agent, the light shielding agent and the plasticizer, the drug action time is further prolonged, the amplitude of blood drug concentration fluctuation is reduced, the drug absorption rate is uniform and stable, and thus the probability of drug adverse reactions is reduced.

[0060] Second aspect. The embodiments of the present application provide a cilnidipine osmotic pump controlled release tablet prepared by the preparation method provided in the first aspect of the embodiments of the present application.

[0061] The cilnidipine osmotic pump controlled release tablet of the embodiments of the present application is prepared by the specific preparation method of the embodiments of the present application. Such cilnidipine osmotic pump controlled release tablet can make the active ingredient cilnidipine have suitable water solubility and fat solubility, so as to well control the release of cilnidipine, prolong the drug action time, improve the bioavailability of the drug, reduce the peak-trough effect of the blood drug concentration of the drug, and improve the compliance of patients taking the drug.

[0062] In summary, the prepared cinitapril osmotic pump controlled release tablets of the embodiments of the present application can improve the solubility and release rate of cinitapril, prolong the drug action time, control the fluctuation range of blood drug concentration, and make the drug be absorbed more effectively, uniformly and continuously in the intestine.

[0063] The embodiments will be described in detail below with reference to the accompanying drawings.

[0064] Example 1

[0065] A cinitapril osmotic pump controlled release tablet: the prescription amount is shown in Table 1 below.

[0066] Table 1

[0067]

[0068]

[0069] The preparation method of the cinitapril osmotic pump controlled release tablet comprises the following steps:

[0070] Step 1: Preparation of cinitapril cyclodextrin inclusion compound.

[0071] The prescription amount of 2,3,6-trihydroxypropyl-β-cyclodextrin was weighed and placed in a stainless steel barrel, and the prescription amount of 2,3,6-trihydroxypropyl-β-cyclodextrin was added 10 times of ethanol, and stirred to dissolve completely. The obtained filtrate was a 2,3,6-trihydroxypropyl-β-cyclodextrin saturated solution, which was placed in a homogenizer bin for standby.

[0072] The cinitapril was weighed and placed in a beaker, and 2L of ethyl acetate was added and mixed uniformly to obtain a cinitapril ethyl acetate solution. The cinitapril ethyl acetate solution was added to the above-mentioned homogenizer bin containing the 2,3,6-trihydroxypropyl-β-cyclodextrin ethanol saturated solution, the door was closed and locked, and the rotation speed was adjusted to 9000 rpm. The homogenizer was started, and the homogenization was carried out for 3-5 minutes. Then, it was taken out to a stainless steel container and placed in a refrigerator at 4-7°C to precipitate crystals. After suction filtration, it was washed with ethanol and placed in a stainless steel barrel to obtain cinitapril 2,3,6-trihydroxypropyl-β-cyclodextrin inclusion compound crystals for standby.

[0073] The above cinaldipine 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion complex crystals are vacuum dried, crushed, and cinaldipine cyclodextrin inclusion complex fine powder is obtained according to the following procedure. 1) Packaging: Place the cinaldipine 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion complex crystals in the oven tray of a vacuum drying oven, push into the vacuum drying oven, and close the oven door. 2) Drying: Start vacuum until the vacuum degree reaches -0.06 MPa to -0.09 MPa, set the drying temperature to 60°C, the upper limit to 65°C, and the lower limit to 55°C, start heating and drying, until the moisture content is 3.5% to 3.9%, cool to room temperature, turn off the vacuum pump until the internal pressure of the oven is zero, open the vacuum drying oven, and take out the cinaldipine 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion complex crystal dry product. 3) Crushing and sieving: Crush the crystal dry product to 120 mesh fine powder using a wind-cooled airflow crusher, and cinaldipine cyclodextrin inclusion complex fine powder is obtained.

[0074] Step 2: Preparation of cinaldipine cyclodextrin inclusion complex granules.

[0075] Weigh the prescribed amount of lactose (diluent), povidone (disintegrant), sodium lauryl sulfate (solubilizer), mannitol (osmotic pressure promoter), and low-substituted hydroxypropyl cellulose (first binder), add the above cinaldipine cyclodextrin inclusion complex fine powder, mix well, then add 2% hydroxypropyl methyl cellulose solution (dissolve the prescribed amount of second binder hydroxypropyl methyl cellulose in purified water to obtain), make suitable soft material, use a 20 mesh nylon screen to make wet granules, and place them in a fluidized bed dryer to dry, control the bed temperature to 60-70°C, dry until the moisture content of the granules is 3.1-3.6%, cool to room temperature, and sieve with a 14 mesh nylon screen to obtain cinaldipine cyclodextrin inclusion complex granules.

[0076] Step 3: Preparation of cinaldipine osmotic pump controlled release tablet core.

[0077] Mix the above cinaldipine cyclodextrin inclusion complex granules with the prescribed amount of dextrates (glidant) and sodium stearyl fumarate (lubricant), place them in a square cone mixer, control the rotation speed to 12 rpm / minute, mix for 13 minutes, and discharge, and total mixed granules are obtained. Use a rotary tablet press to press the total mixed granules into tablets using a Ф10.5 mm shallow arc punch to obtain cinaldipine osmotic pump controlled release tablet cores, with a tablet weight of 0.4 g / tablet.

[0078] Step 4: Preparation of cinaldipine osmotic pump controlled release tablet by coating the core.

[0079] Preparation of coating liquid: Take the prescribed amount of micronized dibutyl phthalate (plasticizer) and mix it uniformly with titanium dioxide (sunscreen agent), add it to 1600 ml of 95% ethanol, and stir it vigorously to dissolve the dibutyl phthalate (plasticizer) in the 95% ethanol and suspend the titanium dioxide in the 95% ethanol solution containing the dissolved dibutyl phthalate (plasticizer). Then add xylitol (pore-forming agent) and stir it to dissolve, and finally add ethyl cellulose (coating material) and stir it to completely dissolve and mix it uniformly, to obtain the coating liquid.

[0080] Coating: Place the above-mentioned cinitapril osmotic pump controlled-release tablet core in a high-efficiency coating machine, control the rotation speed of the coating machine at 2-3 revolutions per minute, preheat the inlet air temperature to 70-80°C to an outlet air temperature of 50-55°C, after 30 minutes, adjust the rotation speed of the coating machine to 6-8 revolutions per minute, the inlet air temperature to 80-90°C, and the outlet air temperature to 60-70°C, spray the coating liquid, and make the coating liquid uniformly distributed on the tablet core. Adjust the air volume and the amount of sprayed slurry to make the coating liquid fully cover the surface of the tablet core and dry layer by layer (keep the coating liquid sprayed on the surface of the tablet core dry at all times by sending hot air into the coating pot), and finally coat the tablet core to an increase in weight of 4%, to obtain the cinitapril osmotic pump controlled-release tablet.

[0081] Example 2

[0082] A cinitapril osmotic pump controlled-release tablet: according to the formulation of Example 1, reduce the amount of 2,3,6-trihydroxypropyl-β-cyclodextrin to 500 g, and increase the amount of lactose to 1760 g; the other components and the preparation method of the preparation are the same as in Example 1.

[0083] Example 3

[0084] A cinitapril osmotic pump controlled-release tablet: according to the formulation of Example 1, reduce the amount of povidone to 200 g, and increase the amount of lactose to 1460 g; the other components and the preparation method of the preparation are the same as in Example 1.

[0085] Example 4

[0086] A cinitapril osmotic pump controlled-release tablet: according to the formulation of Example 1, reduce the amount of mannitol to 200 g, and increase the amount of lactose to 1460 g; the other components and the preparation method of the preparation are the same as in Example 1.

[0087] Example 5

[0088] A cinitapril osmotic pump controlled-release tablet: according to the formulation of Example 1, reduce the amount of sodium dodecyl sulfate to 100 g, and increase the amount of lactose to 1360 g; the other components and the preparation method of the preparation are the same as in Example 1.

[0089] Example 6

[0090] A kind of cininnide osmotic pump controlled-release tablet: according to the formulation of example 1, xylitol is reduced to 12.8g, ethyl cellulose is increased to 75.2g;Other components and the preparation method of preparation are same with example 1.

[0091] Example 7

[0092] A kind of cininnide osmotic pump controlled-release tablet: according to the formulation of example 1, dibutyl phthalate is reduced to 64g, ethyl cellulose is increased to 80g;Other components and the preparation method of preparation are same with example 1.

[0093] Example 8

[0094] A kind of cininnide osmotic pump controlled-release tablet: prescription amount and table 1 of example 1 are same. Preparation method is different from step 1 in example 1, other steps are same, step 1 in this embodiment is as follows.

[0095] Step 1: cininnide cyclodextrin inclusion preparation.

[0096] The prescription amount 1.2 times 2, 3, 6-trihydroxypropyl-β-cyclodextrin is weighed into a stainless steel barrel, and the prescription amount 10 times 2, 3, 6-trihydroxypropyl-β-cyclodextrin ethanol is added, stirred to dissolve thoroughly, and the obtained filtrate is a 2, 3, 6-trihydroxypropyl-β-cyclodextrin saturated solution, which is placed in a ball mill bin for standby.

[0097] The cininnide is weighed into a beaker, 2L of ethyl acetate is added, stirred thoroughly, and mixed uniformly to obtain a cininnide ethyl acetate solution. The cininnide ethyl acetate solution is added to the ball mill bin containing the 2, 3, 6-trihydroxypropyl-β-cyclodextrin saturated solution, and the bin door is closed tightly. The ball mill is started and ground for 60 minutes, and then taken out into a stainless steel barrel and stored at 4-7°C for crystallization. After suction filtration, the obtained cininnide 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion crystal is washed with ethanol and used for standby.

[0098] The above-mentioned cininnide 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion crystal is vacuum dried and crushed according to the following procedure to obtain a cininnide cyclodextrin inclusion fine powder. 1) The cininnide 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion crystal is placed in a vacuum drying oven tray, pushed into the vacuum drying oven, and the oven door is closed. 2) The vacuum is started until the vacuum degree reaches -0.006 MPa to -0.09 MPa, the drying temperature is set to 60°C, the upper limit is 65°C, and the lower limit is 55°C, the heating drying is started, and the moisture is 3.5% to 3.9%, and the temperature is cooled to room temperature. 3) The dried cininnide 2, 3, 6-trihydroxypropyl-β-cyclodextrin inclusion crystal is crushed into a fine powder, and sieved through a 120 mesh sieve to obtain a cininnide cyclodextrin inclusion fine powder.

[0099] Example 9

[0100] A sustained-release tablet of cinaldipine osmotic pump: replace xylitol (pore-forming agent) in the prescription of Example 1 with sodium chloride (pore-forming agent), other components and preparation method of the preparation are the same as Example 1.

[0101] Comparative Example 1

[0102] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete 2,3,6-trihydroxypropyl-β-cyclodextrin, the corresponding weight is increased to the lactose diluent, other components are the same as Example 1. The preparation method is without step 1 of Example 1, and the subsequent granulation, tabletting and coating steps are directly performed on cinaldipine.

[0103] Comparative Example 2

[0104] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete povidone (disintegrant), the corresponding weight is increased to the lactose diluent, other components are the same as Example 1. The preparation method is without povidone in step 2 of Example 1, and other steps are the same as Example 1.

[0105] Comparative Example 3

[0106] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete mannitol (osmotic pressure promoter), the corresponding weight is increased to the lactose diluent, other components are the same as Example 1. The preparation method is without mannitol in step 2 of Example 1, and other steps are the same as Example 1.

[0107] Comparative Example 4

[0108] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete sodium lauryl sulfate (co-solvent), the corresponding weight is increased to the lactose diluent, other components are the same as Example 1. The preparation method is without sodium lauryl sulfate in step 2 of Example 1, and other steps are the same as Example 1.

[0109] Comparative Example 5

[0110] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete xylitol (pore-forming agent), the corresponding weight is increased to the amount of ethyl cellulose and dibutyl phthalate, other components are the same as Example 1. The preparation method is without xylitol in step 4 of Example 1, and other steps are the same as Example 1.

[0111] Comparative Example 6

[0112] A sustained-release tablet of cinaldipine osmotic pump: according to the prescription of Example 1, delete dibutyl phthalate (plasticizer), the corresponding weight is increased to ethyl cellulose, other components are the same as Example 1. The preparation method is without dibutyl phthalate in step 4 of Example 1, and other steps are the same as Example 1.

[0113] Comparative Example 7

[0114] A sustained-release tablet of cinaldipine: the prescription amount is shown in Table 2 below.

[0115] Table 2

[0116] Raw material name Weight Raw material name Parts by weight Raw material name Weight Cinacalcet hydrochloride 200g Hydroxypropyl cellulose 700g Polyvinylpyrrolidone 180g Mannitol 2200g Magnesium stearate 400g Starch 540g Cellulose acetate 800g Talc 55g Polyethylene glycol 25g

[0117] The preparation method of the cinaldipine osmotic pump controlled-release tablet comprises the following steps: 1) grinding cinaldipine through a 100-mesh sieve, uniformly mixing with starch, grinding hydroxypropyl cellulose, povidone, mannitol and magnesium stearate through an 80-mesh sieve, uniformly mixing with the above mixture, adding an appropriate amount of 70% ethanol to prepare a soft material, preparing 30-mesh granules, drying at 60°C, the moisture being 3.9%-4.5%, sieving through a 20-mesh sieve, tabletting, and obtaining a tablet core with a weight of 0.422 g per tablet; 2) coating the tablet core, and obtaining the tablet by punching an 80-μm hole on one side of the tablet with a laser after coating.

[0118] Effect test

[0119] I. Release rate determination

[0120] 1. Determination of the content of cinaldipine in the preparation: determination according to the high performance liquid chromatography method (0512) in Chinese Pharmacopoeia 2020 Edition Volume IV General Rules.

[0121] 1.1 Chromatographic conditions and system suitability: octadecylsilane-bonded silica gel is used as the filler; ethanol-0.025 mol / L ammonium dihydrogen phosphate solution-cyclohexane (volume ratio 60:39:1) is used as the mobile phase; the detection wavelength is 240 nm; the injection volume is 10 μl; the separation degree between the peak of cinaldipine and the peak of the adjacent impurity meets the requirements. The theoretical plate number calculated according to the peak of cinaldipine is not less than 7000.

[0122] 1.2 Preparation of the reference solution: an appropriate amount of cinaldipine reference substance is accurately weighed, dissolved in methanol and quantitatively diluted to prepare a solution containing about 0.1 mg of cinaldipine per 1 ml.

[0123] 1.3 Preparation of the test solution: 20 tablets of the cinaldipine osmotic pump controlled-release tablet are accurately weighed, finely ground, and an appropriate amount (about equivalent to 10 mg of cinaldipine) is accurately weighed, placed in a 100-ml volumetric flask, an appropriate amount of methanol is added, ultrasonic is used to dissolve the cinaldipine, the solution is diluted to the mark with methanol, shaken uniformly, filtered, and the filtrate is taken.

[0124] 1.4 Determination method: the test solution and the reference solution are accurately measured and injected into the liquid chromatograph, respectively, the chromatogram is recorded, and the peak area is calculated according to the external standard method.

[0125] 2 Cinaldopril release determination: find the dissolution and release determination method (Chinese Pharmacopoeia 2020 edition four general rules 0931 first method).

[0126] 2.1 Dissolution conditions: 0.4% sodium dodecyl sulfate solution 900ml as dissolution medium, rotation speed is 75 revolutions per minute, according to the operation, respectively at 0 hour, 0.25 hour, 0.5 hour, 1.0 hour, 3.0 hour, 6.0 hour, 12.0 hour, 24.0 hour, 48.0 hour sampling.

[0127] 2.2 Test solution: take the dissolution liquid, filter, take the filtrate.

[0128] Reference solution: take about 10mg of cinaldopril reference substance, accurately weigh, put into 100ml volumetric flask, add 2ml of anhydrous ethanol to dissolve, dilute to the mark with dissolution medium, shake well, accurately take 10ml, put into 50ml volumetric flask, dilute to the mark with dissolution medium, shake well, get it.

[0129] Determination method: take the test solution and reference solution, according to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 edition four general rules 0401), at the wavelength of 242nm, respectively determine the absorbance, respectively calculate the release of each tablet.

[0130] II. The results of each test item are as follows:

[0131] The release data results are shown in table 3 and table 4.

[0132] Table 3

[0133]

[0134] Table 4

[0135]

[0136]

[0137] III. Test conclusion:

[0138] The release test data confirmed that:

[0139] Comparative Example 1 has a release rate similar to Example 6 with reduced amount of xylitol (pore-forming agent), but much lower than other examples, and its zero-order release level is also much lower than all examples. Comparative Example 3 has a release rate lower than all examples because of no mannitol (osmotic pressure promoter), and its zero-order release level is also much lower than all examples. Comparative Example 4 has a release rate and zero-order release level lower than all examples because of no sodium dodecyl sulfate (solubilizer). Comparative Example 5 has a release rate and zero-order release level lower than all examples because of no xylitol (pore-forming agent). Comparative Example 3 has a release rate higher than Comparative Example 5, and its zero-order release level is slightly lower than Comparative Example 5. Comparative Example 4 has a release rate and zero-order release level lower than all examples because of no sodium dodecyl sulfate (solubilizer). Comparative Example 5 has a release rate and zero-order release level lower than all examples and other comparative examples because of pore-forming agent. Comparative Example 6 has a release rate higher than all examples and other comparative examples because of no dibutyl phthalate (plasticizer), which may cause insufficient shaping of the controlled release membrane, resulting in local rupture, thus accelerating the release rate. Its zero-order release level is also only higher than Comparative Example 7 with laser drilling. Comparative Example 7 has a release rate higher than all examples and other comparative examples because of the small hole of 80 μm on the controlled release membrane prepared by the existing published technology, which plays a decisive role in the release rate. Its 24-hour cumulative release degree is more than 99%, and its 24-hour correlation coefficient is 0.9977, but the correlation coefficient is reduced to 0.912 when extended to 48 hours, which is lower than all examples and other comparative examples.

[0140] In all examples, Example 1 has a release rate curve R of 0.9995 and a slope of 0.0208. Its zero-order release level, i.e. the linear cumulative release degree curve, ranks first among all examples. Its release rate is only lower than Example 7 with reduced amount of plasticizer, and Example 9 with sodium chloride as pore-forming agent, but the correlation coefficients of Example 7 and Example 9 are obviously smaller than that of Example 1. Other examples have a zero-order release level obviously lower than Example 1 because of reduced amounts of cyclodextrin, osmotic pressure promoter, solubilizer, disintegrant, pore-forming agent, plasticizer and ball mill for preparing the inclusion complex. Specifically, Example 2 has a release rate slightly lower than Example 1 because of reduced amount of cyclodextrin. Example 3 has a release rate slightly lower than Example 1 because of reduced amount of disintegrant. Example 5 has a release rate and zero-order release level much smaller than Example 1 because of reduced amount of solubilizer. Example 6 has a release rate lower than all examples because of reduced amount of pore-forming agent.

[0141] In summary, Example 1 of the present application is the best technical solution of the present application.

[0142] The above only describes preferred embodiments of the present application and is not used to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing cinidipine osmotic pump controlled-release tablets, characterized in that, include: Cinidipine and cyclodextrin derivatives were mixed and treated to obtain cinidipine cyclodextrin inclusion complexes; The cinidipine cyclodextrin inclusion complex was mixed with an osmotic pressure promoter, a solubilizer, a disintegrant, a binder, and a diluent and then granulated to obtain cinidipine cyclodextrin inclusion complex particles. The cinidipine cyclodextrin inclusion complex particles were mixed with a flow aid and a lubricant and then compressed into tablets to obtain cinidipine osmotic pump controlled-release tablet cores. The cilnidipine osmotic pump controlled-release tablet core is mixed with a pore-forming agent, a light-blocking agent, a plasticizer, and a coating material for coating treatment to obtain the cilnidipine osmotic pump controlled-release tablet.

2. The preparation method according to claim 1, characterized in that, The process of mixing cinidipine and cyclodextrin derivatives includes: The cyclodextrin derivatives were dissolved in ethanol to obtain a saturated solution of the cyclodextrin derivatives. The cilnidipine was dissolved in ethyl acetate to obtain a cilnidipine ethyl acetate solution; The saturated solution of the cyclodextrin derivative and the ethyl sinedipine solution were mixed and then subjected to crystallization treatment to obtain crystals. The crystals were subjected to vacuum drying to obtain the cinidipine cyclodextrin inclusion complex.

3. The preparation method according to claim 2, characterized in that, The crystallization treatment temperature is 4–7°C.

4. The preparation method according to claim 2, characterized in that, The vacuum drying process includes: placing the crystals under vacuum conditions of -0.06MPa to -0.09MPa and temperature of 55 to 65°C to vacuum dry them until the moisture content is 3.5 to 3.9%, then cooling them and pulverizing them to 120 mesh.

5. The preparation method according to claim 1, characterized in that, The adhesive includes a first adhesive and a second adhesive, wherein the first adhesive is a dry powder and the second adhesive is formulated into a solution; The mixing and granulation process includes: mixing the cinidipine cyclodextrin inclusion complex, the diluent, the osmotic pressure promoter, the solubilizer, the disintegrant, and the powdered first binder, then adding the solution-state second binder to form a soft material, followed by granulation through a 20-mesh granulator and boiling drying at 55-65°C.

6. The preparation method according to claim 1, characterized in that, The coating process involves mixing the cinidipine osmotic pump controlled-release tablet core with a pore-forming agent, a light-blocking agent, a plasticizer, and a coating material, including: The pore-forming agent, the light-blocking agent, the plasticizer, and the coating material are dissolved in ethanol to obtain a coating solution; The coating solution is sprayed onto the surface of the cinidipine osmotic pump controlled-release tablet core at 70℃~90℃ for coating, and then dried.

7. The preparation method according to any one of claims 1-6, characterized in that, The cyclodextrin derivatives are selected from at least one of hydroxypropyl-β-cyclodextrin, 2,3,6-trimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 6-deoxy-β-cyclodextrin derivatives, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin derivatives, maltotriose-β-cyclodextrin derivatives, and 2,6-dimethyl-β-cyclodextrin. And / or, the osmotic pressure enhancer is selected from at least one of lactose, sodium chloride, sodium carbonate, sodium sulfate, mannitol, sodium chloride, sodium phosphate, and sucrose; And / or, the co-solvent is selected from at least one of sodium dodecyl sulfate and Tween-80; And / or, the disintegrant is selected from at least one of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, microcrystalline cellulose, sodium carboxymethyl starch, polyethylene glycol, hydroxypropyl methylcellulose and povidone; And / or, the diluent is selected from at least one of lactose, dextran, starch, sucrose, dextrin, maltitol, fructose, mannitol, and pregelatinized starch; And / or, the adhesive comprises a first adhesive and a second adhesive, wherein the first adhesive is selected from at least one of low-substituted hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, and cellulose acetate butyrate, and the second adhesive is selected from at least one of hydroxypropyl methylcellulose, povidone, dextrin, maltodextrin, pregelatinized starch, lactose, ethyl cellulose, and hydroxypropyl cellulose.

8. The preparation method according to any one of claims 1-6, characterized in that, The flow aid is selected from at least one of sodium phosphate, magnesium trisilicate, calcium phosphate, glucose binder, and micronized silica gel. And / or, the lubricant is selected from at least one of magnesium stearate, sodium stearate, zinc stearate, glyceryl behenate, sodium stearate fumarate, and glyceryl monostearate; And / or, the pore-forming agent is selected from at least one of xylitol, mannitol, sodium chloride, and polyethylene glycol; And / or, the light-blocking agent is selected from titanium dioxide; And / or, the plasticizer is selected from at least one of triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, diethyl succinate, propylene glycol, and triacetin. And / or, the coating material is selected from at least one of cellulose acetate, ethyl cellulose, methyl cellulose, acrylic resin, polyvinyl phthalate, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate.

9. The preparation method according to any one of claims 1-6, characterized in that, The weight ratio of the cinidipine, the cyclodextrin derivative, the binder, the disintegrant, the diluent, the osmotic pressure enhancer, the solubilizer, the flow aid, and the lubricant is (25-75):(125-375):(80-160):(80-120):(150-450):(60-140):(30-80):(5-15):(3-8); And / or, the weight ratio of the coating material, the light-blocking agent, the pore-forming agent, and the plasticizer is (4-5):(2-3):(0.8-1.2):(4-5); And / or, the total weight of the coating material, the light-blocking agent, the pore-forming agent, and the plasticizer accounts for 4 to 6% of the weight of the silnidipine osmotic pump controlled-release tablet core.

10. A cinidipine osmotic pump controlled-release tablet, characterized in that, It is prepared by the preparation method according to any one of claims 1-9.

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