CN114224859A - Compound antihypertensive medicinal composition and preparation method thereof - Google Patents

Compound antihypertensive medicinal composition and preparation method thereof Download PDF

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CN114224859A
CN114224859A CN202111620840.4A CN202111620840A CN114224859A CN 114224859 A CN114224859 A CN 114224859A CN 202111620840 A CN202111620840 A CN 202111620840A CN 114224859 A CN114224859 A CN 114224859A
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salt
pharmaceutical composition
amlodipine
tablet
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CN114224859B (en
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蔡燕霞
叶冠豪
李莉娜
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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    • A61P9/12—Antihypertensives

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Abstract

The invention belongs to the technical field of medicinal preparations, relates to a compound antihypertensive medicinal composition and a preparation method thereof, and particularly relates to a medicinal composition of allisartan isoproxil and/or salt thereof and amlodipine and/or salt thereof and a preparation method thereof.

Description

Compound antihypertensive medicinal composition and preparation method thereof
Technical Field
The invention belongs to the technical field of medicinal preparations, relates to a compound antihypertensive medicinal composition and a preparation method thereof, and particularly relates to a medicinal composition of allisartan isoproxil and/or salt thereof and amlodipine and/or salt thereof and a preparation method thereof.
Background
Allisartan Isoproxil (Allisartan Isoproxil), chemical name: 2-butyl-4-chloro-1- [2 '- (1H-tetrazol-5-yl) -1, 1' -biphenyl-methyl ] -imidazole-5-carboxylic acid, 1- [ (isopropoxy) -carbonyloxy ] -methyl ester, trade name: xinritan is a novel angiotensin II receptor antagonist. Chinese patent CN200680000397.8 discloses the structural formula of an allisartan isoproxil compound, the allisartan isoproxil has low toxicity and the blood pressure reducing effect is better than that of the same type of products (such as losartan), and the allisartan isoproxil compound generates an active metabolite (EXP3174) through metabolism in vivo so as to play the role of reducing the blood pressure. Chinese patents CN106188012A, CN104610232A, CN109320501A, CN109694369A, CN105232489A and CN107441497A have studied the physical form, preparation and the like of the compound.
Figure BDA0003437966450000011
Amlodipine (amlodipine), the benzenesulfonate of which is commonly used, amlodipine besylate, belongs to a Calcium Channel Blocker (CCB) and exerts an antihypertensive effect mainly by blocking calcium ion channels outside cells of cardiac muscle and vascular smooth muscle.
For people with severe hypertension and/or those with multiple risk factors, target organ damage or clinical disorders, administration of a single antihypertensive drug often fails to achieve optimal therapeutic efficacy, whereas for such patients administration of two or more different antihypertensive agents is generally considered. Chinese patent CN109865139A discloses a compound pharmaceutical composition of alisartan medoxomil or salt thereof and a calcium ion channel antagonist, wherein the compound composition realizes a blood pressure reduction synergistic effect by limiting the mass ratio of alisartan medoxomil and/or salt thereof to amlodipine, and is beneficial to improving the blood pressure reduction effect and reducing adverse drug reactions.
Chinese patent CN101822836A discloses a pharmaceutical composition of alisartan medoxomil or a salt thereof and at least one cardiovascular and cerebrovascular drug or a pharmaceutically acceptable salt thereof, wherein the examples specifically disclose tablets of alisartan medoxomil and levamlodipine besylate with a mass ratio of 28.7:1, and capsules of alisartan medoxomil and amlodipine besylate with a mass ratio of 14.4: 1. The preparation is prepared by directly tabletting or subpackaging a mixture with a certain prescription into capsules.
Chinese patent CN101822837A discloses a pharmaceutical composition of alisartan medoxomil or a salt thereof and at least one cardiovascular and cerebrovascular drug or a pharmaceutically acceptable salt thereof, wherein the examples specifically disclose tablets of alisartan medoxomil potassium salt and levamlodipine besylate with a mass ratio of 5.7:1, and capsules of alisartan medoxomil potassium salt and amlodipine besylate with a mass ratio of 2.9: 1. The preparation is prepared by directly tabletting or subpackaging a mixture with a certain prescription into capsules.
Researches find that the two medicaments of the alisartan medoxomil and the amlodipine are mutually influenced and cannot achieve biological equivalence with combined medicaments, so that in order to solve the technical problem, the search of a preparation scheme which is in line with clinical use is very important, and further research and development are needed.
Disclosure of Invention
In view of the problems in the prior art, the invention provides a novel compound antihypertensive medicinal composition and a preparation method thereof.
The compound antihypertensive drug composition comprises active ingredients of allisartan isoproxil and/or salt thereof, amlodipine and/or salt thereof and more than one pharmaceutically acceptable carrier, and is characterized in that the drug composition is prepared into a double-layer tablet or a core-spun tablet.
One layer of the double-layer tablet is a tablet containing the active ingredient of the allisartan isoproxil and/or the salt thereof, and the other layer of the double-layer tablet is a tablet containing the active ingredient of the amlodipine isoproxil and/or the salt thereof.
The core-spun tablet takes a tablet of an active ingredient amlodipine and/or a salt thereof as a tablet core and takes an active ingredient alisartan ester and/or a salt thereof as an outer layer.
The compound antihypertensive drug composition contains 8-60% by weight of allisartan isoproxil and/or salt thereof, 0.4-5% by weight of amlodipine and/or salt thereof, and more than one pharmaceutically acceptable carrier.
Preferably, the mass ratio of the alisartan medoxomil and/or the salt thereof to the amlodipine and/or the salt thereof is 24:1 or 48:1, wherein the mass of the alisartan medoxomil and/or the salt thereof is calculated by alisartan medoxomil, and the mass of the amlodipine and/or the salt thereof is calculated by amlodipine.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier comprises a solubilizing carrier, wherein the solubilizing carrier comprises one or a mixture of two or more of homopolymers or copolymers of vinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and hydroxypropyl methylcellulose acetate succinate, and is used in an amount of 8% to 45%, preferably 15% to 35%, in the pharmaceutical composition.
As a preferred technical scheme of the present invention, the solubilizing carrier includes one or a mixture of two of povidone, crospovidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate, which are mixed in any proportion.
As a preferred technical scheme of the invention, the solubilization carrier comprises one or a mixture of two of povidone, crospovidone and copovidone mixed in any proportion.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier comprises a filler, wherein the filler comprises one or a mixture of two or more of microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, calcium sulfate, calcium phosphate, and calcium hydrogen phosphate at any ratio, and the amount of the filler used in the pharmaceutical composition is 5% to 55%.
As a preferred technical solution of the present invention, the pharmaceutically acceptable carrier comprises a disintegrant, and the disintegrant comprises one or more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and the like, and is used in an amount of 1% to 25% by weight of the pharmaceutical composition.
As a preferable technical scheme of the invention, the pharmaceutically acceptable carrier comprises an adhesive, the adhesive comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch slurry and gelatin, and the usage amount is 0.5-5% of the weight of the pharmaceutical composition.
As a preferred embodiment of the present invention, the pharmaceutically acceptable carrier comprises a lubricant, and the lubricant comprises one or a mixture of two or more of silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol and hydrogenated castor oil, and is used in an amount of 0.1% to 2% by weight of the pharmaceutical composition.
Except for other descriptions, the sum of the percentages of the raw materials and the auxiliary materials in the pharmaceutical composition is 95-100%, and the use amounts are mass use amounts.
As a preferred technical scheme of the invention, the allisartan isoproxil and/or the salt thereof refers to a compound pharmaceutical composition containing allisartan isoproxil, or containing allisartan isoproxil salt, or containing a mixture obtained by mixing the allisartan isoproxil and the allisartan isoproxil salt in any proportion; the aforementioned allisartan isoproxil salt refers to pharmaceutically acceptable salts of allisartan isoproxil including, but not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, ammonium salts and the like; the mass of the allisartan isoproxil and/or the salt thereof described in the present invention is calculated as allisartan isoproxil, unless otherwise specified.
As a preferred technical scheme, the amlodipine and/or the salt thereof refers to a mixture which is obtained by mixing one or more than two of amlodipine, levamlodipine or pharmaceutically acceptable salts thereof in any proportion in the compound pharmaceutical composition; the pharmaceutically acceptable salt includes but is not limited to inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and a mixture obtained by mixing one or more than two organic acid salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, hemifumarate, succinate, citrate, ascorbate, tartrate, trifluoroacetate, lactate and the like in any proportion; the pharmaceutically acceptable salt is preferably a benzene sulfonate, and the mass of the amlodipine, the levamlodipine or the pharmaceutically acceptable salt of the amlodipine and the levamlodipine is calculated by the amlodipine unless particularly specified.
In a preferred embodiment of the present invention, the mass of the alisartan medoxomil and/or the salt thereof (calculated as alisartan medoxomil) is 20% to 60% of the weight of the pharmaceutical composition, and the specific use amount is preferably 10mg, 15mg, 20mg, 30mg, 50mg, 60mg, 80mg, 90mg, 100mg, 120mg, 150mg, 160mg, 180mg, 200mg, 210mg, 240mg, 270mg, 300mg, and the like. The content of the amlodipine and/or the salt thereof (calculated by amlodipine) can be 0.02-10 mg, and the preferable specific content can be 0.5mg, 1mg, 1.25mg, 2.5mg, 5mg, 8mg, 10mg and the like.
As a preferred embodiment of the present invention, the coating agent comprises any gastric coating. Specifically, for example, the gastric coating comprises 295F620048-CN, and the gastric coating is prepared by mixing a solvent mixture such as water (preferably, the gastric coating agent and purified water are mixed according to a mass ratio of 1: 5-1: 8 and then coated), and the weight is increased by about 0.1-4% after coating.
The pharmaceutical composition is a solid formulation suitable for oral administration, preferably a tablet or capsule for oral administration.
The invention further provides a preparation method of the pharmaceutical composition, the raw and auxiliary materials are prepared by a direct compression process or a dry granulation process and then tableted, and then the coating agent is adopted for coating, so that the coated pharmaceutical composition is obtained.
As a preferred technical scheme of the invention, the preparation process of the pharmaceutical composition comprises the following steps:
(1) uniformly mixing the amlodipine and/or the salt thereof, the filler and the disintegrating agent in the prescription amount through a 40-mesh sieve, adding the lubricant, mixing to obtain total mixed powder, and then tabletting and coating to obtain the amlodipine tablet;
(2) weighing a prescription amount of allisartan isoproxil and/or salt thereof and a solubilizing carrier, dissolving the allisartan isoproxil and/or salt thereof and the solubilizing carrier in a proper amount of organic solvent to prepare a medicinal solution, placing a prescription amount of filler in a fluidized bed, adding the medicinal solution in a top spraying manner, carrying out fluidized bed spray granulation and drying, adding a prescription amount of disintegrant, filler and lubricant, and mixing to obtain an allisartan isoproxil total mixed particle;
(3) weighing the total mixed granules of the alisartan medoxomil and/or the salt thereof in a prescription amount as an outer layer, and taking the amlodipine tablet as a tablet core to press a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, after the preheating of the coating machine is finished, filling a tablet core into a coating pot for preheating, setting parameters such as the rotating speed of a host, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after preheating the tablet core, and starting spraying coating liquid to increase the coating weight by 1.5-2.5%.
As a preferred technical scheme of the invention, the preparation process of the pharmaceutical composition comprises the following steps:
(1) weighing a prescription amount of allisartan isoproxil and/or salt thereof and a solubilizing carrier, dissolving the allisartan isoproxil and/or salt thereof and the solubilizing carrier in a proper amount of organic solvent to prepare a medicinal solution, placing a prescription amount of filler in a fluidized bed, adding the medicinal solution in a top spraying manner, carrying out fluidized bed spray granulation and drying, adding a prescription amount of disintegrant, filler and lubricant, and mixing to obtain an allisartan isoproxil total mixed particle;
(2) weighing the total mixed granules of the allisartan isoproxil and/or the salt thereof according to the prescription amount, and uniformly mixing for later use;
(3) uniformly mixing the amlodipine and/or the salt thereof, the filler and the disintegrating agent in the prescription amount through a 40-mesh sieve, and then adding the lubricant for mixing to obtain amlodipine granules;
(4) and prepressing and forming the allisartan isoproxil and/or the total mixed granules of the allisartan isoproxil and/or the salt thereof by a double-layer tablet press to obtain a tablet core, filling the amlodipine layer granules, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil and amlodipine double-layer tablet.
The invention further provides the application of the pharmaceutical composition in medicines for preventing and/or treating hypertension and complications thereof.
The beneficial effects of the invention compared with the prior art comprise:
(1) the embodiment of the invention can effectively ensure the disintegration and dissolution of the medicine, has stable dissolution rate level and can maintain stable blood concentration, thereby reducing the administration times, prolonging the administration interval and reducing the treatment cost.
(2) The medicinal composition obtained by the invention realizes bioequivalence with combined medication through bioequivalence test verification, and can be applied to medicaments for preventing and/or treating hypertension and complications thereof.
(3) The pharmaceutical composition preparation of the invention has good stability, thereby effectively ensuring the safety and the effectiveness of the use of the medicine.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
Example 1
Calculating and weighing the components with the corresponding prescription amount, and then preparing the alisartan medoxomil preparation according to the following preparation process, wherein the specific prescription composition is shown in table 1.
TABLE 1 compositions of different formulations
Figure BDA0003437966450000051
The preparation process of the allisartan isoprothiolate total mixed particle comprises the following steps: weighing formula amount of allisartan isoproxil and polyvinylpyrrolidone, dissolving in proper amount of dichloromethane and absolute ethyl alcohol to prepare a drug solution, placing formula amount of crospovidone in a fluidized bed, adding the drug solution in a top spraying manner, performing fluidized bed spray granulation and drying, adding formula amount of lactose monohydrate, microcrystalline cellulose, crospovidone and magnesium stearate, and mixing to obtain the allisartan isoproxil total mixed granule.
The specific preparation process of the formula A and the formula B is as follows:
(1) uniformly mixing the amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium in a prescription amount by a 40-mesh sieve, mixing for 10min, adding magnesium stearate, mixing for 5min to obtain total mixed powder, and tabletting and coating to obtain amlodipine besylate tablets;
(2) weighing the allisartan isoproxil total mixed particles with the prescription amount as an outer layer, and taking the amlodipine besylate tablet as a tablet core to press a core-spun tablet;
(3) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, preheating a tablet core, and then starting to spray coating liquid to increase the coating weight by 1.5-2.5%.
The specific preparation processes of the formula C and the formula D are as follows:
(1) weighing the allisartan isoproxil total mixed particles according to the prescription amount, and uniformly mixing for later use;
(2) uniformly mixing the amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium in a prescription amount by a 40-mesh sieve, mixing for 10min, adding magnesium stearate, and mixing for 5min to obtain amlodipine besylate granules;
(3) and prepressing and forming the allisartan isoproxil total mixed granules by a double-layer tablet press to obtain a tablet core, filling the amlodipine besylate layer granules, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil amlodipine double-layer tablet.
Example 2
Prescription
Figure BDA0003437966450000061
Preparation: (1) weighing a prescription amount of allisartan isoproxil and polyvinylpyrrolidone, dissolving the allisartan isoproxil and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicinal solution, placing a prescription amount of microcrystalline cellulose and hydroxypropyl cellulose in a fluidized bed, adding the medicinal solution in a top spraying manner, performing fluidized bed spray granulation and drying, adding a prescription amount of lactose monohydrate, microcrystalline cellulose, carboxymethyl starch sodium and magnesium stearate, and mixing to obtain an allisartan isoproxil total mixed particle;
(2) uniformly mixing the amlodipine besylate, mannitol, pregelatinized starch and carboxymethyl starch sodium in a prescription amount by a sieve of 40 meshes, mixing for 10min, adding hydrogenated castor oil, and mixing for 5min to obtain amlodipine besylate particles;
(3) and prepressing and forming the allisartan isoproxil total mixed granules by a double-layer tablet press to obtain a tablet core, filling the amlodipine besylate layer granules, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil amlodipine double-layer tablet.
Example 3
Prescription
Figure BDA0003437966450000071
Preparation: (1) uniformly mixing the amlodipine besylate, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium in the formula amount through a 40-mesh sieve, adding magnesium stearate, mixing to obtain total mixed powder, and then tabletting and coating to obtain amlodipine tablets;
(2) weighing the alisartan medoxomil, the copovidone and the polyvinylpyrrolidone with the prescription amount, dissolving the alisartan medoxomil, the copovidone and the polyvinylpyrrolidone with the prescription amount in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the anhydrous calcium hydrophosphate with the prescription amount in a fluidized bed, adding the medicine solution in a top spraying mode, carrying out fluidized bed spray granulation and drying, adding the carboxymethyl starch sodium and the magnesium stearate with the prescription amount, and mixing to obtain alisartan medoxomil total mixed particles;
(3) weighing a prescription amount of the allisartan isoproxil total mixed granules as an outer layer, and taking the amlodipine tablets as tablet cores to press the core-spun tablets;
(4) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, after the preheating of the coating machine is finished, filling a tablet core into a coating pot for preheating, setting parameters such as the rotating speed of a host, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after preheating the tablet core, and starting spraying coating liquid to increase the coating weight by 1.5-2.5%.
Comparative example 1
Prescription
Figure BDA0003437966450000072
Figure BDA0003437966450000081
Preparation: (1) weighing a prescription amount of allisartan isoproxil and polyvinylpyrrolidone, dissolving the allisartan isoproxil and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicinal solution, placing the crospovidone in the prescription amount in a fluidized bed, adding the medicinal solution in a top spraying manner, performing fluidized bed spray granulation and drying, adding the microcrystalline cellulose, lactose monohydrate, crospovidone and magnesium stearate in the prescription amount, mixing to obtain an allisartan isoproxil total mixed particle, and uniformly mixing for later use;
(2) uniformly mixing the amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium in a prescription amount by a 40-mesh sieve, mixing for 10min, adding magnesium stearate, and mixing for 5min to obtain amlodipine besylate granules;
(3) and uniformly mixing and pressing the allisartan isoproxil total mixed particles and the amlodipine besylate particles to obtain the allisartan isoproxil amlodipine tablets.
Comparative example 2
Prescription
Figure BDA0003437966450000082
Preparation: (1) weighing formula amount of allisartan isoproxil and polyvinylpyrrolidone, dissolving in proper amount of dichloromethane and absolute ethyl alcohol to prepare a drug solution, putting a blank pill core (formula amount of hydroxypropyl cellulose and microcrystalline cellulose) in a fluidized bed, adding the drug solution in a top spraying manner, drying, adding formula amount of microcrystalline cellulose, lactose monohydrate and crospovidone, mixing, adding magnesium stearate, and mixing to obtain an allisartan isoproxil pellet;
(2) uniformly mixing the amlodipine besylate with mannitol, pregelatinized starch and carboxymethyl starch sodium in a formula amount by passing through a 40-mesh sieve, mixing for 10min, adding a proper amount of purified water, uniformly mixing, extruding the materials into strips by using an extruder, cutting off, and then rolling at high speed by using a rolling machine to obtain amlodipine besylate pellets;
(3) and mixing the alisartan medoxomil pellet with the amlodipine besylate pellet, adding stearic acid, mixing, and then carrying out capsule canning to obtain the alisartan medoxomil pellet capsule.
Comparative example 3
Prescription
Figure BDA0003437966450000091
Preparation: (1) uniformly mixing the amlodipine besylate, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium in the formula amount through a 40-mesh sieve, adding magnesium stearate, mixing to obtain total mixed powder, and then tabletting and coating to obtain amlodipine tablets;
(2) weighing a prescription amount of allisartan isoproxil and polyvinylpyrrolidone, dissolving the allisartan isoproxil and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicinal solution, placing the crospovidone, microcrystalline cellulose and calcium hydrophosphate in a fluidized bed, adding the medicinal solution in a top spraying manner, performing fluidized bed spray granulation and drying, adding the carboxymethyl starch sodium and magnesium stearate in the prescription amount, and mixing to obtain the allisartan isoproxil total mixed particle;
(3) weighing a prescription amount of the allisartan isoproxil total mixed granules as an outer layer, and taking the amlodipine tablets as tablet cores to press the core-spun tablets;
(4) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, after the preheating of the coating machine is finished, filling a tablet core into a coating pot for preheating, setting parameters such as the rotating speed of a host, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after preheating the tablet core, and starting spraying coating liquid to increase the coating weight by 1.5-2.5%.
Comparative example 4
Prescription
Figure BDA0003437966450000101
Preparation: (1) uniformly mixing the amlodipine besylate, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium in the formula amount through a 40-mesh sieve, adding magnesium stearate, mixing to obtain total mixed powder, and then tabletting and coating to obtain amlodipine tablets;
(2) weighing the alisartan medoxomil, the copovidone and the polyvinylpyrrolidone with the prescription amount, dissolving the alisartan medoxomil, the copovidone and the polyvinylpyrrolidone with the prescription amount in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the anhydrous calcium hydrophosphate with the prescription amount in a fluidized bed, adding the medicine solution in a top spraying mode, carrying out fluidized bed spray granulation and drying, adding the carboxymethyl starch sodium and the magnesium stearate with the prescription amount, and mixing to obtain alisartan medoxomil total mixed particles;
(3) weighing a prescription amount of the allisartan isoproxil total mixed granules as an outer layer, and taking the amlodipine tablets as tablet cores to press the core-spun tablets;
(4) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, after the preheating of the coating machine is finished, filling a tablet core into a coating pot for preheating, setting parameters such as the rotating speed of a host, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after preheating the tablet core, and starting spraying coating liquid to increase the coating weight by 1.5-2.5%.
Comparative example 5
Prescription
Figure BDA0003437966450000102
Figure BDA0003437966450000111
Preparation: (1) weighing the alisartan medoxomil, poloxamer and polyvinylpyrrolidone in a prescription amount, dissolving the alisartan medoxomil, the poloxamer and the polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing microcrystalline cellulose in the prescription amount in a fluidized bed, adding the medicine solution in a top spraying manner, performing fluidized bed spray granulation and drying, adding microcrystalline cellulose, crospovidone, lactose monohydrate and magnesium stearate in the prescription amount, and mixing to obtain alisartan medoxomil total mixed particles;
(2) uniformly mixing the amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium in a prescription amount by a 40-mesh sieve, mixing for 10min, adding magnesium stearate, and mixing for 5min to obtain amlodipine besylate granules;
(3) and prepressing and forming the allisartan isoproxil total mixed granules by a double-layer tablet press to obtain a tablet core, filling the amlodipine besylate layer granules, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil amlodipine double-layer tablet.
EXAMPLE 4 dissolution determination
The prepared preparation product is examined for dissolution behavior according to a second method of the dissolution method in the appendix of the second part of the Chinese pharmacopoeia 2015 year edition. The dissolution rate in the hydrochloric acid dissolution medium of pH1.2 was used as an evaluation index (the volume of the dissolution medium was 900mL, the temperature was 37. + -. 0.5 ℃ and the rotation speed was 50r/min), and the dissolution profile results are shown in Table 2.
TABLE 2 in vitro dissolution results for different formulations
Figure BDA0003437966450000112
Figure BDA0003437966450000121
From the above dissolution results, it is clear that: the alisartan medoxomil and the amlodipine of the formulas A to D in example 1 and the examples 2 to 3 show high dissolution rates, the dissolution rates of the two main drugs are both over 90 percent in 30 minutes, the drug can quickly exert the drug effect through quick dissolution, the dissolution is very uniform, the dissolution rate level of the drug is relatively stable, and the stable blood concentration can be maintained.
In comparative example 3, although the desired dissolution effect was achieved, the use of an excessive amount of solubilizing carrier resulted in a higher quality of the unit preparation and poor patient compliance.
Whereas the dissolution of comparative example 4 and comparative example 5 was slow and incomplete. Comparative example 4 except that the amount of the solubilizing carrier was less than the amount of the present invention, the amounts of the active drug and other excipients were the same as in example 3, and the 30-minute dissolution rate was lower than that of the allisartan isoproxil pharmaceutical composition of example 3 at 30 minutes; in comparative example 5, since the solubilizing carrier exemplified in the present invention was not used, the dissolution rate of the drug was rather decreased, which did not meet the clinical medicinal requirements.
Example 5 bioequivalence study
This experiment was conducted to study the effect of co-administration of healthy subjects in an fasting state [ marketed single formulation a allisartan cilexetil tablet (specification 240mg, trade name:
Figure BDA0003437966450000123
) With a commercially available single formulation, amlodipine besylate tablet (specification: 5mg, trade name:
Figure BDA0003437966450000124
)]with respect to the formulations of the alisartan medoxomil composition of the above examples and comparative examples, which were orally administered once, the main pharmacokinetic parameters were calculated, and the differences in pharmacokinetic parameters AUC and Cmax between the formulations were compared, to preliminarily evaluate the consistency of the absorption kinetics of alisartan medoxomil and amlodipine between the combined administration and the compound formulation. The experiment used a 2x2 crossover design. Blood sampling time points: 4mL of venous blood was collected before administration (0h) and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 14h, 24h, 48h and 72h after administration, respectively. The results are shown in Table 3.
TABLE 3 in vivo pharmacokinetic results for different prescription samples
Figure BDA0003437966450000122
Figure BDA0003437966450000131
Note: EXP3174 is an active metabolite of alisartan medoxomil.
The results show that the compound pharmaceutical composition of the invention is bioequivalent to the allisartan isoproxil amlodipine, and the compound pharmaceutical composition and the allisartan isoproxil amlodipine have expected clinical treatment effects in terms of in vivo pharmacokinetics and efficacy.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (11)

1. A compound antihypertensive drug composition comprises active ingredients of allisartan isoproxil and/or salt thereof, amlodipine and/or salt thereof, and more than one pharmaceutically acceptable carrier; the preparation is characterized in that the pharmaceutical composition is prepared into a double-layer tablet or a core-spun tablet; wherein one layer of the double-layer tablet is a tablet containing the active ingredient of the allisartan isoproxil and/or the salt thereof, and the other layer of the double-layer tablet is a tablet containing the active ingredient of the amlodipine isoproxil and/or the salt thereof; the core-spun tablet takes a tablet of an active ingredient amlodipine and/or a salt thereof as a tablet core and takes an active ingredient alisartan ester and/or a salt thereof as an outer layer.
2. The combination antihypertensive drug composition according to claim 1, wherein the pharmaceutically acceptable carrier comprises a solubilizing carrier, the solubilizing carrier comprises a mixture of one or more than two of vinyl pyrrolidone homopolymer or copolymer, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic acid polymer, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate and hydroxypropyl methyl cellulose acetate succinate in any ratio, and the amount of the solubilizing carrier used in the pharmaceutical composition is 8% -45%.
3. The compound antihypertensive pharmaceutical composition according to any one of claims 1-2, wherein the solubilizing carrier comprises one or a mixture of two of povidone, crospovidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate, which are mixed in any proportion, and the amount of the solubilizing carrier used in the pharmaceutical composition is 15% -35%.
4. The compound antihypertensive pharmaceutical composition according to any one of claims 1-3, wherein the mass of the alisartan medoxomil and/or the salt thereof (calculated as alisartan medoxomil) is 8% -60% of the weight of the pharmaceutical composition; the weight of the amlodipine and/or the salt thereof (calculated by the amlodipine) is 0.4-5% of the weight of the pharmaceutical composition; wherein the mass ratio of the alisartan ester and/or the salt thereof to the amlodipine and/or the salt thereof is 24:1 or 48: 1.
5. The compound antihypertensive pharmaceutical composition according to any one of claims 1-4, wherein the amount of the alisartan medoxomil and/or the salt thereof (calculated as alisartan medoxomil) is 10mg, 15mg, 20mg, 30mg, 50mg, 60mg, 80mg, 90mg, 100mg, 120mg, 150mg, 160mg, 180mg, 200mg, 210mg, 240mg, 270mg, 300 mg; the using amount of the amlodipine and/or the salt thereof (calculated by amlodipine) is 0.5mg, 1mg, 1.25mg, 2.5mg, 5mg, 8mg and 10 mg.
6. The compound antihypertensive pharmaceutical composition according to claim 1, wherein the one or more other excipients include one or more fillers, disintegrants, binders, and lubricants;
the filler comprises one or a mixture of more than two of microcrystalline cellulose, lactose, mannitol, starch, pregelatinized starch, calcium sulfate, calcium phosphate and calcium hydrophosphate in any proportion, and the usage amount is 5-55% of the weight of the pharmaceutical composition;
the disintegrant comprises one or more of croscarmellose sodium, crospovidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, etc., and the usage amount is 1-25% of the weight of the pharmaceutical composition;
the adhesive comprises one or a mixture of more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone, starch slurry and gelatin, and the using amount of the adhesive is 0.5-5% of the weight of the pharmaceutical composition;
the lubricant comprises one or a mixture of more than two of silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol and hydrogenated castor oil, and the using amount of the lubricant is 0.1-2% of the weight of the pharmaceutical composition.
7. The compound antihypertensive pharmaceutical composition according to any one of claims 1-6, wherein the pharmaceutical composition is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration.
8. The compound antihypertensive pharmaceutical composition according to any one of claims 1-7, wherein the pharmaceutical composition is prepared by a direct compression process or a dry granulation process.
9. The compound antihypertensive pharmaceutical composition according to any one of claims 1-8, wherein the preparation process of the pharmaceutical composition comprises the following steps:
(1) uniformly mixing the amlodipine and/or the salt thereof, the filler and the disintegrating agent in the prescription amount through a 40-mesh sieve, adding the lubricant, mixing to obtain total mixed powder, and then tabletting and coating to obtain the amlodipine tablet;
(2) weighing a prescription amount of allisartan isoproxil and/or salt thereof and a solubilizing carrier, dissolving the allisartan isoproxil and/or salt thereof and the solubilizing carrier in a proper amount of organic solvent to prepare a medicinal solution, placing a prescription amount of filler in a fluidized bed, adding the medicinal solution in a top spraying manner, carrying out fluidized bed spray granulation and drying, adding the prescription amount of filler and a lubricant, and mixing to obtain an allisartan isoproxil total mixed particle;
(3) weighing the total mixed granules of the alisartan medoxomil and/or the salt thereof in a prescription amount as an outer layer, and taking the amlodipine tablet as a tablet core to press a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into purified water according to the prescription amount, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, after the preheating of the coating machine is finished, filling a tablet core into a coating pot for preheating, setting parameters such as the rotating speed of a host, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after preheating the tablet core, and starting spraying coating liquid to increase the coating weight by 1.5-2.5%.
10. The compound antihypertensive pharmaceutical composition according to any one of claims 1-8, wherein the preparation process of the pharmaceutical composition comprises the following steps:
(1) weighing a prescription amount of allisartan isoproxil and/or salt thereof and a solubilizing carrier, dissolving the allisartan isoproxil and/or salt thereof and the solubilizing carrier in a proper amount of organic solvent to prepare a medicinal solution, placing a prescription amount of filler in a fluidized bed, adding the medicinal solution in a top spraying manner, carrying out fluidized bed spray granulation and drying, adding the prescription amount of filler and a lubricant, and mixing to obtain an allisartan isoproxil total mixed particle;
(2) weighing the total mixed granules of the allisartan isoproxil and/or the salt thereof according to the prescription amount, and uniformly mixing for later use;
(3) uniformly mixing the amlodipine and/or the salt thereof, the filler and the disintegrating agent in the prescription amount through a 40-mesh sieve, and then adding the lubricant for mixing to obtain amlodipine granules;
(4) and prepressing and forming the allisartan isoproxil and/or the total mixed granules of the allisartan isoproxil and/or the salt thereof by a double-layer tablet press to obtain a tablet core, filling the amlodipine layer granules, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil and amlodipine double-layer tablet.
11. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the preparation of a medicament for the prevention and/or treatment of hypertension and its complications.
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