CN114306263A - Compound antihypertensive medicinal composition and preparation method thereof - Google Patents
Compound antihypertensive medicinal composition and preparation method thereof Download PDFInfo
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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 salts thereof and indapamide and a preparation method thereof.
Description
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 salts thereof and indapamide 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.
The thiazide diuretic mainly comprises a thiazide diuretic and a thiazide diuretic, and indapamide is the currently clinically optimal thiazide diuretic, has the effects of reducing blood pressure, promoting urination and calcium antagonism, is quickly and completely absorbed by oral administration, has reliable curative effect, is mainly used for treating various kinds of hypertension and edema clinically, and is recommended as a first-line medicament for treating the hypertension by an authoritative medical organization.
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 CN109833481A discloses a compound pharmaceutical composition of alisartan medoxomil or salt thereof and a diuretic, wherein the compound composition realizes a blood pressure reduction synergistic effect by limiting the mass ratio of alisartan medoxomil and/or salt thereof to indapamide, and is beneficial to improving the blood pressure reduction effect and reducing adverse drug reactions.
Researches find that the mutual influence of the two medicines of the allisartan isoproxil and the indapamide can not reach the biological equivalent of combined medication, and 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 invention is realized by the following technical scheme that the compound antihypertensive drug composition comprises active ingredients of allisartan isoproxil and/or salts thereof, indapamide and more than one pharmaceutically acceptable carrier, and is characterized in that the drug composition is prepared into a bale core. The core-spun tablet takes an active ingredient indapamide sustained-release tablet as a tablet core and takes an active ingredient allisartan isoproxil and/or salt thereof as an outer layer.
The compound antihypertensive drug composition contains 8-40% by weight of allisartan isoproxil and/or salt thereof, 0.1-5% by weight of indapamide and more than one pharmaceutically acceptable carrier.
Preferably, the mass ratio of the alisartan medoxomil and/or the salt thereof to the indapamide is 96:1, 160:1 or 192:1, wherein the mass of the alisartan medoxomil and/or the salt thereof is calculated by alisartan medoxomil.
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 is used in an amount of 5% to 40% in the pharmaceutical composition.
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, the pharmaceutically acceptable carrier comprises a slow-release framework material, the slow-release framework material comprises one or a mixture of more of methylcellulose, ethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable oil, glyceryl behenate and polyvinyl alcohol, and the using amount of the slow-release framework material is 5% -20% of the 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 a mixture of more of hypromellose, hyprolose, sodium carboxymethylcellulose, povidone, starch slurry and gelatin, and the usage amount is 0.1-5% 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.
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 40% 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 indapamide can be 0.03-7.5 mg, and the preferable specific content can be 7.5mg, or 5mg, or 2.5mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.625mg, or 0.5mg 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, wherein the raw and auxiliary materials are prepared by a wet granulation process, or a powder direct compression process, or a dry granulation process and then tableted, and then coated by a coating agent to obtain the coated pharmaceutical composition.
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, spraying the medicinal solution, performing fluidized bed spray granulation and drying, and then adding a prescription amount of disintegrant, filler and lubricant for mixing to obtain an allisartan isoproxil total mixed particle for later use;
(2) weighing the indapamide, the sustained-release framework material, the adhesive, the filler and the lubricant according to the prescription amount, preparing the indapamide by a wet granulation method, a dry granulation method or a powder direct compression method, and then carrying out tablet coating to obtain the indapamide sustained-release tablet core.
(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 indapamide sustained-release 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 1.5-3.0%.
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 medadapalide preparation according to the following preparation process, wherein the specific prescription composition is shown as follows.
The preparation process comprises the following steps:
(1) weighing the alisartan medoxomil and polyvinylpyrrolidone in the formula amount, dissolving the alisartan medoxomil and the polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the crospovidone in the formula amount in a fluidized bed, spraying the medicine solution, performing fluidized bed spray granulation and drying, and then adding the lactose, microcrystalline cellulose, crospovidone and stearic acid in the formula amount for mixing to obtain the alisartan medoxomil total mixed particle.
(2) Adding povidone with the prescription amount into absolute ethyl alcohol and purified water, stirring until the povidone is completely dissolved, adding indapamide, hydroxypropyl cellulose and lactose with the prescription amount into a wet granulator, mixing, adding povidone solution for granulation, drying by a fluidized bed, sieving and mixing with added silicon dioxide and magnesium stearate, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain 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, preheating a tablet core, starting coating liquid spraying to increase the coating weight by 1.5-3.0%, and drying for 30min after the liquid spraying is finished.
Example 2
Prescription
Preparation:
(1) weighing the alisartan medoxomil and polyvinylpyrrolidone in the amount of the prescription, dissolving the alisartan medoxomil and the polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a drug solution, placing copovidone in the amount of the prescription in a fluidized bed, spraying the drug solution, performing fluidized bed spray granulation and drying, and then adding lactose, pregelatinized starch, carboxymethyl starch sodium and magnesium stearate in the amount of the prescription, and mixing to obtain the alisartan medoxomil total mixed granule.
(2) Mixing the indapamide, hydroxypropyl methylcellulose and calcium hydrophosphate according to the prescription amount, adding the mixture into a dry granulating machine, pressing into large tablets, crushing and granulating to obtain granules, mixing the granules with stearic acid and hydrogenated castor oil which are added, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into purified water, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting a coating liquid spraying process to increase the coating weight by 1.5-3.0%, and drying for 30min after the liquid spraying process is finished.
Example 3
Prescription
Preparation: (1) weighing the alisartan medoxomil and the copovidone according to the prescription amount, dissolving the alisartan medoxomil and the copovidone into a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the crospovidone according to the prescription amount into a fluidized bed, spraying the medicine solution, performing fluidized bed spray granulation and drying, and then adding the lactose monohydrate, the mannitol, the crospovidone and the magnesium stearate according to the prescription amount to mix to obtain the alisartan medoxomil total mixed granule.
(2) Mixing the indapamide, hydroxypropyl methylcellulose and calcium hydrophosphate in the prescription amount with the added silicon dioxide and stearic acid uniformly, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain 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, preheating a tablet core, starting a coating liquid spraying process to increase the coating weight by 1.5-3.0%, and drying for 30min after the liquid spraying process is finished.
Comparative example 1
Prescription
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 a fluidized bed, spraying the medicinal solution, performing fluidized bed spray granulation and drying, adding microcrystalline cellulose, lactose and stearic acid in the prescription amount, mixing to obtain an allisartan isoproxil total mixed particle, and uniformly mixing for later use;
(2) uniformly mixing the indapamide with hydroxypropyl methylcellulose and lactose according to the prescription amount, then adding silicon dioxide and magnesium stearate, and uniformly mixing to obtain indapamide granules;
(3) and prepressing and forming the allisartan isoproxil total mixed particles by a double-layer tablet press to obtain a tablet core, then filling the indapamide layer particles, and pressing by a second layer of pressing wheel to obtain the allisartan isoproxil double-layer tablet.
Comparative example 2
Prescription
Preparation: (1) weighing the alisartan medoxomil and polyvinylpyrrolidone in the amount of the prescription, dissolving the alisartan medoxomil and the polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a drug solution, placing copovidone in the amount of the prescription in a fluidized bed, spraying the drug solution, performing fluidized bed spray granulation and drying, adding pregelatinized starch, lactose, carboxymethyl starch sodium and magnesium stearate in the amount of the prescription, and mixing to obtain the alisartan medoxomil total mixed granule.
(2) Weighing the allisartan isoprothiolate total mixed particles in a prescription amount in a centrifugal granulator, and adjusting the rotating speed of a host machine to prepare an allisartan isoprothiolate micro pill;
(3) uniformly mixing the indapamide with hydroxypropyl cellulose and microcrystalline cellulose according to the prescription amount, preparing a soft material by using a proper amount of absolute ethyl alcohol and purified water, then placing the soft material in an extruder for extrusion, transferring the soft material to a spheronizer to prepare spherical pellets, and then drying the pellets to prepare the indapamide pellets;
(4) mixing the alisartan medoxomil pellet and the indapamide pellet, and then filling the capsule to obtain the alisartan medoxomil and indapamide pellet capsule.
Comparative example 3
Prescription
Preparation:
(1) weighing the alisartan medoxomil and the poloxamer according to the prescription amount, dissolving the alisartan medoxomil and the poloxamer into a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the crospovidone according to the prescription amount into a fluidized bed, spraying the medicine solution, carrying out fluidized bed spray granulation and drying, and then adding the lactose, the microcrystalline cellulose, the crospovidone and the stearic acid according to the prescription amount for mixing to obtain the alisartan medoxomil total mixed particle.
(2) Adding the povidone with the prescription amount into the purified water and the absolute ethyl alcohol with the prescription amount, stirring until the povidone is completely dissolved, adding the indapamide, the hydroxypropyl cellulose and the lactose with the prescription amount into a wet granulator, mixing, adding the povidone solution for granulation, then drying by a fluidized bed, sieving and mixing with the added silicon dioxide and magnesium stearate, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into the purified water in the formula amount in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting the spraying coating liquid to increase the coating weight by 1.5-3.0%, and drying for 30min after the spraying is finished.
Comparative example 4
Prescription
Preparation: (1) weighing the alisartan medoxomil and polyvinylpyrrolidone in the prescribed amount, dissolving the alisartan medoxomil and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the crospovidone in the prescribed amount in a fluidized bed, spraying the medicine solution, performing fluidized bed spray granulation and drying, and then adding microcrystalline cellulose, the crospovidone, lactose and stearic acid in the prescribed amount to mix to obtain the alisartan medoxomil total mixed particle.
(2) Adding povidone with the prescription amount into purified water and absolute ethyl alcohol with the prescription amount, stirring until the povidone is completely dissolved, adding indapamide, hydroxypropyl cellulose and lactose with the prescription amount into a wet granulator, mixing, adding povidone solution for granulation, drying by a fluidized bed, sieving and mixing with added silicon dioxide and magnesium stearate, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into the purified water in the formula amount in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting the spraying coating liquid to increase the coating weight by 1.5-3.0%, and drying for 30min after the spraying is finished.
Comparative example 5
Prescription
Preparation: (1) weighing the alisartan medoxomil and polyvinylpyrrolidone in the prescribed amount, dissolving the alisartan medoxomil and the polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a medicine solution, placing the crospovidone in the prescribed amount in a fluidized bed, spraying the medicine solution, performing fluidized bed spray granulation and drying, and then adding the lactose monohydrate, mannitol, crospovidone and magnesium stearate in the prescribed amount to mix to obtain the alisartan medoxomil total mixed granule.
(2) Mixing the indapamide, hydroxypropyl methylcellulose and calcium hydrophosphate in the prescription amount with the added silicon dioxide and stearic acid uniformly, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the alunite total mixed granules of the prescription amount as an outer layer, and pressing the indapamide sustained-release tablet as a tablet core to obtain a core-spun tablet;
(4) coating the core-spun tablets: adding the film coating premix into the purified water in the formula amount in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting the spraying coating liquid to increase the coating weight by 1.5-3.0%, and drying for 30min after the spraying is finished.
EXAMPLE 4 dissolution determination
The preparation product prepared above and a commercially available single formulation allisartan cilexetil tablet (specification 240mg, trade name:
) And Indapamide sustained-release tablet (a) prepared from Shiweiya (Tianjin) pharmaceutical Co., LtdSpecification: 1.5mg, trade name:
) And (4) carrying out dissolution behavior investigation according to a second method of a dissolution method in the appendix of the second part of the Chinese pharmacopoeia 2015 year edition. The dissolution rate in the phosphate buffered saline dissolution medium with pH of 6.8 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 curve results are shown in Table 1.
TABLE 1 in vitro dissolution results for different formulations
From the above dissolution results, it is clear that: the allisartan cilexetil and indapamide of examples 1-3 both showed high dissolution, the dissolution rate of the allisartan cilexetil was above 90% in 30 minutes, the drug was rapidly released to exert its drug effect, the dissolution was very uniform, the drug release rate was relatively stable, and stable blood concentration could be maintained. In addition, the release curves of the alisartan medoxomil and the indapamide in the compound preparation of the examples 1 to 3 in the medium with pH6.8 are similar to those of a single preparation alisartan medoxomil tablet (Xinlitan) and an indapamide sustained release tablet (Nakaiyi).
Whereas the dissolution of comparative example 3 and comparative example 4 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 substantially the same as in example 1, and the 30-minute dissolution rate thereof was less than that of the allisartan cilexetil pharmaceutical composition of example 1 at 30 minutes; in comparative example 3, 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.
In comparative example 5, although the desired dissolution effect was achieved, the use of an excessive amount of solubilizing carrier increased the weight of the unit preparation, and the patient had poor compliance.
Example 5 bioequivalence study
The trial was aimed at studying the presence of healthy subjectsIn the abdominal state, combined administration [ marketed single formulation a allisartan cilexetil tablet (specification 240mg, trade name:
) And indapamide sustained-release tablets (specification: 1.5mg, trade name:
)]with the formulations of the alisartan and indapamide compositions of the above examples and comparative examples orally taken once, the main pharmacokinetic parameters were calculated, and the differences between the pharmacokinetic parameters AUC and Cmax between the formulations were compared, to preliminarily evaluate the consistency of the absorption kinetics of alisartan ester and indapamide in the single formulation and the compound formulation. The test adopts a self-contrast cross test design. Blood sampling time points: 4mL of venous blood was collected before administration (0h) and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 11h, 12h, 13h, 14h, 16h, 18h, 24h, 36h, 48h and 72h after administration, respectively. The results are shown in Table 3.
TABLE 2 in vivo pharmacokinetic results for different prescription samples
Note: EXP3174 is an active metabolite of alisartan medoxomil.
The results show that the compound medicine composition and the alisartan medapamide are combined and bioequivalent, and the internal medicine generation and the medicine effect show that the compound medicine composition accords with the expected clinical treatment effect.
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 (10)
1. A compound antihypertensive drug composition comprises active ingredients of allisartan isoproxil and/or salt thereof, indapamide and more than one pharmaceutically acceptable carrier; it is characterized in that the pharmaceutical composition is prepared into a bale chip; the core-spun tablet takes an active ingredient indapamide sustained-release tablet as a tablet core and takes an active ingredient alisartan medoxomil and/or salt thereof as an outer layer.
2. The combination as claimed in 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 polymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and hydroxypropyl methylcellulose 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% -40% of the weight of the pharmaceutical composition; the mass of the indapamide is 0.1-5% of the weight of the pharmaceutical composition, wherein the mass ratio of the alisartan ester and/or the salt thereof to the indapamide is 96:1, 160:1 or 192: 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 usage amount of the indapamide is 7.5mg, 5mg, 2.5mg, 1.5mg, 1.25mg, 1mg, 0.75mg, 0.625mg and 0.5 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, slow-release matrix materials 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 5-40% 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 0.1-5% of the weight of the pharmaceutical composition;
the slow release framework material comprises one or a mixture of more of methylcellulose, ethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable oil, glyceryl behenate and polyvinyl alcohol, and the using amount of the slow release framework material is 5-20% 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 wet granulation process, or a powder 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) 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, spraying the medicinal solution, performing fluidized bed spray granulation drying, adding the prescription amount of filler and a lubricant, and mixing to obtain an allisartan isoproxil total mixed particle;
(2) weighing the indapamide, the sustained-release framework material, the adhesive, the filler and the lubricant according to the prescription amount, preparing the indapamide, the sustained-release framework material, the adhesive, the filler and the lubricant by a wet granulation method, a dry granulation method or a powder direct compression method, and then carrying out tablet pressing and coating to obtain an indapamide sustained-release tablet core;
(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 indapamide sustained-release 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 1.5-3.0%.
10. 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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| CN2021100718962 | 2021-01-20 | ||
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142529A (en) * | 2013-03-07 | 2013-06-12 | 宁夏康亚药业有限公司 | Indapamide sustained-release drug composite and preparation method thereof |
| CN105078974A (en) * | 2014-05-23 | 2015-11-25 | 深圳信立泰药业股份有限公司 | Allisartan isoproxil solid dispersion and pharmaceutical composition |
| CN109833481A (en) * | 2017-11-24 | 2019-06-04 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition of A Lishatan ester or its salt and diuretics |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142529A (en) * | 2013-03-07 | 2013-06-12 | 宁夏康亚药业有限公司 | Indapamide sustained-release drug composite and preparation method thereof |
| CN105078974A (en) * | 2014-05-23 | 2015-11-25 | 深圳信立泰药业股份有限公司 | Allisartan isoproxil solid dispersion and pharmaceutical composition |
| US20170135989A1 (en) * | 2014-05-23 | 2017-05-18 | Shenzhen Salubris Pharmaceuticals Co., Ltd | Allisartan isoproxil solid dispersion and pharmaceutical composition |
| CN109833481A (en) * | 2017-11-24 | 2019-06-04 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition of A Lishatan ester or its salt and diuretics |
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