CN114306263B - Compound antihypertensive pharmaceutical composition and preparation method thereof - Google Patents
Compound antihypertensive pharmaceutical 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 in particular relates to a medicinal composition of alisartan ester and/or salt 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 in particular relates to a medicinal composition of alisartan ester and/or salt thereof and indapamide and a preparation method thereof.
Background
Alisartan ester (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: sulbactam is a novel angiotensin ii receptor antagonist. Chinese patent CN200680000397.8 discloses a structural formula of an alisrtan cilexetil compound, which has low toxicity and a better antihypertensive effect than the same type of product (such as losartan), and which generates an active metabolite (EXP 3174) through in vivo metabolism, thereby exerting its antihypertensive effect. Chinese patent CN106188012A, CN104610232A, CN109320501A, CN109694369A, CN105232489A, CN107441497a has studied the physical form, formulation, etc. of the compound, respectively.
The thiazide diuretics mainly comprise thiazide-like diuretics and thiazide-like diuretics, the indapamide is the most clinically optimal thiazide-like diuretics at present, has the effects of reducing blood pressure, promoting urination and antagonizing calcium, and is rapid and complete in oral absorption and reliable in curative effect, so that the thiazide-like diuretics are mainly used for treating various hypertension and oedema clinically, and are recommended as first-line medicaments for treating hypertension by authoritative medical organizations.
For severe hypertension and/or populations with multiple risk factors, target organ damage or clinical conditions, administration of a single hypotensive drug often fails to achieve optimal therapeutic results, and for such patients it is often desirable to consider administration of two or more hypotensive drugs with different hypotensive mechanisms. Chinese patent CN109833481a discloses a compound pharmaceutical composition of alisrtan medoxomil or a salt thereof and a diuretic, and the compound composition realizes a synergistic effect of reducing blood pressure by limiting the mass ratio of alisrtan medoxomil and/or a salt thereof to indapamide, thereby being beneficial to improving the blood pressure reducing effect and reducing adverse drug reactions.
The study finds that the two medicines of the alisartan and the indapamide have mutual influence and cannot achieve bioequivalence with the combined medicine, so that in order to solve the technical problem, the searching of a preparation scheme conforming to clinical use is important, and further research and development are needed.
Disclosure of Invention
In view of the problems existing in the prior art, the invention provides a novel compound antihypertensive pharmaceutical composition and a preparation method thereof. The invention is realized by the following technical scheme, and the compound antihypertensive pharmaceutical composition comprises active ingredients of alisartan, and/or salts thereof, indapamide, and more than one pharmaceutically acceptable carrier, and is characterized in that the pharmaceutical composition is prepared into a chip-in-package. The core-spun tablet takes the indapamide sustained release tablet as an active ingredient and the alisartan ester and/or the salt thereof as an outer layer.
The compound antihypertensive pharmaceutical composition contains 8-40% by weight of alisartan ester and/or salt thereof, 0.1-5% by weight of indapamide and more than one pharmaceutically acceptable carrier.
Preferably, the mass ratio of the alisrtan medoxomil and/or salt thereof to indapamide is 96:1, 160:1 or 192:1, wherein the mass of the alisrtan medoxomil and/or salt thereof is calculated on the basis of the alisrtan medoxomil.
As a preferred embodiment of the present invention, the pharmaceutically acceptable carrier comprises a solubilizing carrier, and the solubilizing carrier comprises one or more of homo-or copolymer of vinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, cellulose ethers, polyacrylic polymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, and a mixture of any proportions, and the use amount of the solubilizing carrier in the pharmaceutical composition is 8% -45%, preferably 15% -35%.
As a preferred technical scheme of the invention, the solubilizing carrier comprises one or a mixture of two of povidone, crospovidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose phthalate mixed in any proportion.
As a preferred embodiment of the present invention, the solubilizing carrier comprises one or a mixture of two of povidone, crospovidone and copovidone mixed in any ratio.
As a preferred technical scheme of the invention, the pharmaceutically acceptable carrier comprises a filler, wherein 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 dosage of the filler in the pharmaceutical composition is 5-40%.
As a preferred technical scheme of the invention, the pharmaceutically acceptable carrier comprises a disintegrating agent, wherein the disintegrating agent comprises one or more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and the like, and the use amount of the disintegrating agent is 1-25% of the weight of the pharmaceutical composition.
As a preferred technical scheme of the invention, the pharmaceutically acceptable carrier comprises a slow-release framework material, wherein the slow-release framework material comprises one or more of methyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable oil, glyceryl behenate and polyvinyl alcohol, and the use amount of the slow-release framework material is 5-20% of the weight of the pharmaceutical composition.
As a preferred technical scheme of the invention, the pharmaceutically acceptable carrier comprises a binder, wherein the binder comprises one or a mixture of more of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch slurry and gelatin, and the use amount is 0.1-5% of the weight of the pharmaceutical composition.
As a preferred technical scheme of the invention, the pharmaceutically acceptable carrier comprises a lubricant, wherein 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 use amount of the lubricant is 0.1-2% of the weight of the pharmaceutical composition.
The sum of the percentages of the raw materials and the auxiliary materials in the pharmaceutical composition is 95-100% unless otherwise indicated, and the use amounts are all mass use amounts.
According to a preferred technical scheme, the alisrtan medoxomil and/or the salt thereof refer to a mixture obtained by mixing alisrtan medoxomil, or an alisrtan medoxomil salt with an alisrtan medoxomil salt in any proportion in a compound pharmaceutical composition; the foregoing aliskirsite ester salts refer to pharmaceutically acceptable salts of aliskirsite esters, including, but not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, ammonium salts, and the like; unless otherwise specified, the mass of the alisrtan medoxomil and/or the salt thereof in the present invention is calculated on the alisrtan medoxomil.
As a preferred technical scheme of the invention, the mass of the alisrtan medoxomil and/or the salt thereof (calculated by the alisrtan medoxomil) is 20-40% of the weight of the pharmaceutical composition, and the specific use amounts are 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, etc.
As a preferred embodiment of the present invention, the coating agent comprises any gastric soluble coating. Specifically, for example, the gastric soluble coating comprises 295F620048-CN, wherein the gastric soluble coating adopts a solvent mixture such as water (preferably, the gastric soluble coating agent and purified water are mixed according to the mass ratio of 1:5-1:8 for coating), and the weight gain after coating is about 0.1% -4%.
The pharmaceutical composition is a solid formulation suitable for oral administration, preferably an oral tablet or capsule.
The invention further provides a preparation method of the pharmaceutical composition, wherein the raw materials and the auxiliary materials are subjected to wet granulation, or a powder direct compression process, or a dry granulation process, and then subjected to tabletting, and then a coating agent is used 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) Weighing a prescription amount of alisartan ester and/or salt thereof and a solubilizing carrier, dissolving in a proper amount of organic solvent to prepare a pharmaceutical solution, placing the prescription amount of filler in a fluidized bed, spraying the pharmaceutical solution, performing spray granulation and drying on the fluidized bed, and then adding the prescription amount of disintegrant, filler and lubricant to mix to obtain the alisartan ester total mixed particles for later use;
(2) The indapamide, the slow-release matrix material, the adhesive, the filler and the lubricant are weighed according to the prescription, the indapamide slow-release tablet is prepared by a wet granulation method, a dry granulation method or a powder direct compression method, and then tabletting and coating are carried out, so that the indapamide slow-release tablet core is obtained.
(3) Weighing the total mixed particles of the aliskirsite and/or the salt thereof with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, loading a tablet core into a coating pot for preheating after the preheating of the coating machine is finished, setting parameters such as the rotating speed of a host machine, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after the preheating of the tablet core, and starting a coating spraying liquid to increase the coating weight to 1.5% -3.0%.
The invention further provides that the pharmaceutical composition can be applied to medicines for preventing and/or treating hypertension and complications thereof.
The beneficial effects of the invention compared with the prior art include:
(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 biological equivalence test proves that the pharmaceutical composition obtained by the invention realizes biological equivalence with combined medication, and can be applied to medicines for preventing and/or treating hypertension and complications thereof.
(3) The pharmaceutical composition preparation provided by the invention has good stability, so that the safety and effective application of the medicine are effectively ensured.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the invention are not limited thereto.
Example 1
The preparation method comprises the steps of calculating and weighing the components with corresponding prescription amounts, and preparing the preparation of the alisartan ester indapamide according to the following preparation process, wherein the specific prescription compositions are shown as follows.
The specific preparation process is as follows:
(1) Weighing a prescribed amount of alisartan and polyvinylpyrrolidone, dissolving the prescribed amount of alisartan and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescribed amount of crospovidone in a fluidized bed, spraying the pharmaceutical solution into the fluidized bed, performing spray granulation and drying on the fluidized bed, and then adding the prescribed amount of lactose, microcrystalline cellulose, crospovidone and stearic acid to mix to obtain the alisartan ester total mixed particles.
(2) Adding the prescription amount of povidone into absolute ethyl alcohol and purified water, stirring until the povidone is completely dissolved, adding the prescription amount of indapamide, hydroxypropyl cellulose and lactose into a wet granulator, mixing, adding a povidone solution for granulating, drying by a fluidized bed, sieving and mixing with additional silicon dioxide and magnesium stearate, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting spraying coating liquid to enable the coating weight to reach 1.5% -3.0%, and drying for 30min after spraying the coating liquid.
Example 2
Prescription of prescription
Preparation:
(1) Weighing the prescription amount of the aliskirsite and polyvinylpyrrolidone, dissolving the prescription amount of the aliskirsite and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescription amount of the copovidone in a fluidized bed, spraying the pharmaceutical solution, performing fluidized bed spray granulation and drying, and then adding the prescription amount of lactose, pregelatinized starch, carboxymethyl starch sodium and magnesium stearate to mix to obtain the aliskirsite total mixed particles.
(2) Mixing the prescription amount of indapamide, hypromellose and calcium hydrophosphate, adding into a dry granulator, pressing into large tablets, crushing and granulating to obtain granules, mixing with the externally added stearic acid and hydrogenated castor oil, tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into purified water, stirring to uniformly disperse, preheating tablet cores, starting spraying coating liquid to increase the weight of the coating to 1.5% -3.0%, and drying for 30min after spraying liquid.
Example 3
Prescription of prescription
Preparation: (1) Weighing a prescribed amount of alisartan and copovidone, dissolving the prescribed amount of alisartan and copovidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescribed amount of copovidone in a fluidized bed, spraying the pharmaceutical solution, performing fluidized bed spray granulation and drying, and then adding the prescribed amount of lactose monohydrate, mannitol, copovidone and magnesium stearate to mix, thereby obtaining the alisartan ester total mixed particles.
(2) Uniformly mixing the prescription amount of indapamide, hypromellose and calcium hydrophosphate with the added silicon dioxide and stearic acid, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water, stirring to uniformly disperse the film coating premix, preheating the tablet cores, starting spraying coating liquid to increase the weight of the coating to 1.5% -3.0%, and drying for 30min after spraying the coating liquid.
Comparative example 1
Prescription of prescription
Preparation: (1) Weighing a prescribed amount of alisartan and polyvinylpyrrolidone, dissolving the prescribed amount of alisartan and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescribed amount of crospovidone in a fluidized bed, spraying the pharmaceutical solution into the fluidized bed, performing spray granulation and drying on the fluidized bed, adding the prescribed amount of microcrystalline cellulose, lactose and stearic acid to mix, thus obtaining alisartan ester total mixed particles, and uniformly mixing for later use;
(2) Uniformly mixing the prescription amount of indapamide, hypromellose and lactose, adding silicon dioxide and magnesium stearate, and uniformly mixing to obtain indapamide particles;
(3) And pre-pressing the total mixed particles of the alisartan and the indapamide through a double-layer tablet press to obtain tablet cores, filling indapamide layer particles, and pressing through a second layer pressing wheel to obtain the alisartan and indapamide double-layer tablet.
Comparative example 2
Prescription of prescription
Preparation: (1) Weighing the prescription amount of the alisartan and polyvinylpyrrolidone, dissolving the prescription amount of the alisartan and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescription amount of the copovidone in a fluidized bed, spraying the pharmaceutical solution, performing spray granulation and drying on the fluidized bed, and then adding the prescription amount of pregelatinized starch, lactose, carboxymethyl starch sodium and magnesium stearate to mix to obtain the alisartan ester total mixed particles.
(2) Weighing the total mixed particles of the alisrtan cilexetil with the prescription amount in a centrifugal granulator, and adjusting the rotation speed of a host machine to prepare the alisrtan cilexetil pellets;
(3) Uniformly mixing prescription amount of indapamide, hydroxypropyl cellulose and microcrystalline cellulose, preparing a soft material by using a proper amount of absolute ethyl alcohol and purified water, extruding by an extruder, transferring into a spheronization machine to prepare spherical pellets, and drying to prepare the indapamide pellets;
(4) And mixing the alisartan ester pellets with the indapamide pellets, and then canning the mixture to obtain the indapamide pellet capsules.
Comparative example 3
Prescription of prescription
Preparation:
(1) Weighing the prescription amount of the alisrtan medoxomil and poloxamer, dissolving in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescription amount of the crosslinked povidone in a fluidized bed, spraying the pharmaceutical solution, performing spray granulation and drying on the fluidized bed, and then adding the prescription amount of lactose, microcrystalline cellulose, crosslinked povidone and stearic acid to mix so as to obtain the alisrtan medoxomil total mixed particles.
(2) Adding the prescribed amount of povidone into the prescribed amount of purified water and absolute ethyl alcohol, stirring until the povidone is completely dissolved, adding the prescribed amount of indapamide, hydroxypropyl cellulose and lactose into a wet granulator, mixing, adding the povidone solution for granulating, 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 total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting to spray coating liquid to enable the coating weight to reach 1.5% -3.0%, and drying for 30min after spraying the liquid.
Comparative example 4
Prescription of prescription
Preparation: (1) Weighing a prescribed amount of alisartan and polyvinylpyrrolidone, dissolving the prescribed amount of alisartan and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescribed amount of crospovidone in a fluidized bed, spraying the pharmaceutical solution into the fluidized bed, performing spray granulation and drying on the fluidized bed, and then adding the prescribed amount of microcrystalline cellulose, the crospovidone, lactose and stearic acid to mix to obtain the alisartan ester total mixed particles.
(2) Adding the prescribed amount of povidone into the prescribed amount of purified water and absolute ethyl alcohol, stirring until the povidone is completely dissolved, adding the prescribed amount of indapamide, hydroxypropyl cellulose and lactose into a wet granulator, mixing, adding the povidone solution for granulating, 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 total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting to spray coating liquid to enable the coating weight to reach 1.5% -3.0%, and drying for 30min after spraying the liquid.
Comparative example 5
Prescription of prescription
Preparation: (1) Weighing a prescribed amount of alisartan and polyvinylpyrrolidone, dissolving the prescribed amount of alisartan and polyvinylpyrrolidone in a proper amount of dichloromethane and absolute ethyl alcohol to prepare a pharmaceutical solution, placing the prescribed amount of crospovidone in a fluidized bed, spraying the pharmaceutical solution into the fluidized bed, performing spray granulation and drying on the fluidized bed, and then adding the prescribed amount of lactose monohydrate, mannitol, crospovidone and magnesium stearate to mix to obtain the alisartan ester total mixed particles.
(2) Uniformly mixing the prescription amount of indapamide, hypromellose and calcium hydrophosphate with the added silicon dioxide and stearic acid, and tabletting and coating to obtain the indapamide sustained-release tablet core.
(3) Weighing the total mixed particles of the aliskirsite with the prescription amount as an outer layer, and taking the indapamide sustained release tablet as a tablet core pressed package chip;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water in a stirring state, stirring to uniformly disperse the film coating premix, preheating a tablet core, starting to spray coating liquid to enable the coating weight to reach 1.5% -3.0%, and drying for 30min after spraying the liquid.
EXAMPLE 4 dissolution measurement
The preparation product prepared above and the single preparation alisartan cilexetil tablet (specification 240mg, trade name:
) And Shi Weiya (Tianjin) pharmaceutical Co., ltd, the single formulation indapamide sustained release tablets (specification: 1.5mg, trade name: />
) And (5) performing dissolution behavior investigation according to a second method of the second annex dissolution method of the 2015 edition of Chinese pharmacopoeia. The dissolution in phosphate buffer dissolution medium at pH6.8 was evaluated (dissolution medium volume 900mL, temperature 37.+ -. 0.5 ℃ C., rotational speed 50 r/min) and the dissolution profile results are shown in Table 1.
TABLE 1 in vitro dissolution results for different prescriptions
From the above elution results, it can be seen that: the alisartan ester and indapamide of examples 1-3 both show higher dissolution, the dissolution rate of the alisartan ester is above 90% in 30 minutes, the dissolution is rapid, so that the medicine can exert the medicine effect faster, the dissolution is very uniform, the dissolution rate level of the medicine is stable, and the stable blood concentration can be maintained. And the release curve of the alisartan and the indapamide in the compound preparation of the examples 1-3 in a medium with pH of 6.8 is similar to that of a single preparation of an alisartan ester tablet (sulbactam) and an indapamide sustained release tablet (nano-catalysis).
Whereas comparative example 3 and comparative example 4 were slower in dissolution and did not dissolve completely. Comparative example 4 the amount of active agent and other excipients was substantially the same as example 1 except that the amount of solubilizing carrier was less than the amount of the present invention, and the 30 minute dissolution was less than that of the alisrtan medoxomil pharmaceutical composition of example 1; comparative example 3, in which the dissolution rate of the drug was rather lowered due to the fact that the solubilizing carrier exemplified in the present invention was not used, did not meet the clinical requirements.
For comparative example 5, although the desired dissolution effect was achieved, the dosage compliance of patients was poor due to the high weight of the unit formulation caused by the use of excessive solubilizing carrier.
EXAMPLE 5 bioequivalence study
The test aims at studying that healthy subjects were co-administered in a fasting state [ single formulation a alisrtan cilexetil tablet (specification 240mg, trade name:
) And Shi Weiya (Tianjin) pharmaceutical Co., ltd, the single formulation B indapamide sustained release tablet (specification: 1.5mg, trade name: />
)]And (3) calculating main pharmacokinetic parameters, comparing differences of the pharmacokinetic parameters AUC and Cmax between preparations and preliminarily evaluating the consistency of absorption kinetics of the alisartan ester and the indapamide in the single preparation and the compound preparation compared with single oral administration of the alisartan indapamide composition preparations of the above examples and the comparative examples. The test adopts self-control cross test design. Blood collection time point: pre-dose (0 h), 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 11h, 12h, 13h, 14h, 16h, 18h, 24h, 36h, 48h and 72h after dose, respectively, were collectedVenous blood 4mL. The results are shown in Table 3.
TABLE 2 in vivo pharmacokinetic results for different prescription samples
Note that: EXP3174 is an active metabolite of alisartan ester.
From the results, the compound pharmaceutical composition provided by the invention is bioequivalent to the combination of the aliskirilowii and the indapamide, and the compound pharmaceutical composition meets the expected clinical treatment effect in terms of in-vivo drug generation and drug effect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A compound antihypertensive pharmaceutical composition, which comprises active ingredients of alisartan cilexetil and/or salt thereof, indapamide and more than one pharmaceutically acceptable carrier; the preparation method is characterized in that the pharmaceutical composition is prepared into a chip; wherein the core-spun tablet takes the indapamide sustained release tablet as a tablet core and takes the active ingredient alisartan ester and/or the salt thereof as an outer layer; the pharmaceutically acceptable carrier comprises a solubilizing carrier, wherein the solubilizing carrier comprises a mixture of povidone and crospovidone, copovidone and povidone, and copovidone which are mixed in any proportion, and the using amount of the solubilizing carrier in the pharmaceutical composition is 15% -35%; the more than one pharmaceutically acceptable carrier comprises more than one filler, a disintegrating agent, an adhesive, a slow-release framework material and a lubricant; 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 use amount is 5-40% of the weight of the pharmaceutical composition; the disintegrating agent comprises one or more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and the like, and the use amount of the disintegrating agent is 1-25% of the weight of the pharmaceutical composition; the adhesive comprises one or more of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch slurry and gelatin, and the use 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 methyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methylcellulose, hydrogenated vegetable oil, glyceryl behenate and polyvinyl alcohol, and the use amount is 5-20% of the weight of the pharmaceutical composition; the lubricant comprises one or more than two of silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol and hydrogenated castor oil, and the use amount of the lubricant is 0.1-2% of the weight of the pharmaceutical composition.
2. The compound antihypertensive pharmaceutical composition according to claim 1, wherein the mass of the alisrtan medoxomil and/or the salt thereof (calculated as alisrtan 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.
3. The compound antihypertensive pharmaceutical composition according to any one of claims 1-2, wherein the amount of the alisrtan medoxomil and/or salt thereof (calculated as alisrtan medoxomil) is 10mg, 15mg, 20mg, 30mg, 50mg, 60mg, 80mg, 90mg, 100mg, 120mg, 150mg, 160mg, 180mg, 200mg, 210mg, 240mg, 270mg, 300mg; the use amount of indapamide is 7.5mg, 5mg, 2.5mg, 1.5mg, 1.25mg, 1mg, 0.75mg, 0.625mg and 0.5mg.
4. The compound antihypertensive pharmaceutical composition according to any one of claims 1-2, wherein the pharmaceutical composition is a tablet suitable for oral administration.
5. A compound antihypertensive pharmaceutical composition according to claim 3, characterized in that it is a tablet suitable for oral administration.
6. The compound antihypertensive pharmaceutical composition according to any one of claims 1-2 and 5, wherein the pharmaceutical composition is prepared by a wet granulation process, a powder direct compression process, or a dry granulation process.
7. The compound antihypertensive pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is prepared by a wet granulation process, a powder direct compression process, or a dry granulation process.
8. The compound antihypertensive pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is prepared by a wet granulation process, a powder direct compression process, or a dry granulation process.
9. The compound antihypertensive pharmaceutical composition according to claim 1, wherein the preparation process of the pharmaceutical composition comprises the following steps:
(1) Weighing a prescription amount of alisartan ester and/or salt thereof and a solubilizing carrier, dissolving in a proper amount of organic solvent to prepare a pharmaceutical solution, placing the prescription amount of filler in a fluidized bed, spraying the pharmaceutical solution, performing spray granulation and drying on the fluidized bed, and then adding the prescription amount of filler and a lubricant to mix to obtain the alisartan ester total mixed particles;
(2) Weighing the prescription amount of indapamide, a slow-release framework material, an adhesive, a filler and a lubricant, preparing by a wet granulation method, a dry granulation method or a powder direct compression method, and tabletting and coating to obtain an indapamide slow-release tablet core;
(3) Weighing the total mixed particles of the aliskirsite and/or the salt of the aliskirsite with the prescription amount as an outer layer, and pressing and packaging the indapamide sustained release tablet as a tablet core;
(4) Coating the chip: adding the film coating premix into the prescribed amount of purified water, stirring to uniformly disperse the film coating premix, starting a coating machine for preheating, loading a tablet core into a coating pot for preheating after the preheating of the coating machine is finished, setting parameters such as the rotating speed of a host machine, the air inlet temperature, the rotating speed of a peristaltic pump, the atomizing pressure and the like after the preheating of the tablet core, and starting a coating spraying liquid to increase the coating weight to 1.5% -3.0%.
10. Use of a pharmaceutical composition according to any one of claims 1-5 for the preparation of a medicament for the prevention and/or treatment of hypertension and complications thereof.
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