CN110917170A - Candesartan cilexetil-containing capsule preparation and preparation method thereof - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a capsule preparation containing candesartan cilexetil and a preparation method thereof. Mixing 2-32 parts of candesartan cilexetil, 110-150 parts of diluent, 210-150 parts of diluent, 0.5-8 parts of disintegrant, 1-10 parts of adhesive and 0.5-10 parts of low-melting-point oily compound according to parts by weight, preparing the mixture into pellets by an extrusion spheronization method, adding 0.05-4 parts of lubricant into the pellets, mixing, filling the mixture into a capsule shell, and preparing a capsule preparation. The capsule preparation containing candesartan cilexetil disclosed by the invention adopts an extrusion rounding preparation process, has high dissolution, and greatly improves the bioavailability of candesartan cilexetil compared with a commercially available candesartan cilexetil preparation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a capsule preparation containing candesartan cilexetil and a preparation method thereof.
Background
Candesartan cilexetil (candesartan cilexetil) is a novel angiotensin ii receptor antagonist used in hypertension and chronic heart failure. The candesartan cilexetil is an inactive prodrug, is almost completely hydrolyzed into candesartan after gastrointestinal absorption, is an antagonist of a diphenylimidazole angiotensin II type receptor (AT1), and achieves the effect of reducing blood pressure by blocking vasoconstriction, sympathetic nerve excitation and baroreceptor sensitivity caused by AT1 in circulation and local tissues through antagonism AT1 and increasing the like.
The investigation shows that the candesartan cilexetil is an insoluble drug and has low oral bioavailability. The invention patent CN1086998A discloses a preparation method of candesartan cilexetil tablets by adding an oily compound with a low melting point to improve the stability of candesartan cilexetil medicaments, but the relative bioavailability of the original candesartan cilexetil tablets (8mg) prepared according to the method is only 34% (95% CI: 28-40%), and the absorption and onset time is relatively slow. CN101623275A discloses a candesartan cilexetil capsule and a preparation method thereof, wherein a hydroxypropyl cellulose capsule shell is adopted, the purpose is to solve the problem of dissolution reduction in the storage process, but the in vivo bioavailability of the candesartan cilexetil capsule cannot be improved.
Disclosure of Invention
The invention aims to provide a capsule preparation containing candesartan cilexetil and a preparation method thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a capsule preparation containing candesartan cilexetil is prepared by mixing 2-32 parts of candesartan cilexetil, 110-150 parts of diluent, 210-150 parts of diluent, 0.5-8 parts of disintegrant, 1-10 parts of adhesive and 0.5-10 parts of low-melting-point oily compound in parts by weight, preparing the mixture into a pellet by an extrusion spheronization method, adding 0.05-4 parts of lubricant into the pellet for mixing, and filling the mixture into a capsule shell to prepare the capsule preparation.
The method specifically comprises the following steps:
a: uniformly mixing candesartan cilexetil, a diluent 1, a diluent 2, a disintegrating agent, an adhesive and a low-melting-point oily compound in parts by weight;
b: b, adding water or alcohol-water solution mixed according to any proportion into the mixture obtained in the step a to prepare soft materials;
c: preparing into pellet by extrusion and spheronization method, and drying the pellet;
d: adding the lubricant into the pellets and uniformly mixing;
e; and d, filling the mixture obtained in the step d into a capsule shell to prepare a capsule preparation.
The extrusion rounding method adopts a screen with the aperture of 200-; the rolling time in the extrusion rolling method is 10-1200 seconds.
The preferred extrusion rolling method adopts a screen with the aperture of 500-1200 mu m, the rotating speed of a rolling machine in the extrusion rolling method is 500-2000rpm, and the rolling time in the extrusion rolling method is 50-240 seconds.
The preferred weight parts are: 2-32 parts of candesartan cilexetil, 110-120 parts of diluent, 210-120 parts of diluent, 1-4 parts of disintegrating agent, 3-7 parts of adhesive, 1-5 parts of low-melting-point oily compound and 0.05-2 parts of lubricant.
Preferably, each 1000 capsules of the preparation comprises, by weight, 2-32 g of candesartan cilexetil, 110-120 g of diluent, 210-120 g of diluent, 1-4 g of disintegrant, 3-7 g of adhesive, 1-5 g of low-melting-point oily compound and 0.05-2 g of lubricant.
The low-melting-point oily compound is one or more of hydrocarbons, higher fatty acid, higher alcohol, fatty acid ester of polyhydric alcohol, higher alcohol ether of polyhydric alcohol, high polymer of ethylene oxide or copolymer of ethylene oxide;
the diluent 1 is microcrystalline cellulose, and the diluent 2 is one or more of lactose, corn starch or calcium hydrophosphate;
the adhesive is one or more of acacia, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose;
the disintegrating agent is one or more of carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose or dry starch;
the lubricant is one or more of magnesium stearate, talcum powder or glyceryl behenate.
Preferably, the low-melting oily compound is polyethylene glycol;
the diluent 2 is one or two of lactose and corn starch;
the adhesive is hydroxypropyl cellulose;
the disintegrant is croscarmellose sodium;
the lubricant is magnesium stearate.
The capsule shell is selected from gelatin capsule shell or hydroxypropyl methylcellulose capsule shell.
Compared with the prior art, the invention has the advantages that:
1. the capsule preparation containing candesartan cilexetil of the invention adopts an extrusion rolling preparation process, has high dissolution, and greatly improves the bioavailability of candesartan cilexetil compared with the commercially available candesartan cilexetil preparation (such as candesartan cilexetil tablets of Wutian pharmaceutical company, Japan, trade name: Bilos, and the like).
2. In the prior art, the combination of candesartan cilexetil medicament and extrusion spheronization technology is not seen, the extrusion spheronization method is not a conventional method for improving bioavailability, the invention adopts the extrusion spheronization method to prepare the pellets, and the pellets are filled into a capsule preparation, so that the problem of low bioavailability of candesartan cilexetil in vivo is solved, and the candesartan cilexetil capsule has the characteristic of remarkably improving the bioavailability of candesartan cilexetil.
3. The preparation method has the advantages of simple process, good reproducibility of production process and strong operability, can meet the requirement of scale-up production, and is suitable for commercial production.
Description of the drawings:
fig. 1 is a graph comparing mean plasma concentration versus time curves for example 1, comparative example 1, and sample 4 in healthy adults.
The specific implementation mode is as follows:
the candesartan cilexetil capsule formulation of the present invention is further specifically illustrated by the following examples, but is not limited thereto.
Example 1:
candesartan cilexetil capsule (1000 pieces in batch)
The usage and dosage are as follows: once a day, 4-8 mg once.
The preparation method comprises the following steps:
a: adding candesartan cilexetil, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, carboxymethylcellulose calcium and polyethylene glycol 6000 into a wet granulator, and stirring to mix uniformly;
b: adding purified water into the mixture obtained in the step a to prepare a soft material;
c: preparing into pellet by extrusion and spheronization method, drying the pellet in fluidized bed to water content below 4%;
d: adding magnesium stearate into the pellet, and mixing;
e; and d, filling the mixture obtained in the step d into a No. 3 gelatin capsule shell to obtain the candesartan cilexetil-containing capsule.
The extrusion rounding method adopts a screen with the aperture of 1200 mu m, and the rotating speed of a rounding machine in the extrusion rounding method is 1000 rpm; the spheronization time in the extrusion spheronization process was 180 seconds.
Example 2:
candesartan cilexetil capsule (1000 pieces in batch)
The preparation method comprises the following steps:
a: adding candesartan cilexetil, microcrystalline cellulose, lactose, hydroxypropyl cellulose, croscarmellose sodium and polyethylene glycol into a wet granulator, and stirring to mix 6000 uniformly;
b: adding purified water into the mixture obtained in the step a to prepare a soft material;
c: preparing into pellet by extrusion and spheronization method, drying the pellet in fluidized bed to water content below 4%;
d: adding magnesium stearate into the pellet, and mixing;
e; and d, filling the mixture obtained in the step d into a No. 3 gelatin capsule shell to obtain the candesartan cilexetil-containing capsule.
The adhesive solution is obtained by adding hydroxypropyl cellulose into water and uniformly stirring;
the extrusion rounding method adopts a screen with the aperture of 600 mu m, and the rotating speed of a rounding machine in the extrusion rounding method is 1000 rpm; the spheronization time in the extrusion spheronization process was 120 seconds.
Comparative example 1
Candesartan cilexetil capsule (1000 pieces in batch)
The preparation method comprises the following steps:
a: uniformly mixing candesartan cilexetil, microcrystalline cellulose, corn starch, carboxymethylcellulose calcium and polyethylene glycol 6000;
b: adding a hydroxypropyl cellulose solution into the mixture obtained in the step a, and adding the mixture into a wet granulator to prepare a soft material;
c: wet granulating, drying in fluidized bed to obtain granules with water content below 4%;
d: dry granulating, adding magnesium stearate, and mixing;
e; and d, filling the mixture obtained in the step d into a No. 3 gelatin capsule shell to obtain the candesartan cilexetil-containing capsule.
The adhesive solution is obtained by adding hydroxypropyl cellulose into water and uniformly stirring.
Application example
Comparison of plasma concentration-time curves in vivo
A commercially available preparation (trade name: Biluos, standard 8mg, manufactured by Wuta corporation, Japan) was purchased.
Blood samples were collected from 9 healthy subjects who fasted overnight for at least 10 hours, on an empty stomach with the test drugs (example 1, comparative example 1 and the commercially available formulations) within 1 hour before (0 hour) and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 8h, 10h, 12h, 24h, 36h, 48h and 60h after administration, and subjected to biological sample analysis, the results of which are shown in table 1.
Table 1 example 1, comparative example 1 and commercial formulation Cmax、AΜC0-tAnd A m C0-∞
As can be seen from table 1, a μm C of example 1 was significantly higher than that of comparative example 1 and the commercial formulation.
The capsule preparation containing candesartan cilexetil of the invention adopts an extrusion rolling preparation process, has high dissolution, and greatly improves the bioavailability of candesartan cilexetil compared with the commercially available candesartan cilexetil preparation (such as candesartan cilexetil tablets of Wutian pharmaceutical company, Japan, trade name: Bilos, and the like).
Claims (9)
1. A capsule preparation containing candesartan cilexetil is characterized in that: according to parts by weight, 2-32 parts of candesartan cilexetil, 110-150 parts of diluent, 210-150 parts of diluent, 0.5-8 parts of disintegrating agent, 1-10 parts of adhesive and 0.5-10 parts of low-melting-point oily compound are mixed and then prepared into pellets by an extrusion and spheronization method, 0.05-4 parts of lubricant is added into the pellets and mixed, and the mixture is filled into a capsule shell to prepare a capsule preparation.
2. The candesartan cilexetil-containing capsule formulation according to claim 1, wherein:
a: uniformly mixing candesartan cilexetil, a diluent 1, a diluent 2, a disintegrating agent, an adhesive and a low-melting-point oily compound in parts by weight;
b: b, adding water or alcohol-water solution mixed according to any proportion into the mixture obtained in the step a to prepare soft materials;
c: preparing into pellet by extrusion and spheronization method, and drying the pellet;
d: adding the lubricant into the pellets and uniformly mixing;
e; and d, filling the mixture obtained in the step d into a capsule shell to prepare a capsule preparation.
3. The candesartan cilexetil-containing capsule formulation according to claim 1 or 2, wherein: the extrusion spheronization method adopts a sieve with the aperture of 200 plus 2000 mu m, and the rotating speed of a spheronizer in the extrusion spheronization method is 200 plus 4000 rpm; the rolling time in the extrusion rolling method is 10-1200 seconds.
4. The candesartan cilexetil-containing capsule formulation according to claim 3, wherein: the extrusion rolling method adopts a screen with the aperture of 500-1200 mu m, the rotating speed of a rolling machine in the extrusion rolling method is 500-2000rpm, and the rolling time in the extrusion rolling method is 50-240 seconds.
5. The candesartan cilexetil-containing capsule formulation according to claim 1, wherein: the weight portions are as follows: 2-32 parts of candesartan cilexetil, 110-120 parts of diluent, 210-120 parts of diluent, 1-4 parts of disintegrating agent, 3-7 parts of adhesive, 1-5 parts of low-melting-point oily compound and 0.05-2 parts of lubricant.
6. The candesartan cilexetil-containing capsule formulation according to claim 5, wherein: every 1000 capsules of the candesartan cilexetil capsule preparation comprise, by weight, 2-32 g of candesartan cilexetil, 110-120 g of diluent, 210-120 g of diluent, 1-4 g of disintegrant, 3-7 g of adhesive, 1-5 g of low-melting-point oily compound and 0.05-2 g of lubricant.
7. The candesartan cilexetil-containing capsule formulation according to claim 1, wherein: the low-melting-point oily compound is one or more of hydrocarbons, higher fatty acid, higher alcohol, fatty acid ester of polyhydric alcohol, higher alcohol ether of polyhydric alcohol, high polymer of ethylene oxide or copolymer of ethylene oxide;
the diluent 1 is microcrystalline cellulose, and the diluent 2 is one or more of lactose, corn starch or calcium hydrophosphate;
the adhesive is one or more of acacia, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose;
the disintegrating agent is one or more of carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose or dry starch;
the lubricant is one or more of magnesium stearate, talcum powder or glyceryl behenate.
8. The candesartan cilexetil-containing capsule formulation according to claim 7, wherein: the low-melting-point oily compound is polyethylene glycol;
the diluent 2 is one or two of lactose and corn starch;
the adhesive is hydroxypropyl cellulose;
the disintegrant is croscarmellose sodium;
the lubricant is magnesium stearate.
9. The candesartan cilexetil-containing capsule formulation according to claim 1, wherein: the capsule shell is selected from gelatin capsule shell or hydroxypropyl methylcellulose capsule shell.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112294769A (en) * | 2020-10-27 | 2021-02-02 | 浙江诺得药业有限公司 | Candesartan cilexetil orally disintegrating tablet and preparation method thereof |
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Application publication date: 20200327 |