CN112294769A

CN112294769A - Candesartan cilexetil orally disintegrating tablet and preparation method thereof

Info

Publication number: CN112294769A
Application number: CN202011163433.0A
Authority: CN
Inventors: 胡小艳; 丁南南; 殷学治; 计莹
Original assignee: Zhejiang Nord Pharmaceutical Co ltd; Zhejiang Tianyu Pharmaceutical Co Ltd
Current assignee: Zhejiang Nord Pharmaceutical Co ltd; Zhejiang Tianyu Pharmaceutical Co Ltd
Priority date: 2020-10-27
Filing date: 2020-10-27
Publication date: 2021-02-02

Abstract

The invention discloses a candesartan cilexetil orally disintegrating tablet and a preparation method thereof, wherein the candesartan cilexetil orally disintegrating tablet comprises the following steps: half of the pellets of candesartan cilexetil with a therapeutically effective amount, the remaining candesartan cilexetil mixed with the pellets, and other pharmaceutically acceptable excipients. The pellet adopts a mixture of microcrystalline cellulose and sodium alginate with equal mass as a base material, and is prepared into a pellet core with candesartan cilexetil by a fluidized bed granulation method and then is coated with HPMC. The pharmaceutically acceptable auxiliary materials comprise a diluent, an adhesive, a disintegrating agent, a flavoring agent, a lubricant and a glidant. The candesartan cilexetil orally disintegrating tablet prepared by the invention has smooth surface form, can be rapidly disintegrated in oral cavity without gritty feeling, can be completely disintegrated within 1min, and the dissolution rate in a phosphate buffer solution within 30min can reach more than 90%.

Description

Candesartan cilexetil orally disintegrating tablet and preparation method thereof

Technical Field

The invention relates to the field of medicinal preparations, in particular to an orally disintegrating tablet of candesartan cilexetil for treating type II diabetes and a preparation method thereof.

Background

Candesartan Cilexetil (Candesartan cilxetil), chemical name: (±) -1- [ [ (cyclohexyloxy) carbonyl ] oxo ] ethyl-2-ethoxy-1- [ [2'- (1H-tetrazolyl-5) - [1,1' -biphenyl ] -4-yl ] methyl ] -1H-benzimidazole-7-carboxylate. The molecular formula is as follows: C33H34N6O6, structural formula as follows:

clinically, candesartan cilexetil is used for angiotensin ii receptor antagonism in the treatment of hypertension. The candesartan cilexetil is rapidly hydrolyzed in vivo into the active metabolite candesartan, which is a selective angiotensin ii receptor (ATl) antagonist and antagonizes the vasoconstrictive action of angiotensin ii by binding to vascular smooth muscle ATl receptors, thereby reducing peripheral vascular resistance. In addition, it is believed that: candesartan can exert a certain antihypertensive effect by inhibiting secretion of aldosterone by the adrenal gland. Candesartan does not inhibit kininase ii and does not affect bradykinin degradation. Therefore, this type of drug has been a competitive player in the hypertensive market, compared to angiotensin converting enzyme inhibitor (ACE-i), which has increased hypotensive effects with reduced side effects and does not cause coughing, and also has vasoprotective, renal and cardioprotective effects. The commercially available dosage form is a tablet.

The candesartan cilexetil is a precursor drug of candesartan, is rapidly and completely hydrolyzed into the candesartan during the gastrointestinal tract absorption, the absolute bioavailability of the candesartan is about 15%, and the peak reaching time of plasma candesartan concentration is 3-4 hours. The binding rate of the candesartan and the plasma protein is more than 99 percent, and the apparent distribution volume is 0.13L/kg. Rat experiments demonstrated that candesartan rarely passes the blood brain barrier, but can penetrate the placental barrier and distribute to the fetus. In vivo, candesartan is excreted mainly in its original form through urine and feces, and very little part of candesartan produces inactive metabolite in liver through O-deacetylation reaction. The excretory half-life of candesartan is about 9 hours. The product is orally taken by patients with hypertension for 2-L6 mg/day for 4 weeks, the plasma clearance rate of candesartan is 14.07L/h, and the terminal elimination half-life period is 9-L3 hours. The data show that the total clearance rate of the candesartan is 0.37 ml/min-kg, the kidney clearance rate is 0.19ml, and 33 percent and 67 percent of radioactive substances are respectively recovered from urine and feces after the 14C marked candesartan cilexetil is orally taken.

Chinese patent application with publication number CN110638764A discloses a candesartan cilexetil quick-release pellet, which sequentially comprises a blank pellet core and a drug-loaded layer from inside to outside; the blank pellet core consists of sucrose and starch, and the particle size of the blank pellet core is 0.2-0.3 mm; the drug-loaded layer is composed of candesartan cilexetil, lactose monohydrate, pregelatinized starch, hydroxypropyl cellulose and polyvinyl alcohol-polyethylene glycol copolymer, wherein the particle size distribution D90 of the candesartan cilexetil is less than 10 um; the mass ratio of the blank pill core to the medicine carrying layer is (5-10): (8-12). The powder lamination preparation process is adopted for production, and can be used for filling capsules. Compared with the marketed candesartan cilexetil tablets, the candesartan cilexetil quick-release pellet prepared by the invention can avoid the degradation of candesartan cilexetil caused by overhigh local temperature during tabletting, and has high quality stability.

The Chinese application with the publication number of CN201210424430.7 discloses a candesartan cilexetil double-release capsule and a preparation method thereof, wherein the content of each capsule is formed by mixing quick-release particles and slow-release particles according to the weight ratio of 1.0: 0.5-2.0, and the quick-release candesartan cilexetil solid dispersion consists of candesartan cilexetil and a water-soluble carrier; the slow release granule is prepared by coating quick release granule with slow release retardant. Solves the technical problems of slow dissolution speed, short onset time and poor blood concentration persistence of the existing candesartan cilexetil preparation.

The orally disintegrating tablet solves the problems of slow effect and inconvenient taking of the tablet, and the medicament does not need to be chewed when being placed in the oral cavity, and can take effect after being rapidly disintegrated by saliva and entering the stomach by swallowing. Is convenient for patients to use, especially for the elderly, children, patients with dysphagia and special conditions without water availability. Therefore, the problem to be solved is to prepare the candesartan cilexetil orally disintegrating tablet which can be disintegrated in oral cavity rapidly without water and has good taste. At present, no report about candesartan cilexetil orally disintegrating tablets exists.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides the candesartan cilexetil orally disintegrating tablet and the preparation method thereof. Completely disintegrated in 2ml of water within 1min and passed through a 40 mesh sieve. The dissolution rate in the phosphate buffer solution within 30min can reach more than 90%. The preparation method is simple in process and suitable for industrial production.

In order to solve the problems in the prior art, the technical solution adopted by the invention is as follows:

a candesartan cilexetil orally disintegrating tablet comprising: comprises a micropill of partial candesartan cilexetil with effective treatment dose, the micropill is coated, partial candesartan cilexetil mixed with the micropill and other pharmaceutically acceptable auxiliary materials.

The pellet is prepared by granulating microcrystalline cellulose and candesartan cilexetil accounting for 1/2 of the total mass of the main medicaments by a fluidized bed. Preferably, the mixture of microcrystalline cellulose and sodium alginate is used as a base material, so that the slow release of candesartan cilexetil in the pellet can be better maintained.

The coating is to coat the HPMC sustained-release layer on the surface of the pellet by adopting a fluidized bed.

By adopting the technical scheme of the invention, part of candesartan cilexetil is coated in the pellet and slowly released under the action of the HPMC coating layer to continuously play a role in reducing blood pressure, and part of candesartan cilexetil is positioned outside the coated pellet, is mixed with other auxiliary materials and the pellet, is prepared into orally disintegrating tablets after wet granulation and tabletting, and is rapidly disintegrated in oral cavity, so that the drug effect can be more rapidly played compared with the traditional tablets. The candesartan cilexetil is uniformly distributed in the pellet and the outer layer of the excipient, while the coated pellet is uniformly dispersed in the orally disintegrating tablet.

The pharmaceutically acceptable auxiliary materials comprise a diluent, an adhesive, a disintegrating agent, a flavoring agent, a lubricant and a glidant.

In detail, in every 100g of orally disintegrating tablet raw materials, the mass of each raw material is as follows: (unit: g)

The candesartan cilexetil accounts for 1-45 g, preferably 4-30 g

The diluent (filler) accounts for 10-85 g, preferably 20-60 g. Is selected from one or more of pregelatinized starch, mannitol, lactose, and crospovidone.

The adhesive accounts for 20-95 g, preferably 40-85 g, more preferably 70-80 g, and water is used as an adhesive solvent in the invention.

The disintegrating agent accounts for 1-60 g, preferably 5-45 g, and is one or a mixture of more than two of microcrystalline cellulose, pregelatinized starch, crospovidone and L-hydroxypropyl cellulose. Preferably, the disintegrant is L-hydroxypropyl cellulose.

The flavoring agent accounts for 0.01-10 g, preferably 0.5-3 g, and more preferably 1 g. The correctant is one or mixture of aspartame and sodium cyclamate.

The lubricant accounts for 0.1-15 g, preferably 0.5-3 g, and more preferably 1 g; selected from magnesium stearate or talc.

The flow aid accounts for 0.1-12 g, preferably 0.5-3 g, and more preferably 1 g; selected from silica gel micropowder.

The candesartan cilexetil orally disintegrating tablet is obtained by wet granulation, and comprises the following steps:

(1) microcrystalline cellulose, sodium alginate, 1/2 parts of candesartan cilexetil and a part of adhesive, and water as a solvent are prepared into the pellets by a fluidized bed granulation method.

(2) Coating the surface of the pellet by a fluidized bed method, wherein the adopted coating solution is an HPMC coating film. The coated pellets obtained after the coating treatment had an average particle size of about 100. mu.m.

(3) Wet granulating the pellet with the rest candesartan cilexetil and binder solution in the adjuvants, drying, adding lubricant, disintegrant, correctant, and glidant into the dried pellet, grading, and tabletting.

Has the advantages that:

1. the candesartan cilexetil orally disintegrating tablet prepared by the invention has smooth surface morphology and no gritty feeling.

2. The tablet is quick to disintegrate, can completely disintegrate in 2ml of water within 1min and passes through a 40-mesh sieve, and the existing tablet can completely disintegrate after 4 min.

3. The dissolution rate is high, and the dissolution rate can reach more than 90% in 30min when phosphate buffer is used as a dissolution medium.

4. The method is simple, low in energy consumption and suitable for industrial production.

5. The gastrointestinal mucosa has small stimulation, the main medicines uniformly distributed in the orally disintegrating tablets uniformly enter the stomach after the orally disintegrating tablets are rapidly disintegrated, and the main medicines in the pellets are mainly released and absorbed in the intestinal tract under the protection of HPMC, so that the main medicine amount in the stomach is reduced, and the bioavailability is better.

Drawings

Fig. 1 is a dissolution profile of candesartan cilexetil orally disintegrating tablets prepared in example 1 of the present invention in phosphate buffer.

Figure 2 is the dissolution profile of candesartan cilexetil tablets in phosphate buffer.

Fig. 3 is a plot of blood concentration versus time for orally disintegrating tablets of candesartan cilexetil versus commercially available tablets.

Detailed Description

The present invention will be described in further detail with reference to the following drawings and examples.

The mass of each raw material of the orally disintegrating tablets prepared in examples 1 to 4 is shown in table 1: (unit: g):

TABLE 1

Note: the number of tablets pressed is measured according to the conventional tablet weight of orally disintegrating tablets

Appearance: the candesartan cilexetil orally disintegrating tablets prepared in examples 1-4 are off-white and have a smooth surface morphology.

In vitro disintegration: putting 1 piece of the prepared candesartan cilexetil orally disintegrating tablet into 2ml of water with the temperature of 37 ℃, standing, completely disintegrating within 37 seconds, and completely disintegrating and passing through a 40-mesh sieve.

Dissolution rate: the candesartan cilexetil orally disintegrating tablet 6 prepared in example 2 was taken and the dissolution rate was examined for 30min by using phosphate buffer solution with pH6.5 as dissolution medium, as shown in FIG. 1. (second appendix XC of the second part of the Chinese pharmacopoeia 2010 edition).

Example 5 the candesartan cilexetil orally disintegrating tablets prepared in example 2 were subjected to stability tests, and the specific test conditions, test times, test items and test results are shown in tables 2 and 3:

TABLE 2

TABLE 3

Example 6 the candesartan cilexetil orally disintegrating tablets and the ordinary candesartan cilexetil tablets prepared in example 2 were subjected to in vivo pharmacokinetic studies in beagle dogs.

Selecting 6 healthy beagle dogs with male and female halves and 20-21kg body weight, randomly dividing the 6 healthy beagle dogs into a candesartan cilexetil orally disintegrating tablet group (tested preparation) and a candesartan cilexetil tablet group (reference preparation) by adopting a double-cycle cross administration method for testing, taking 1 candesartan cilexetil orally disintegrating tablet and 1 candesartan cilexetil tablet respectively for 3 dogs, collecting about 4ml of blood from the forelimb vein of the dog after 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 24 and 36h after administration, separating serum, preserving the blood in a refrigerator at-20 ℃, detecting, stopping administration for one week, and performing cross test by adopting the same method.

The main pharmacokinetic parameters are shown in table 4. The results show that the processes in vivo of the candesartan cilexetil orally disintegrating tablets and the candesartan cilexetil tablets are basically consistent. The blood concentration-time curves of the candesartan cilexetil orally disintegrating tablets and the commercially available tablets are shown in fig. 3.

TABLE 4

And calculating the relative bioavailability F of the candesartan cilexetil orally disintegrating tablet according to the area under the blood concentration time curve (AUC) of the beagle dog after the test reagent T box and the reference preparation R are taken alternately.

F=AUC_T/AUC_R×100%=503/489=102%。

Claims

1. A candesartan cilexetil orally disintegrating tablet, comprising: a therapeutically effective amount of a portion of the amount of candesartan cilexetil pellets, the remainder of candesartan cilexetil mixed with the pellets, and other pharmaceutically acceptable excipients;

the pellet adopts a mixture of microcrystalline cellulose and sodium alginate with equal mass as a base material, and is coated after being prepared into a pellet core with candesartan cilexetil by a fluidized bed granulation method.

2. The candesartan cilexetil orally disintegrating tablet according to claim 1, wherein the portion that constitutes a therapeutically effective amount is half the mass.

3. The candesartan cilexetil orally disintegrating tablet according to claim 1, wherein the pellet coating is prepared by coating the surface of the pellet with a HPMC sustained release layer by using a fluidized bed.

4. The candesartan cilexetil orally disintegrating tablet according to claim 1, wherein the pharmaceutically acceptable excipients comprise diluents, binders, disintegrants, flavoring agents, lubricants and glidants.

5. The candesartan cilexetil orally disintegrating tablet according to claim 4, wherein the mass of each raw material and each auxiliary material in each 100g of orally disintegrating tablet is as follows: (unit: g)

1-45 g of candesartan cilexetil

The diluent accounts for 10-85 g

The adhesive accounts for 20-95 g

The disintegrating agent accounts for 1-60 g

0.01-10 g of flavoring agent

0.1-15 g of lubricant

The flow aid accounts for 0.1-12 g.

6. The candesartan cilexetil orally disintegrating tablet according to claim 4, wherein the mass of each raw material is as follows per 100g of orally disintegrating tablet raw materials: (unit: g)

The candesartan cilexetil accounts for 4-30 g

The diluent accounts for 20-60 g

70 g-80 g of adhesive

The disintegrating agent accounts for 5-45 g

0.5-3 g of flavoring agent

0.5-3 g of lubricant

The flow aid accounts for 0.5-3 g.

7. The candesartan cilexetil orally disintegrating tablet according to claim 4,

the diluent is selected from one or more of pregelatinized starch, mannitol, lactose, and crospovidone;

the disintegrating agent is one or more of microcrystalline cellulose, pregelatinized starch, crospovidone and L-hydroxypropyl cellulose, and the correctant is one or more of aspartame and sodium cyclamate;

the lubricant is selected from magnesium stearate or pulvis Talci;

the glidant is selected from aerosil.

8. The process for the preparation of candesartan cilexetil orally disintegrating tablets according to claim 2, characterized by the following steps:

(1) mixing microcrystalline cellulose, sodium alginate and the like, mixing with part of candesartan cilexetil and part of adhesive which account for effective treatment amount, taking water as a solvent, and preparing into pellets by a fluidized bed granulation method;

(2) coating the surface of the pellet by a fluidized bed method, wherein the adopted coating solution is an HPMC coating film; the average particle size of the coated pellets after coating treatment is about 100 mu m;