KR20100112934A - Oral composition containing candesartan cilexetil - Google Patents

Abstract

PURPOSE: A composition for oral administration containing dandesartan cilexetil with improved storage stability is provided to ensure drug stability. CONSTITUTION: A composition for oral administration containing candesartan cilexetil contains 20-40 weight% of maltodextrin and pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is filler, binder, disintegrant, lubricant or coloring agent. The composition is used in the form of tablet or capsule.

Description

Ordes composition containing candesartan cilexetil with improved storage stability

The present invention relates to a composition for oral administration containing candesartan cilexetil containing improved storage stability.

The non-peptide candesartan cilexetil is (ㅁ) -1-[[(cyclohexyloxy) carbonyloxy)] ethyl 2-ethoxy-1-[[[2 '-(1H-tetrazol-5-yl) )] 1,1'-biphenyl-4-yl] -methyl] -1H-benzimidazole-7-carboxylic acid. Candesartan cilexetil is a biphenyl tetrazole compound that is particularly useful as an angiotensin II antagonist in the treatment of circulatory diseases such as hypertension, heart disease (eg hypercardia, heart failure, myocardial infarction, etc.), seizures, stroke, and nephritis. to be. The compound is cande chemically 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] -methyl] -1H-benzimidazole-7-carboxylate Satan's ester prodrug.

Candesartan cilexetil is a white to gray powder and water insoluble.

In the field of hypertension treatment, angiotensin II receptor antagonists have been noted as effective hypertension therapeutics. Candesartan cilexetil contains one chiral center in the cyclohexyloxycarbonyloxy ethyl ester group, and upon oral administration to the human body, the compound undergoes hydrolysis at the ester bond, converting it to the active drug candesartan (which is achiral). do. Candesartan cilexetil is rapidly and fully bioactive to candesartan, an optional ATi subtype angiotensin II receptor antagonist, by ester hydrolysis during absorption from the gastrointestinal tract. Such compounds fall into the class of benzimidazole-7-carboxylic acids and derivatives thereof. The agents exhibit stronger and more effective blood pressure lowering action than other classes of ACE inhibitors.

Candesartan cilexetil is stable to temperature, moisture and light when alone in the solid state. However, when the compounds are prepared in tablets and integrated with other ingredients, due to the deformation of the crystals caused by pressure, abrasion and heat, the active ingredient is subjected to, for example, granulation or molding steps under elevated pressure during the manufacturing process. It was observed to degrade over time.

U. S. Patent No. 5,534, 534 discloses that by incorporating an oily substance having a low melting point in the pharmaceutical composition, candesartan cilexetil in the pharmaceutical composition can be degraded over time to reduce its decrease in content. According to this patent, the oily material is integrated with the active ingredient to form a stable composition that inhibits the degradation over time caused by compression.

The stability of the candesartan cilexetil pharmaceutical composition is associated with desethyl candesartan and various other degradation products, with increasing levels of desethyl candesartan resulting in unstable or less stable formulations.

Accordingly, the present inventors have completed the present invention by confirming that the candesartan composition including maltodextrin has improved storage stability as a result of research efforts to prepare the improved candesartan composition.

Accordingly, an object of the present invention is to provide a composition for oral administration of candesartan cilexetil containing improved storage stability.

The invention is characterized by an oral dosage composition comprising candesaltan cilexetil and 20-40% by weight of maltodextrin, based on the total composition.

Oral dosage compositions according to the present invention have excellent drug stability under various formulation preparation and storage conditions.

Hereinafter, the present invention will be described in detail.

The present invention relates to a composition for oral administration in which candesartan cilexetil is used as an active ingredient and maltodextrin as a stabilizer is used in an amount of 20 to 40% by weight of the entire composition to improve stability of the active ingredient in the composition.

The present invention relates to a stable oral dosage form in tablet form or other solid form that solves the problems associated with degradation of the active ingredient candesartan cilexetil, and a method for preparing the same.

Embodiments of the composition may include one or more of the following features. For example, the pharmaceutical composition may be a solid dosage form selected from the group comprising tablets, granules, pellets and powders. Preferably, tablet and capsule forms are used, most preferably tablet forms.

The term 'candesartan cilexetil' as used herein refers to prodrugs that are hydrolyzed to candesartan during absorption from the gastrointestinal tract. The content of the active ingredient candesartan cilexetil is 1 to 30% by weight, more preferably 2 to 14% by weight based on the total composition.

As the stabilizer used in the present invention, maltodextrin is preferable, and it is 20 to 40% by weight, preferably 25 to 40% by weight, more preferably 30 to 40% by weight, most preferably 35 to 40% based on the total composition. Use weight percent. It was confirmed by the experiment that the stability of the formulation prepared with the composition falls outside the above range.

In addition, the oral dosage composition according to the present invention may include one or more pharmaceutically acceptable excipients in addition to maltodextrin as an active ingredient and stabilizer. Its content is preferably 30 to 70% by weight based on the total composition.

Pharmaceutically acceptable excipients suitable for the present invention include one or more selected from fillers, binders, disintegrants, lubricants and colorants.

The fillers include corn starch, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, sorbitol, pregelatinized starch, white sugar, glucose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate And sucrose and mixtures thereof.

The binder is one of methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, ethylcellulose, polyvinyl alcohol, pregelatinized starch, tragacanth, sodium alginate, propylene glycol and mixtures thereof It may be abnormal.

The disintegrant may be one or more of calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxy propyl cellulose and mixtures thereof.

The lubricant may be one or more of colloidal silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline waxes, yellow beeswax, white beeswax and mixtures thereof.

The compositions of the invention can be prepared by methods known in the art, for example by wet granulation, dry granulation or direct compression. The final dosage form may be in the form of a tablet or capsule.

Candesartan cilexetil tablets are granulated with maltodextrin; Drying of the granules; Sizing and lubrication of the granules; And by squeezing the lubricated granules.

In another embodiment, the candesartan cilexetil tablet comprises: dispersing candesartan cilexetil in a maltodextrin solution; Granulating with at least one filler and at least one disintegrant in a fluid bed processor; Drying the granules; Sizing and lubricating the granules; It can be prepared by pressing the lubricated granules.

In another embodiment, the candesartan tablet comprises dispersing candesartan cilexetil in a maltodextrin solution; Spray drying in a spray dryer; Blending with one or more fillers, binders and disintegrants; Lubricating the blend; It can be prepared by pressing the lubricated blend.

In addition, the present invention can produce a stable composition by tableting at a pressure of less than 9 KP, preferably 3 to 8 KP, more preferably 3 to 7 KP.

The dosage of the composition according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. The oral dosage of candesartan cilexetil is to use 8 to 32 mg once or twice daily for the treatment of essential hypertension, heart failure, and the like. The total weight of the composition thus prepared is generally from 10 to 400 mg.

Hereinafter, the present invention will be described in more detail based on Examples, but the present invention is not limited to the following Examples.

Examples 1-4: Tablet Preparation Using High Speed Mixer Granulator

The tablets were prepared as follows in the composition and content of Table 1.

Candesartan cilexetil and 1 part maltodextrin were granulated with purified water in a high speed mixer. The wet granules were then dried in a tray dryer, passed through a screen and sized to produce granules. The remaining portions of maltodextrin, MCC (microcrystalline cellulose) or lactose monohydrate, corn starch, L-HPC (hydroxypropyl cellulose) 11 or HPC-L, CMC.Ca (calcium carboxymethyl cellulose) are passed through the screen and the granules And blended. Magnesium stearate was passed through the screen, lubricated with the blend, and the mixture was compressed to make a tablet.

TABLE 1

Examples 5-6: Tablet Preparation Using Fluidized Bed Granulator

The tablets were prepared as follows in the composition and content of Table 2.

Candesartan cilexetil and 1 part maltodextrin were dispersed in purified water. The remaining portions of maltodextrin, starch and L-HPC were mixed in a fluid bed granulator and granulated with the dispersion. The dried granules were then passed through a screen and sized to produce granules. The MCC or lactose monohydrate and CMC.Ca were passed through a screen and blended with the granules. The magnesium stearate was passed through a screen, lubricated with the blend, and the mixture was compressed to make a tablet.

TABLE 2

Examples 7-9: Tablet Preparation Using Spray Drying

The tablets were prepared as follows in the composition and content of Table 3.

Candesartan cilexetil and 1 part maltodextrin were dispersed in purified water. The dispersion was spray dried and powder was obtained using a spray dryer. The remaining portion of maltodextrin, MCC or lactose monohydrate, corn starch, L-HPC 11 or HPC-L, CMC Ca was passed through the screen and blended with the powder. The magnesium stearate was passed through a screen, lubricated with the blend, and the mixture was compressed to make a tablet.

[Table 3]

Comparative Examples 1 to 7

The tablets were prepared in the same manner as in Examples 5 to 6, using the same ingredients and contents as in Table 4 below.

[Table 4]

Experimental Example 1: Stability Test

Tablets prepared as in Examples 1 to 9 and Comparative Examples 1 to 7 were stored at 40 ° C./75% RH for 2 weeks, and stability tests were performed. The stability of the formulations was confirmed by the amount of desethyl candesartan and 2-N-ethyl CNS, which are degradation products of candesartan cilexetil, and measured by HPLC are shown in Tables 5 and 6 below. The same test was performed for commercial Atacand ™ 32.

TABLE 5

TABLE 6

As shown in Table 5 and Table 6, it was confirmed that the composition of the present invention is superior in stability to the comparative example and the control.

Experimental Example 2: Stability Test According to Hardness

The tablets having the following five hardnesses were prepared using the composition of Example 6, and then the results of the accelerated stability test for 2 weeks as in Experimental Example 1 are shown in Table 7 below.

TABLE 7

As shown in Table 7, the composition of the present invention showed stability in the range of less than 9 KP.

Claims (4)

A composition for oral administration of candesartan cilexetil containing candesaltan cilexetil, 20 to 40% by weight of maltodextrin in the total composition, and a pharmaceutically acceptable excipient. The composition of claim 1, wherein the pharmaceutically acceptable excipient is at least one selected from fillers, binders, disintegrants, lubricants and colorants. The composition of claim 1 or 2, wherein the composition is formulated in a tablet or capsule. The composition of claim 3, wherein the tablet has a hardness of 3 to 8 KP.