KR100441745B1 - Composition of itraconazole for oral administration and process for preparing thereof - Google Patents

Abstract

The present invention relates to a composition for oral administration of itraconazole, comprising itraconazole and a saccharide-based surfactant in the form of a solid melt, and more particularly, to a method for preparing oral administration of itraconazole and a saccharide-based surfactant. By changing the crystallinity of the solubility, the solubility and dissolution rate is increased, has a high wettability, can contain a high content of the drug in one unit, and the manufacturing process is easy and reproducible, economical and human-safe properties It relates to a composition for oral administration of itraconazole having a.

Description

Composition for oral administration of itraconazole and its preparation method {Composition of itraconazole for oral administration and process for preparing}

The present invention relates to a composition for oral administration of itraconazole comprising itraconazole and a saccharide-based surfactant in the form of a solid melt, and a method for preparing the same.

Itraconazole, an azole antifungal agent, has a chemical name of (±) -cis-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2 (1H-1,2,4-triazole) -1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H An antifungal compound having a broad spectrum developed for oral, parenteral and topical use with -1,2,4-triazol-3-one is disclosed in US Pat. No. 4,267,179.

The development of pharmaceutical compositions having the efficacy of azole antifungal agents such as itraconazole is considerably limited by the fact that the antifungal agents are almost insoluble in water.

In general, methods for increasing the solubility of the compounds include the formation of complexes using cyclodextrins and derivatives thereof (WO 85/02767, US Pat. No. 4,764,604), bead formulations using water-soluble polymers and drugs (international Publication No. 94/05263), preparation of solid dispersions by melt-extrusion using water-soluble polymers and drugs (International Publication No. 97/44014), eutectic using organic acids and drugs Preparation of the mixture (Korean Patent Publication No. 1999-001565), Preparation of the melt mixture using sugars and drugs (Korean Patent Publication No. 1999-051527), Preparation of the melt dispersion using phosphoric acid and the drug (Korean Patent Publication No. 2001 -002590) and the preparation of a solid dispersion using a pH-dependent water-soluble polymer and drugs (Korean Patent Publication No. 1999-062448).

However, among these methods, the use of clathrate compounds of itraconazole and cyclodextrin (WO 85/002767 and US Pat. No. 4,764,604) hardly improves the solubility of itraconazole in water, The production process is also undesirable because it requires several complex steps to form inclusions.

On the other hand, the bead formulation using a water-soluble polymer and a drug has a three-layer structure in which itraconazole and a hydrophilic polymer are coated on a core made of pharmaceutically inert or neutral sugar, dextrin, and starch, and then coated with a polymer such as polyethylene glycol. It is developed and marketed by Janssen Corporation (International Publication No. 94/05263, trade name; Sporanox capsule). However, this method uses a small core having a diameter of 600 to 700 ㎛, there is a difficulty in the production process, such as agglomeration occurs during the coating process.

In addition, the bioavailability of itraconazole is increased and is hardly affected by food, which has been a problem of conventional commercial formulations. A water-soluble polymer mixture such as itraconazole and hydroxypropyl methylcellulose is prepared according to a melt-extrusion method. Although solid dispersions have been developed in which melted itraconazole is dispersed in an unmelted water-soluble polymer by heating to 245 to 265 ° C. (International Publication No. 97/44014, product name; Sporanox tablet, Janssen), The melt-extrusion process has to be carried out at a high temperature of 245 to 265 ° C., and the molten extraconazole must be dispersed very uniformly in the polymer. It is difficult to obtain a reproducible product because it can affect absorption. There is.

In addition, the preparation of eutectic mixtures using drugs and organic acids (Korean Patent Publication No. 1999-001565), the preparation of melt mixtures using drugs and sugars (Korean Patent Publication No. 1999-051527) or melting using drugs and phosphoric acid In the case of dispersion preparation (Korean Patent Publication No. 2001-002590), solubility can be increased only by preparing a solid dispersion using an excipient in an amount equal to or greater than the amount of the drug, and formulated into a pharmaceutical formulation. In order to achieve a powder form, it is not easily wetted by water due to the electrostatic force of the powder and the hydrophobicity of the drug, so that it is not easy to exhibit a rapid dissolution rate by eutectic mixture, melt mixture or melt dispersion alone. In addition, in the case of the melt dispersion using the drug and phosphoric acid, there is a problem that the strong acidic phosphoric acid is used to increase the solubility and improve the dissolution rate, and thus may cause irritation to the stomach during oral administration.

In addition, since the pH-dependent water-soluble polymer and the solid dispersion using the drug (Korean Patent Publication No. 1999-062448) have to use an organic solvent such as methylene chloride to dissolve the drug and the polymer during the manufacturing process, the method is not environmentally friendly There is a difficulty in the production process that requires careful attention because there is a possibility of residual solvent remaining during incomplete drying.

Itraconazole, on the other hand, is filled into hard-gelatin capsules (size 0), or about 460 mg of tablets, which is equivalent to 100 mg of itraconazole, which is made up of about 460 mg of tablets, which in many countries are Sporanox ^TM . It is marketed under the brand name. These capsules or tablets are given once daily to patients suffering from fungal infections. This can significantly limit the patient from easily following his regimen. For example, some patients are unable to eat or swallow the medication normally due to illness, nausea or fungal infections of the esophagus. Therefore, it is required in the pharmaceutical development of itraconazole to provide a dosage form containing a high content of a drug containing the daily necessary amount of the active ingredient in one unit instead of two units, but the above-described prior art amounts of excipients used. Its development is limited. Although the preparation of a solid dispersion by melt-extrusion using water-soluble polymers and drugs (International Publication No. 97/44014) provides a composition for a tablet containing 200 mg as itraconazole, the coating is applied. The final tablet weighs 924.7 mg, which is not easy to take.

As a result of the diligent efforts of the present inventors to solve the above problems of the prior art, the saccharide-based surfactant easily forms a solid melt in a small amount with itraconazole, so that the solubility and dissolution rate are improved, and high wettability without addition of other excipients. It is confirmed that the carrier to provide a high content of the drug in one unit through the use of a small excipient, and to provide an economical and safe composition for itraconazole it is easy and reproducible manufacturing process The invention was completed

Fig. 1 shows the dissolution rates of the capsules of the itraconazole-sucrose monopalmitate solid melt prepared in Example 7 and the capsules filled with the itraconazole raw material in the capsules (○: Itraconazole raw material capsules ●: Itraconazole-sucrose monopalmi) Tate solid melt capsule).

Figure 2 shows the comparison of the dissolution rate of the commercially available itraconazole-sucrose monopalmitate solid melt prepared in Example 9 with the commercially available Sporanox capsule (○: Sporanox capsule ●: Purification of the itraconazole-sucrose monopalmitate solid melt ).

The present invention relates to a composition for oral administration of itraconazole comprising itraconazole and a saccharide-based surfactant in the form of a solid melt, and a method for preparing the same.

In the composition of the present invention, the mixing ratio of itraconazole and the saccharide-based surfactant forming the solid melt is preferably in a weight ratio of 1: 0.1 to 10, more preferably 1: 0.5 to 5.

The saccharide-based surfactant used as the melt carrier in the composition of the present invention is not only able to significantly increase the solubility of itraconazole, but also to form a solid state well when formulated.

As such a saccharide-based surfactant, it is preferable to use one in which one or more fatty acid derivatives are esterified in one sugar (sucrose). Representative examples of such saccharide-based surfactants are sucrose monostearate, sucrose distearate (trade name: sucrose ester 7, manufacturer: Gattefosse), sucrose mono-distearate (Sucrose mono) -distearate; trade name: sucrose ester 11, manufactured by Gattefosse, sucrose monopalmitate; trade name: sucrose ester 15, manufactured by Gattefosse, sucrose dipalmitate, sucrose monolau Sucrose monolaurate, Sucrose diraurate, Sucrose monooleate, Sucrose dioleate, Sucrose monocaprate, Sucrose dicaprate ( Sucrose dicaprate, Sucrose monocaprylate, Sucrose dicaprylate, Sucrose monomyris Tate (Sucrose monomyristate), sucrose dimyristate (Sucrose dimyristate), sucrose monolinolenate (Sucrose monolinolenate), sucrose dilinolinate (Sucrosedilinolenate) and the like, in the present invention, these as sugar-based surfactant One or two or more selected from among them may be used in combination.

Solid melt in the composition of the present invention, in order to increase the powder properties of the solid preparation, lactose, dextrin, starch, microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, Polyethylene glycol, polyoxyethylene glycolated natural or hydrogenated castor oil derivatives, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsul Trans-esterification reaction products of monosuccinate or sodium lauryl sulfate, phospholipids, propylene glycol mono-fatty acid esters or propylene glycol di-fatty acid esters, natural vegetable oils triglycerides and polyalkylene polyols, mono, di- or mono / Di-glycerides, sorbate A carbon fatty acid one or more excipients selected from an ester, silicon dioxide, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, aluminum silicate, magnesium aluminum metasilicate, the group consisting of bentonite can be made by further comprising. In addition, such excipients may be included in the composition of the present invention together with the solid melt prepared previously.

The method for producing a solid melt in a composition of the present invention is as follows. First, itraconazole and saccharide-based surfactants are mixed, and then, heated to 140 ° C to 200 ° C to homogeneously melt, and solidified by solidifying on ice water while cooling the molten mixture, followed by grinding to prepare a solid melt.

In the above process, during the cooling of the mixture, a solid acceptable melt may be prepared by further adding a pharmaceutically acceptable excipient and solidifying it on ice water to grind it.

A pharmaceutically acceptable excipient may be added to the solid melt prepared by the above method as needed to prepare a composition for oral administration of itraconazole according to the present invention.

The composition of the present invention may be prepared in the form of tablets, capsules, granules, fine granules, liquid preparations, suspensions or syrups, for example, solid melts are filled directly into the hard capsules in the form of powders or granules or solids. A method of filling a hard capsule in the form of powder or granules by adding a lubricant and other pharmaceutical additives to the melt, or by adding a pharmaceutical additive necessary for tableting and tableting the tablet, dissolving the solid melt in an aqueous solution to a liquid formulation. It may be formulated according to the method of formulating, the preparation of suspension or syrup by adding pharmaceutically acceptable thickener or syrup to powder or granule of solid melt.

When the composition of the present invention is prepared in a dosage form selected from tablets or capsules, since the saccharide-based surfactant easily forms a solid melt even in small amounts with itraconazole, it can be formulated to contain up to 200 mg of itraconazole in one unit, In this case the weight of the formulation can be made up to 900 mg, at least 320 mg. Accordingly, the present invention can provide a formulation that eliminates the inconvenience of taking conventional formulations by size. That is, since the size of the patient can easily take a formulation containing 200 mg of the drug, one capsule or one tablet can be used to finish the administration once, and thus the administration side or the patient taking it is convenient. In particular, it may be of great help to patients who cannot or cannot swallow the formulation normally.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention in more detail, whereby the scope of the present invention is not limited.

Example 1 Preparation of Itraconazole-Sugar Surfactant Solid Melt (1 / 0.5)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Put 15 g of sucrose monopalmitate (trade name: Sucrose ester 15, manufacturer: Gattefosse) into the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final melt of itraconazole-saccharide surfactant.

Example 2 Preparation of Itraconazole-saccharide Surfactant Solid Melt (1 / 0.5)

A solid melt was prepared in the same manner as in Example 1 except that sucrose mono-distearate (trade name: Sucrose ester 11, manufactured by Gattefosse) was used instead of sucrose monopalmitate as a saccharide-based surfactant.

Example 3 Preparation of Itraconazole-saccharide Surfactant Solid Melt (1 / 0.5)

A solid melt was prepared in the same manner as in Example 1 except that sucrose distearate (trade name: sucrose ester 7, manufacturer: Gattefosse) was used instead of sucrose monopalmitate as a saccharide surfactant.

Example 4 Preparation of Itraconazole-saccharide Surfactant Solid Melt (1/1)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Put 30 g of sucrose monopalmitate (trade name: Sucrose ester 15, manufacturer: Gattefosse) in the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final melt of itraconazole-saccharide surfactant.

Example 5 Preparation of Itraconazole-saccharide Surfactant Solid Melt (1/3)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Put 90 g of sucrose monopalmitate (trade name: Sucrose ester 15, manufacturer: Gattefosse) into the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final melt of itraconazole-saccharide surfactant.

Example 6 Preparation of Itraconazole-saccharide Surfactant Solid Melt (1/5)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) 150 g of sucrose monopalmitate (trade name: Sucrose ester 15, manufacturer: Gattefosse) is added to the melt and melted together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final melt of itraconazole-saccharide surfactant.

Example 7. Preparation of Hard Capsule

The itraconazole-saccharide surfactant solid melt prepared in Example 1 and calcium carboxymethyl cellulose were mixed homogeneously, and then magnesium stearate was mixed with a lubricant and filled into capsule No. 0 to prepare a capsule.

Hard capsule prescription

Itraconazole 100.0mg

Sucrose Monopalmitate 50.0mg

Calcium Carboxymethyl Cellulose 150.0mg

Magnesium Stearate 3.0mg

0 capsule

Example 8 Preparation of Hard Capsule

The itraconazole-saccharide surfactant solid melt prepared in Example 1 and calcium carboxymethyl cellulose were mixed homogeneously, and then magnesium stearate was mixed with a lubricant and filled into capsule No. 0 to prepare a capsule.

Hard capsule prescription

Itraconazole 200.0mg

Sucrose monopalmitate 100.0 mg

Calcium Carboxymethyl Cellulose 250.0mg

Magnesium Stearate 5.0mg

0 capsule

Example 9. Preparation of Tablets

After homogeneously mixing the itraconazole-saccharide-based surfactant solid melt, microcrystalline cellulose and calcium carboxymethyl cellulose prepared in Example 1 to prepare granules using a roller compactor by dry granulation method and then granules Magnesium stearate is mixed with water as a lubricant and compressed into tablets.

Tablets prescription

Itraconazole 100mg

Sucrose Monopalmitate 50mg

50mg crystalline cellulose

Calcium Carboxymethyl Cellulose 150mg

Magnesium Stearate 5mg

Example 10 Preparation of Tablets

After homogeneously mixing the itraconazole-saccharide-based surfactant solid melt, microcrystalline cellulose and calcium carboxymethyl cellulose prepared in Example 1 to prepare granules using a roller compactor by dry granulation method and then granules Magnesium stearate is mixed with water as a lubricant and compressed into tablets.

Tablets prescription

Itraconazole 200mg

Sucrose Monopalmitate 100mg

Microcrystalline Cellulose 100mg

Calcium Carboxymethyl Cellulose 250mg

Magnesium Stearate 5mg

Example 11 Preparation of Suspending Syrup

A solid melt of the itraconazole-saccharide surfactant prepared in Example 1 was added to a solution in which polyvinylpyrrolidone K30 was dissolved, and then suspended homogeneously, followed by adding a fragrance or the like to prepare a suspension syrup.

Suspension Syrup Prescription (30ml)

Itraconazole 100.0mg

Sucrose Monopalmitate 50.0mg

Polyvinylpyrrolidone K 30 100.0 mg

Strawberry flavor 4.0mg

Comparative Example 1. Preparation of Itraconazole-White Sugar Solid Melt (1 / 0.5)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Put 15 g of white sugar into the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, pulverize and apple with 60 mesh sieve to obtain final itraconazole-white solid melt.

Comparative Example 2. Preparation of Itraconazole-citric Acid Solid Melt (1 / 0.5)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Put 15 g of citric acid into the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final itraconazole-citric acid solid melt.

Comparative Example 3. Preparation of Itraconazole-PEG 20000 Solid Melt (1 / 0.5)

1) First, 30 g of itraconazole is heated and melted with stirring at about 160 to 180 ° C. to form a transparent melt.

2) Add 15 g of PEG 20000 to the melt and melt together with stirring.

3) The melt is cooled rapidly on ice water with stirring.

4) After cooling sufficiently, it is pulverized and appled into a 60 mesh sieve to obtain a final itraconazole-PEG 20000 solid melt.

Experimental Example 1. Solubility Measurement

The solubility of the itraconazole raw material, the itraconazole-saccharide surfactant solid melts prepared in Examples 1, 2, 3, 4, 5, and 6 and the itraconazole solid melts prepared in Comparative Examples 1, 2, and 3 were measured, respectively. The solubility was measured by adding excess sample to pH 1.2 artificial gastric solution and stirring at 37 ° C. for 2 hours, followed by centrifugation of the supernatant and analyzing the supernatant using high-performance liquid chromatography.

division Concentration (μg / ml) Itraconazole Raw Material 3.5 Example 1 Itraconazole-Sucrose Monopalmitate Solid Melt (1 / 0.5) 241.0 Example 2: Itraconazole-Sucrose Mono-Distearate Solid Melt (1 / 0.5) 214.6 Example 3: Itraconazole-Sucrose Distearate (1 / 0.5) 239.8 Example 4: Itraconazole-Sucrose Monopalmitate Solid Melt (1/1) 200.6 Example 5 Itraconazole-Sucrose Monopalmitate Solid Melt (1/3) 181.0 Example 6: Itraconazole-Sucrose Monopalmitate Solid Melt (1/5) 179.5 Comparative Example 1: Itraconazole-White Sugar Solid Melt (1 / 0.5) 146.3 Comparative Example 2: Itraconazole-citric acid solid melt (1 / 0.5) 40.4 Comparative Example 3: Itraconazole-PEG 20000 Solid Melt (1 / 0.5) 64.8

As can be seen from the above table, the itraconazole solubility by the solid melt of the itraconazole-saccharide-based surfactant prepared in the examples of the present invention is significantly greater than that of the itraconazole raw material itself or the various solid melts prepared in the comparative examples. You can check it.

Experimental Example 2. Dissolution Test

The dissolution test was carried out using the itraconazole capsules prepared in Example 7 and the capsules filled with the itraconazole raw material in the capsules. The dissolution test was carried out using the second method (paddle method) of the dissolution test method of the Pharmacopoeia, and the eluate was pH 1.2 artificial gastric fluid and maintained at 37 ° C. for 15 hours, 30, 45, 60, One milliliter of the sample was taken at 90 and 120 minutes, followed by centrifugation, and the supernatant was analyzed by high performance liquid chromatography.

The analysis results are shown in FIG. 1, and it was confirmed that the dissolution rate of the capsules prepared including the itraconazole-sucrose monopalmitate solid melt in Example 7 was significantly increased compared to the capsules filled with the itraconazole raw material (○: Itraconazole raw material capsule agent ●: Itraconazole- sucrose monopalmitate solid melt capsule agent).

Experimental Example 3. Dissolution Test

The dissolution test was carried out using the itraconazole tablets prepared in Example 9 and commercially available Sporanox capsules. The dissolution test was carried out using the second method (paddle method) of the dissolution test method of the Pharmacopoeia, and the eluate was used for 15 hours, 30, 45 and 60 minutes for 2 hours while maintaining the temperature at 37 ℃ using a pH 1.2 artificial gastric fluid One milliliter of the sample was taken and centrifuged, and the supernatant was analyzed by high performance liquid chromatography.

The results of the analysis are shown in FIG. 2, and it was confirmed that the dissolution rate of Example 9, including the itraconazole-sucrose monopalmitate solid melt, was significantly increased compared to the commercially available sporanox capsules (○: Sporanox capsules ●: Purification of itraconazole-sucrose monopalmitate solid melt).

The present invention uses a solid melt of itraconazole and a saccharide-based surfactant to change the crystallinity of itraconazole in the formulation, thereby increasing the solubility and dissolution rate, having high wettability without the addition of other excipients, and the use of less excipients. It can be included in a high content of the drug in one unit, and also the manufacturing process is easy and reproducible in the manufacture of a solid melt is economical, it is possible to provide a composition for oral administration of itraconazole safe to the human body.

Claims (9)

A composition for oral administration of itraconazole comprising a saccharide-based surfactant in which itraconazole and one or more fatty acid derivatives are esterified in one sugar in the form of a solid melt. The composition for oral administration of itraconazole according to claim 1, wherein the mixing ratio of the itraconazole and the saccharide-based surfactant is 1: 0.1 to 10 by weight. delete The method of claim 1, wherein the saccharide-based surfactant is sucrose monostearate, sucrose distearate, sucrose mono-distearate, sucrose monopalmitate, sucrose dipalmitate, sucrose monolaurate, sucrose Cross dilaurate, sucrose monooleate, sucrose dioleate, sucrose monocaprate, sucrose dicaprate, sucrose monocaprylate, sucrose dicaprylate, sucrose monomyristate, sucrose dimyri A composition for oral administration of itraconazole, characterized in that one or a mixture of two or more selected from the group consisting of a state, sucrose monolinolinate, sucrose dilinolinate. The solid melt of claim 1, wherein the solid melt is lactose, dextrin, starch, microcrystalline cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, methylcellulose, polyethylene glycol, polyoxyethylene glycolated Natural or hydrogenated castor oil derivatives, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsulfosuccinate, sodium lauryl sulfate, Phospholipids, propylene glycol mono-fatty acid esters or propylene glycol di-fatty acid esters, trans-esterification reaction products of natural vegetable oil triglycerides and polyalkylene polyols, mono-glycerides, di-glycerides, mono / di-glycerides, sorbates Non-fatty fatty acid esters, silicon dioxide , Hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, aluminum silicate, magnesium aluminum metasilicate and the oral administration composition of itraconazole according to claim 1, further comprising one or more excipients selected from the group consisting of bentonite. After mixing itraconazole and a saccharide-based surfactant in which one or more fatty acid derivatives are esterified in one sugar, it is heated to 140 ° C to 200 ° C and homogeneously melted, and solidified in ice water while cooling the molten mixture. To solidify and then grind to produce a solid melt. The method of claim 6, wherein the pharmaceutically acceptable excipient is further added during cooling of the mixture, solidified by solidification on ice water, and then ground to prepare a solid melt. A method for preparing the composition for oral administration of itraconazole of claim 1 by adding a pharmaceutically acceptable excipient to the solid melt prepared by the method of claim 6 or 7. The composition for oral administration of itraconazole according to claim 1, which has a formulation selected from tablets, capsules, granules, fine granules, liquid preparations, suspensions or syrups.