KR100438485B1 - Pharmaceutical compositions containing of azole antifungal drugs - Google Patents

Abstract

The present invention relates to a method for preparing a pharmaceutical solid dispersion containing a substituted cyclodextrin, wherein the azole antifungal agent and the substituted cyclodextrin are formed using only an organic solvent to form a solid dispersion. That is, the present invention uses a substituted cyclodextrin, which is pharmaceutically stable and has a characteristic of being eluted in a water-soluble medium for a short time in formulating azole antifungal agents insoluble in water, to accelerate the dissolution rate and dissolution rate bioavailability A method for preparing this improved solid dispersion and a pharmaceutical composition containing the same.

Description

Pharmaceutical compositions containing of azole antifungal drugs

The present invention relates to a method and a pharmaceutical composition for preparing a solid dispersion containing cyclodextrin substituted as an insoluble azole antifungal agent and a carrier using only an organic solvent.

Pitha et al. (Int. J. Pharm., 29, 73-82, 1986) and U.S. Pat.No. 4,727,064 describe amorphous clathrate compositions and methods of preparation comprising cyclodextrins and active drugs. The technique involves the process of 1) dissolving a cyclodextrin derivative in an aqueous medium and 2) adding a fat soluble drug to the aqueous medium to form and solubilize the inclusion complex of drugs / cyclodextrins.

WO 85/02767, published July 4, 1985, describes drugs that are unstable or insoluble in aqueous solutions, more specifically rheumatoid therapeutics, steroids, benzodiazepines, benzimidazoles, piperidine, piperazine, imidazole and triazoles. A method of complexing a drug such as β -cyclodextrin esterified with an alkyl group or a hydroxyalkyl group with an aqueous medium is described.

Induction of inclusion of drugs and cyclodextrins by heating has also been introduced. In Hassan et al. (Int. J. Pharm., 58, 19-21, 1990), pamotidine is an aqueous solution of β -cyclodextrin. After addition to the mixture, the mixture was boiled for 1 hour, stirred at room temperature for 5 days, and then dried under reduced pressure to obtain pamotidine- β -cyclodextrin inclusion compound.

WO 94/11031, published May 5, 94, describes a method for the mass production of a high quality clathrate compound in a simple manner using an extrusion technique and an insoluble drug such as indomethacin and cyclodextrin. This method is easy and has the advantage of working at low temperatures, but requires a special twin-screw extruder and has the disadvantage of working with a wet solvent (mixed solvent with water and / or an organic solvent). have.

The above mentioned methods mainly enclose the cyclodextrin / drug complex in an aqueous system containing water. In addition, the method for manufacturing a large amount of inclusions includes a step that requires as much process monitoring and control as the preparation process is complex. The development of effective pharmaceutical compositions of insoluble antifungal agents, in particular because they work in aqueous systems, is significantly hampered by the fact that the antifungal agents are very insoluble in water. The solubility and bioavailability of the compounds can be increased by inclusion with cyclodextrin or derivatives thereof as described above, but when using substantially insoluble active ingredients, the necessary water / or auxiliary The amount of solvent does not allow the technique to be implemented on an industrial scale.

WO 97/18839, published May 29, 1997, describes a solid mixture of cyclodextrins prepared by melt-extrusion. This application describes a process for the preparation of a solid mixture characterized in that it comprises a melt-extrusion step of impregnating itraconazole, lobbyide as a active ingredient in a cyclodextrin carrier. The process by melt-extrusion does not require any solvents, which can be advantageously applied when the active ingredient is sensitive to solvents such as water or organic solvents and is advantageous because it does not require a drying step, Care must be taken because the temperature of the carrier must be elevated above the melting point to affect the stability of the drug and the performance of the formulation depending on the conditions for cooling the melt. In addition, a drug that is unstable in heat or a group of drugs having a melting point different from that of a carrier is difficult to apply.

This problem can be improved by using the solubility of the substituted cyclodextrin in the organic solvent. In other words, substituted cyclodextrins are easily dissolved in alcohols, unlike unsubstituted ones, and are transparently soluble in mixed solvents with alcohols and / or fat-soluble solvents (eg, dichloromethane). After melting transparently, it provides the advantage of obtaining a large amount of solid dispersion by simple operations such as vacuum drying and spray drying.

The present invention is more advantageously applicable to drugs that are sensitive to temperature or water because they do not work at high temperatures or in aqueous systems containing water.

The present invention relates to a method for preparing a pharmaceutical solid dispersion containing a substituted cyclodextrin, wherein the insoluble azole antifungal agent and the substituted cyclodextrin are formed using only an organic solvent to form a solid dispersion. That is, the present invention uses a substituted cyclodextrin, which is pharmaceutically stable and has a characteristic of being eluted in a water-soluble medium for a short time in formulating an azole antifungal agent insoluble in water, thereby accelerating the dissolution rate and dissolution rate A method and a pharmaceutical composition for preparing a solid dispersion with improved bioavailability.

1 is a graph showing the dissolution test results for the formulation example of the present invention.

The present invention relates to a preparation method for producing an itraconazole or sappaconazole / cyclodextrin solid dispersion using only an organic solvent, which is operated under an aqueous system containing water, or is not a hot melting method, and a pharmaceutical composition containing the same. . The present invention is characterized by using an amorphous substituted cyclodextrin as a water-soluble carrier, and provides the pharmaceutical composition for the purpose of improving the bioavailability of the active drug. The pharmaceutical compositions referred to herein do not yield clathrates in an aqueous system comprising water, which is a solvent that is difficult to dissolve effectively insoluble materials and is difficult to volatilize at low temperatures, but instead of cyclodextrins and insoluble active agents substituted with organic solvents alone. Easily solubilized provides a simple dispersion, such as reduced pressure drying and spray drying to obtain a solid dispersion.

Among the groups of compositions described above and hereinafter, compositions of interest are compositions containing cyclodextrin ether derivatives as carriers of solid dispersions. As examples of such cyclodextrins, mention may be made of ethers or mixed ether derivatives of α-, β-, γ -cyclodextrins. In particular, such cyclodextrin derivatives are described in US Pat. No. 3,459,731, EP-A-0,149,197 and EP-A-0,197,571.

Typically, such ethers or mixed ether derivatives are such that one or more cyclodextrin hydroxyl groups are C _1-6 alkyl, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl, C _1-6 alkyloxycar Α- , β-, γ -cyclodextrin substituted with a carbonyl C _1-6 alkyl group. Preferably, such substituted cyclodextrins are ethers in which the hydrogen of at least one cyclodextrin hydroxy group is substituted with C _1-3 alkyl, hydroxy-C _2-4 alkyl, or carboxy-C _1-2 alkyl, or more preferably. Preferably ethers substituted with methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

In the cyclodextrin derivatives described above, the range of D.S. (substitution degree, ie the average number of substituted hydroxy functional groups per glucose unit) is 0.125 to 3, preferably 0.3 to 2, more preferably 0.3 to 1. The range of M.S. (molar substitution degree, ie, the molar average number of substituents per glucose unit) is 0.125 to 10, preferably 0.3 to 3, and more preferably 0.3 to 1.5.

In general, unsubstituted cyclodextrins are technically limited in their low water / lipidity and are therefore limited in forming solid dispersions using organic solvents. Suitable cyclodextrin substituents in the present invention include 2, 6-dimethyl- β -cyclodextrin, 2-hydroxyethyl- β -cyclodextrin, 2-hydroxypropyl- β -cyclodextrin, 2-hydroxyethyl- (gamma) -cyclodextrin, 2-hydroxypropyl- ( gamma ) -cyclodextrin, (2-carboxymethoxy) propyl- ( beta ) -cyclodextrin, etc. can be illustrated.

The cyclodextrins used are preferably amorphous substituted cyclodextrins, in particular hydroxypropyl- β -cyclodextrins with MS in the range from 0.30 to 1.0.

Hydroxypropyl- β -cyclodextrin is water soluble and white crystals. Since hydroxypropyl- β -cyclodextrin is more soluble in organic solvents than β -cyclodextrin (for example, at least 200 g per 100 ml in 95% ethanol), it is preferred to combine itraconazole or sperconazole in the composition of the present invention. Solid dispersions of substituted cyclodextrins can be obtained by simply dissolving these components easily using only an organic solvent and then removing the solvent.

The term 'solid dispersion' refers to a solid state system containing at least two components in which one component is somewhat uniformly dispersed in another component or components, as opposed to a liquid or gaseous state. Dispersions of these components allow the system to remain chemically and physically uniform or homogeneous, or consist of one phase as defined in thermodynamics, which solid dispersions are super homogeneous, such as glassy solid solutions. As well as less homogeneous dispersions.

When the solid dispersion is exposed to water or gastrointestinal fluid, a fine solid water-soluble carrier is released in the aqueous solution, and at the same time, the components of the solid dispersion are dissolved into fine particle sizes, thereby increasing the surface area of the drug. In this case, since the crystal of the drug becomes small and the carrier is completely dissolved in a very short time, solubilization of the drug by the carrier occurs in the microenvironment surrounding the drug particle, that is, the diffusion layer. Therefore, the above factors are combined to increase the solubility and initial dissolution rate of the drug.

Advantageous drug dissolution trends of the compositions also suggest the possibility of inclusion of the composition upon exposure to water or aqueous body fluids. The finely dispersed insoluble azoles antifungal agent / cyclodextrin solid dispersion may generate a supersaturated solution of the drug while encapsulating the insoluble drug in a hydrophobic cavity while melting the more soluble cyclodextrin.

The drug that can be applied in the composition of the present invention is an insoluble azole antifungal agent, which means that the drug is 'very slightly soluble', 'substantially insoluble' and 'insoluble' in water or aqueous solution. `` Very slightly soluble, '' `` practically insoluble, '' or `` insoluble, '' as defined in U.S. Pharmacopoeia 23, NF 18 (1995), page 7, ie, `` very slightly soluble. '' By 'compound' requires 1,000 to 10,000 parts of solvent per part of solute: 'Substantially insoluble' or 'insoluble' compound means that at least 10,000 parts of solvent per part of solute. Here, solute means water or aqueous solution.

Insoluble azole compounds of this type include oxyconazole nitrate, biponazole, isoconazole, isoconazole nitrate, terconazole, clotrimazole, econasol nitrate, ketoconazole, myconazole, myconazole nitrate, and nitric acid. Certaconazole, itraconazole, and saperconazole can be exemplified.

In particular, itraconazole is the most suitable compound for using the present technology, solubility in solvents is difficult to dissolve in water (1 μg / ml or less), very slightly soluble in alcohol (300 μg / ml), and dichloromethane It melts well (239mg / ml). A fat-soluble, weakly basic (pKa = 3.7) drug that has a pH-dependent solubility that is almost ionized in low pH situations such as gastric juice. It is not commercially possible to obtain clathrate compounds in aqueous systems, especially because of their very limited solubility in water, dilute acids and highly polar solvents (eg alcohols, acetone, etc.).

This problem is not an insoluble drug such as itraconazole in cyclodextrin in an aqueous system, but an organic solvent, preferably an ethanol / dichloromethane mixed solvent, in which the two components are transparently dissolved and then dried to form a cyclodextrin and an insoluble active ingredient. It is solved by the present invention for forming a solid dispersion containing.

Solvents that can be used in the production process of the present invention exclude water, and are preferably physiologically acceptable substances, and in general, the boiling point of the solvent or the solvent system is most suitably below 100 ° C. Such solvents can be effectively used in the preparation of the compositions of the present invention and the level of residual solvents is minimal. Solvents that can be used include C _1-6 alkanols (eg ethanol, isopropanol, propanol), acetone, ethyl acetate, methylethylketone, DMF, dichloromethane, chloroform, straight or cyclic ethers (eg di One or more solvents, such as ethyl ether, dimethyl ether, or THF), cyclohexane, and DMSO, are used. More preferably, the conditions of the alcohol / dichloromethane mixed solvent, more preferably the ethanol / dichloromethane mixed solvent are the most suitable solvents for solubilizing the cyclodextrin and the insoluble compound.

As solubilization conditions for the solvent in the production process of the present invention, it is advantageous that the solubilization temperature is generally operated at 0 ° C to 100 ° C, preferably 10 ° C to 80 ° C, more preferably at 20 ° C to 60 ° C.

Solid dispersions of insoluble azole antifungal agents / cyclodextrins in the compositions of the present invention can be obtained by simply dissolving these components in an organic solvent and then removing the solvent. The solution of these components can obtain a solid dispersion of the components as a process of natural drying, heat drying, reduced pressure drying and spray drying, in particular spray drying method using a spray dryer to remove the residual solvent from the solid dispersion It can be effectively removed and has the advantage of obtaining a solid dispersion in large quantities. The amount of organic solvent for spray drying can be optimized by varying the cyclodextrin concentration in such a way that the concentration of cyclodextrin is 3-30% (w / w), more preferably 5-15% (w / w). In addition, the yield of the solid dispersion is above 95%.

In the present invention, the solid dispersion includes an insoluble azole antifungal agent and a substituted cyclodextrin, and the amount of cyclodextrin is 0.01 to 50 parts by weight, preferably 0.5 to 25 parts by weight, more preferably 0.1 to 1 part by weight of the active drug. A solid dispersion containing -10 parts by weight is provided.

The solid dispersion according to the present invention can be prepared in various dosage forms for oral administration such as tablets, powders, granules, as well as tablets by conventional methods, including pharmaceutically acceptable carriers. Therefore, it has a very wide range of choices in product development. Formulations for oral administration using such solid dispersions include tablets, soft or hard capsules, granules, fine granules, solutions, and the like. In the case of tablets and capsules, the dosage ranges from 10 mg to 200 mg per tablet or capsule. It may be formulated into a formulation containing the corresponding amount.

In order to prepare the solid dispersion of the present invention in oral preparations, commonly used binders, disintegrants, thickeners, lubricants, surfactants, stabilizers, organic solvents, solubilizers, preservatives, electrolytes, complexes and complexes, organic acids Or it may be formulated by the addition of other active drugs.

Although the present invention will be described in more detail with reference to the following Examples and Experimental Examples, the present invention is not limited thereto.

Examples 1 to 6 Preparation of Solid Dispersion by Vacuum Drying

Next, the corresponding amount of hydroxypropyl- β -cyclodextrin (MS = 0.6) as indicated in Table 1 was dissolved in 200 ml of ethanol in a 1,000 ml round flask. 100 ml of dichloromethane was added to the resulting solution, and 2 g of itraconazole was added thereto, and the resultant solution was sufficiently stirred until it became clear. Then, the remaining solvent was evaporated under reduced pressure to obtain a white solid. The dose was taken.

Composition ratio of oral itraconazole formulations prepared in Examples 1 to 6 Sample name Itraconazole / HP-β-CD composition (composition ratio) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 2g: 2g (1: 1) 2g: 4g (1: 2) 2g: 5g (1: 2.5) 2g: 6g (1: 3) 2g: 8g (1: 4) 2g: 10g (1: 5)

Example 7 Preparation of Solid Dispersion by Spray Drying Method

350 ml of ethanol was added to a 1,000 ml beaker to dissolve 25 g of hydroxypropyl- β -cyclodextrin (MS = 0.6). 150 ml of dichloromethane was added to the resulting solution, 10 g of itraconazole was added thereto, and the mixture was sufficiently stirred until it became clear, and then filtered through a 10 μm filter to prepare a spray dried solution. Spray dryer conditions were inlet air temperature of 70 ± 5 ℃, outlet air temperature of 60 ± 5 ℃. The spraying rate was initially sprinkled slowly and gradually increased to 15 to 20 ml per minute to obtain a white solid. After sieving through No. 120 sieve, 100 mg of itraconazole was precisely weighed to obtain a single dose.

Preparation Example 1 Itraconazole Pellet Production (C / F Granulator)

Itraconazole: 200 g

2-hydroxypropyl- β -cyclodextrin: 500 g

Sugar sphere: 280 g

Sugar spheres of 25-30 mesh were placed in a centrifugal spherical granulator and preheated at a rotational speed of the fan at 200-250 rpm, an intake air temperature of 60 ° C and an exhaust temperature of 50 ° C.

2-hydroxypropyl- β -cyclodextrin is dissolved in 3,000 ml of ethanol, and itraconazole is dissolved in 2,000 ml of dichloromethane, the two solutions are stirred homogeneously, and then homogeneously sprayed onto sugar spheres in a centrifugal granulator for coating. The obtained particles were dried in a vacuum dryer at 60 ° C. for 6 hours, then sieved through Nos. 14 and 32 to obtain spherical granules, and filled with No. 0 hard capsules containing 100 mg as itraconazole.

Preparation Example 2 and Preparation Example 3 Preparation of Itraconazole Tablets

Itraconazole: 10 g

2-hydroxypropyl- β -cyclodextrin: 25 g

Lactose: 24.9 g

Calcium Carboxymethyl Cellulose: 20g

Magnesium Stearate: 0.1g

After mixing the white powder of the same composition obtained in Example 3 (Reduced Drying Method-Formulation Example 2) and Example 7 (Spray Drying Method-Formulation Example 3) with another excipient and uniformly mixing in a planetary mixer, a circular 13 mm punch was used. Tableting of 100 mg was made as a single itraconazole.

Experimental Example 1 Solubility Measurement

Into a 20 ml volumetric test tube, each of itraconazole powder corresponding to 25 mg of itraconazole and each of the solid dispersions prepared in Examples 1 to 7 was added thereto. 10 ml was added, sonicated for about 30 minutes, and sufficiently wet, followed by stirring at 1,000 rpm for 24 hours at room temperature. After stirring, 5 ml of each sample was taken, centrifuged at 4,000 rpm for 20 minutes, the supernatant was collected, filtered again using a 0.45 μm filter, and the filtrate was analyzed by high performance liquid chromatography. Table 2 below.

Comparison of Solubility of Itraconazole Powder and Solid Dispersion Sample name Solubility (µg / mL) Itraconazole Original Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 3.45 ± 0.31274.70 ± 1.54799.27 ± 3.721,032.07 ± 4.831,293.07 ± 7.521,635.08 ± 9.721,888.08 ± 8.781,165.77 ± 4.33

(Number of samples: 3, mean ± standard deviation)

Experimental Example 2 Elution Comparison Experiment of Itraconazole Powder and Solid Dispersion

The dissolution test was carried out using the dissolution test method 2 (paddle method) of the general pharmaceutical test method of the formulations obtained in Formulation Examples 1 to 3 and the original itraconazole, and the test solution was prepared using the first solution ( pH 1.2 ± 0.1) was used, and 5 ml of the sample solution was collected at a predetermined time under 37 ° C. and 100 rpm conditions, filtered through a 0.45 μm filter, and the filtrate was analyzed by high performance liquid chromatography.

The results are shown in FIG.

As a result of solubility and elution, it was found that the solid dispersion significantly increased the solubility and dissolution rate of itraconazole as compared to the original itraconazole. Itraconazole increased the solubility in proportion to the amount of substituted cyclodextrin, and the solubility and dissolution rate of the solid dispersion obtained by vacuum drying and spray drying were similar.

The present invention provides a solid dispersion having improved bioavailability by using a substituted cyclodextrin, which is pharmaceutically stable and has a characteristic of eluting in a short time upon oral administration, in formulating an oral azole antifungal agent insoluble in water. A method of making a sieve and a pharmaceutical composition containing the same.

The present invention relates to a method for preparing a solid dispersion containing a substituted cyclodextrin, wherein the insoluble antifungal agent and the cyclodextrin are easily solubilized using only an organic solvent without heating to a high temperature or using an aqueous system containing water, and decompression. Simple operations such as drying and spray drying provide the advantage of obtaining a large amount of solid dispersion.

Claims (7)

2,6-dimethyl-β- cyclodextrin, 2-hydroxyethyl -β- cyclodextrin, 2-hydroxyethyl-γ- cyclodextrin, 2-hydroxypropyl-β- cyclodextrin, 2-hydroxypropyl- vacuum drying method after dissolving at least one cyclodextrin selected from γ -cyclodextrin and (2-carboxymethoxy) propyl- β -cyclodextrin and an antifungal agent of itraconazole or sperconazole in an organic solvent not containing water Or a method for producing a solid dispersion by spray drying. The organic solvent according to claim 1, wherein the organic solvent used is chloroform, dichloromethane, methanol, ethanol, isopropanol, propanol, methyl ethyl ketone, acetone, diethyl ether, dimethyl ether, tetrahydrofuran (THF), cyclohexane and ethyl acetate. Method for producing a solid dispersion, characterized in that at least one selected. delete The method for producing a solid dispersion according to claim 1 or 2, wherein the ratio of the antifungal agent of itraconazole or saperconazole and the cyclodextrin is 1: 0.1 to 1:10 by weight. 2,6-dimethyl-β- cyclodextrin, 2-hydroxyethyl -β- cyclodextrin, 2-hydroxyethyl-γ- cyclodextrin, 2-hydroxypropyl-β- cyclodextrin, 2-hydroxypropyl- vacuum drying after dissolving at least one cyclodextrin selected from γ -cyclodextrin and (2-carboxymethoxy) propyl- β -cyclodextrin and an antifungal agent of itraconazole or sperconazole in an organic solvent not containing water Or an oral preparation of an antifungal agent having a solid dispersion prepared by spray drying and a pharmaceutically acceptable carrier. delete 6. The oral preparation of the antifungal agent according to claim 5, wherein the oral preparation is selected from tablets, capsules, granules, solutions and fine granules.