MX2007005427A - Solid dispersion composition of pranlukast with improved bioavailibility and the method of preparing the solid dispersion. - Google Patents

Abstract

Disclosed is a pranlukast solid dispersion composition with an improved and a method of manufacturing the same. More particularly, the present invention provides a pranlukast solid dispersion manufactured by a hot-melting process using a composition comprising pranlukast and at least one water-soluble polymer selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol, which has greatly improved dissolution rate and bioavailability as compared to those prepared by the conventional spray-drying method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.

Description

COMPOSITION OF SOLID DISPERSION OF PRANLUKAST WITH IMPROVED BIOAVAILABILITY AND METHOD FOR PREPARING DISPERSION SOLID REFERENCE TO A RELATED APPLICATION This application claims priority and is based on the Korean Patent Application N ° 10-2004-0089455, presented on November 4, 2004, whose content is incorporated in this document as a reference.

FIELD OF THE INVENTION The present invention relates to new compositions of solid dispersions of pranlukast with improved solubility and dissolution rate, as well as improved bioavailability, and with methods for their preparation and use of these compositions.

BACKGROUND OF THE INVENTION Pranlukast, a 4-oxo-8- (4- (4-phenylbutoxy) benzoyl-amino) -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate, is a compound that exhibits strong antagonistic activity against leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and therefore has been used as a therapeutic agent for the treatment of bronchial asthma and allergic rhinitis. However, since pranlukast is very poorly soluble in water and has a relatively low bioavailability when administered orally, it has been administered in large quantities, which is not economical. Therefore, the need to develop a new formulation and pharmaceutical technology to solve the aforementioned problems persists.

In fact, various types of pranlukast research have been carried out during the last decades considering its utility as a therapeutic drug. For example, in WO 1996/41628 (Korean Patent No.: 10-389606) there are disclosed granules containing pranlukast, a process for producing the granules and a method for decreasing the cohesiveness of pranlukast. For the reduction of the cohesiveness of pranlukast, it provides a process that facilitates its formulation, which comprises: dissolving a saccharide, a water-soluble polymer and a surfactant agent in purified water, suspending the pranlukast and making pellets by means of a spray-drying method improving thus the cohesiveness of pranlukast.

As another example, in the unexamined Japanese Patent Publication of Hei 8/73353 a process is described relating to formulations comprising pranlukast and polyvinylpyrrolidone or β-cyclodextrin.

As yet another example, WO 1999/04790 discloses a method for preparing a water soluble pharmaceutical composition containing a benzopyran derivative as an active ingredient.

As yet another example, a study has been carried out with an aerosol of pranlukast powder which has a higher efficiency of inhalation by a surface modification. { Pharmaceutical Research 1998, 15, 1748-1752).

However, Korean Patent No. 10-389606 only provides a method of formulation through an improvement in physical properties on the surface and the powdered pranlukast was spray dried after being suspended; therefore limitations in the method still exist because the crystallinity of pranlukast is retained, as confirmed by an X-ray diffraction analysis, and its dissolution rate was not improved either.

The unexamined publication of Japanese Patent Hei 8/73353 relates to liquid preparations, such as ophthalmic drops, nasal drops or injections, etc., which employ polyvinylpyrrolidone or β-cyclodextrin as a dissolution aid.

The publication of WO 1999/04790 relates to liquid preparations, such as a solution of water-soluble pranlukast, which contain a surfactant or a suspension of pranlukast containing a water-soluble polymer. Without However, these preparations contain an extremely low concentration of praniukast and therefore some hundreds of milliliters of preparation are needed per dose to administer an adequate normal amount. In addition, preparations with greater solubility by adjusting the pH are likely to precipitate due to the presence of gastric acids when administered orally. Still further, in the unexamined publication of Japanese Patent Hei 8/73353 and in the publication of WO 1999/04790, the dissolution or bioavailability was not very high because the crystallinity of praniukast was maintained as in Korean Patent No.: 10-389606.

One way to improve the oral absorption rate of water insoluble drugs, such as praniukast, is to prepare a solid dispersion. A solid dispersion means a mixture wherein at least one active ingredient is uniformly dispersed in a solid polymer or an inactive carrier, and the oral absorption index can be increased by improving the dissolution properties both in vivo and in vitro of a drug.

There are several methods to prepare a solid dispersion: coprecipitation, coevaporation, freeze drying, spray drying, comolienda, etc. (J. PHARM, Sci. 1993, 82, 32-38).

In Korean Patent No. 0-038 834 a method for improving the dissolution properties and the oral absorption index which comprises making a solid dispersion of praniukast which was prepared by dissolving praniukast in a mixed solution of dichloromethane and methanol is described. of drying. This was a remarkable technology because it was the first method to make a solid dispersion of praniukast and also allowed a relatively high dissolution rate. However, it used a spray drying method, which essentially requires the use of an organic solvent and therefore there was a risk that the solvent could remain in the dispersion and also the risk of environmental contamination due to the use of said organic solvent. In addition, the product obtained by drying by The spray was too bulky to be formulated in the form of capsules and therefore prepared as tablets. In the case of formulating it in tablets, hydroxypropylmethylcellulose was used to increase the rate of dissolution of pranlukast, which is a polymer widely used as a matrix in the manufacture of slow-release tablets, and its rate of dissolution decreases when it is added at a rate of 1. 5 times approximately the amount of drug that will be administered, which requires the use of a large amount of a disintegrating agent. Therefore, when a large amount of a disintegrating agent is added to make tablets, additional processes such as moisture-proof coating, moisture-proof packaging, etc., are required for prescription to a patient, thereby increasing the cost of production. In addition, approval had originally been obtained under the Korean Pharmaceutical Law to prepare the element in the form of capsules and was subsequently developed as tablets based on such approval, but in order to achieve approval of the element to be produced as tablets, a considerable time and represented few commercial benefits, even when it is recognized as a substitute.

The information described in this Background section of the invention is only offered to gain a better understanding of the background of the invention and should not be construed as an acknowledgment or suggestion in any way that this information forms part of the prior art that it is already known to those skilled in the art.

SUMMARY OF THE INVENTION The inventors of the present invention have made great efforts to overcome the disadvantages of conventional methods and, as a result, have been able to produce a solid dispersion of amorphous pranlukast by a hot melt process using a composition comprising pranlukast and minus one water-soluble polymer selected from the group consisting of a polyvinyl pyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol, which has greatly improved dissolution rate and bioavailability as compared to those prepared by the conventional spray drying method, with which could be obtained equivalent pharmaceutical effects with less amount of drug.

Therefore, in one aspect, the present invention provides a composition of a solid dispersion of pranlukast comprising (a) pranlukast and (b) at least one water-soluble polymer selected from the group consisting of a copolymer of polyvinyl pyrrolidone vinylacetate (Plasdone® ), polyvinylpyrrolidone and polyvinyl alcohol.

In another aspect, the present invention provides a method for making a solid dispersion of pranlukast by means of a hot melt process using the pranlukast solid dispersion composition described above.

BRIEF DESCRIPTION OF THE FIGURES The foregoing aspects and other features of the present invention will be explained in the following detailed description, with reference to the accompanying figures, where: FIG. 1 shows a graph comparing the solubility to saturation, of a solid dispersion made by a hot melt process, of a solid dispersion obtained with the spray-drying method described in Korean Patent No. 10-0381834 and the Onon® powder commercially available. It shows an increase of 250 times; FIG. 2 shows a graph comparing the rate of dissolution between preparations, capsules made by a hot melt process, of spray-dried tablets made with the spray-drying method described in Korean Patent No. 10- 0381834 and the commercially available Onon® capsules; Y FIGs. 3a and 3b show the results of an X-ray diffraction for a solid dispersion obtained by hot melting and bulk powder of pranlukast. DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the present invention, an improved solid dispersion composition of pranlukast and a method for making the solid dispersion thereof are provided.

More particularly, the present invention relates to a solid dispersion of pranlukast made by a hot melt process using a composition comprising (a) pranlukast and (b) at least one water-soluble polymer selected from the group consisting of a copolymer of polyvinylpyrrolidone vinyl acetate, polyvinylpyrrolidone and polyvinyl alcohol, which has a greatly improved dissolution rate and bioavailability compared to dispersions prepared by the conventional spray-drying method, whereby equivalent pharmacological effects are obtained with a smaller amount of drug.

In another embodiment of the present invention, a simplified processing process is provided due to the ease of formulation.

In yet another embodiment of the present invention, a final pharmaceutical product is provided that is free of any remaining organic solvent because no organic solvent is employed in the process of making the present invention. This also eliminates the general concern of possible contamination of the environment.

In a further embodiment of the present invention, a composition of a solid dispersion of pranlukast having improved bioavailability is provided.

In yet another further embodiment of the present invention, a method for making a solid dispersion of pranlukast using the solid dispersion composition of pranlukast with higher bioavailability is provided.

The present invention will be described in greater detail hereinafter.

The present invention relates to a method for preparing a solid dispersion of pranlukast by hot melting of pranlukast and a polymer with a vitreous transition temperature of 100-200 ° C.

In order to increase the dissolution and bioavailability of a water-insoluble drug, such as pranlukast, by making a solid dispersion it is important to determine the types of vehicles and the proportion of the content thereof that allows maintaining a relatively fast dissolution rate. high in the absorption area of the drug. In this regard, the present invention designs a solid dispersion using a hot melt process, where pranlukast is hot melted with a polymer having a vitreous transition temperature of 100-200 ° C, whereby a large amount of pranlukast in the area of drug absorption from the intestinal tract.

In order to achieve the desired pharmacological effects according to the present invention, it is preferable to use a pharmaceutical polymer, more preferably a water soluble polymer. The water-soluble polymer to be used in the present invention is preferably one or more selected from the group consisting of a copolymer of polyvinylpyrrolidone-vinylacetate (Plasdone®), polyvinylpyrrolidone (Povidone®) and polyvinylalcohol, which can then be hot melted to produce the solid dispersion.

The Pranlukast compound has the disadvantage that it can not be stably melted without decomposing during the processing of a solid dispersion by a hot melt process because its decomposition temperature and melting temperature are very similar. However, if the pranlukast is melted after it has been mixed with the water-soluble polymer of the present invention, its melting temperature decreases and co-melts, so it is not necessary to increase the temperature to about 230 ° C, which is the melting temperature of the drug.

The pharmaceutical polymer to be used in the present invention is endowed with sufficient plasticity at a temperature below 200 ° C and is not carbonized by the applied heat.

If the conventional cellulose-based polymers, such as hydroxypropylcellulose and hydroxypropylmethylcellulose, are applied, the decomposition of the active ingredients at the melting temperature will occur to the pranlukast and therefore it would be very difficult to carry out a melting process while maintaining the pharmacological effects . That is, it lacks plasticity and is carbonized at the melting temperature of the drug, whereby it would be impossible to make the solid dispersion of the present invention.

The plasticity of a polymer is closely related to the vitreous transition temperature (Tg). The pharmaceutical polymer of the present invention that is suitable for a hot melt process for making a solid dispersion should not be carbonized at 200 ° C. In addition, to improve the ductility, such as to simplify the formulation and the manufacturing process, the Tg should be greater than 50 ° C so that the required plasticity can be achieved at a working temperature of 100-200 ° C. In addition, to improve the solubility as well as the ductility, it is preferable that the Tg is greater than 100 ° C and the water-soluble polymers that meet the above requirement are detailed below.

Examples of the water soluble polymers include polyvinyl pyrrolidones (Povidone®, ISP and BASF, Tg = 155 ° C), polyvinyl pyrrolidone vinylacetate copolymers (Plasdone®, ISP, Kollidone®, VA64®, BASF, Tg = 105 ° C), polyvinylalcohols (Tg = 180-190 ° C) ), polyacrylate copolymers (Carbopol® GoodRich, Tg = 100-105 ° C) and the like.

The content of pranlukast and the pharmaceutical polymer, with a weight ratio of pharmaceutical polymer with reference to pranlukast, is preferably in the range between 0.1: 1 and 10: 1, more preferably between 0.5: 1 and 5: 1 .

If the weight ratio is less than 0.1 there will be no improvement in bioavailability. On the contrary, if the weight ratio is greater than 10, it will result in an increase in the amount of a daily dose, thus generating a problem in the formulation.

The solid dispersion of pranlukast of the present invention may contain other conventional active ingredients, such as a surfactant, a preservative, a complexing agent, electrolytes and other active ingredients, in addition to the above essential constituents. Examples of other active ingredients that can be used together with pranlukast are steroids, a bronchodilator, an antitussive and an expectorant and the like.

The processing of the solid dispersion of pranlukast by means of a hot melt process is not limited to a specific process and a representative example of the manufacturing process is given below.

The compounds pranlukast (10 g) and Plasdone® S-630 (15 g) are weighed accurately, added in a PE bag and then mixed. 5 g of a mixture of pranlukast and a polymer are introduced through a funnel in a flow index meter (CSI 127C, CSI Co.), preset at 150-200 ° C. At 3 min the molten mixture is forcedly discharged from said melt flow meter using a 1 kg weight. The molten product thus obtained is placed in a cold room and then pulverized using a mortar to obtain a solid dispersion by hot melt of drug-polymer.

The method of making the composition of the solid dispersion by a hot melt process has the following advantages with respect to the spray drying method.

First, in the method of spray drying it is essential to use an organic solvent and high pressure which is harmful to operators, generates problems of environmental pollution and can also remain organic solvent in the product final. Second, the spray-dried product prepared by the spray-drying method is too bulky to be formulated and therefore requires an additional forming process such as tablets.

On the contrary, the hot melt process of the present invention does not employ any organic solvent and therefore the product resulting from a solid dispersion does not contain any remnants of organic solvent and does not present the above problems generated due to the presence of the solvents. organic solvents. In addition, the volume of the resulting solid dispersion product is relatively small and therefore easy to handle. Still further, the molten composition is formed into the final product by instantaneous filling in capsules and without going through processes such as tablet forming and moisture-proof coating.

The solid dispersion composition of pranlukast of the present invention can be formulated in a pharmaceutical dosage form containing an effective amount for pharmaceutical use of the drug. For example, it can be formulated in the form of preparations for oral use, such as tablets, capsules, granules and dry granules; and pharmaceutically administrable preparations, such as ophthalmic drops, nasal sprays or preparations for inhalation. For greater convenience and commercial value by approval / authorization, it is more preferable that the preparations be in the form of capsules, and these preparations as capsules can be formulated using a conventional processing method using suitable excipients for capsules.

With respect to oral preparations formulated as tablets, they can be made using conventional tablet-forming technology with conventional ingredients or excipients. Examples of these excipients include a diluent, a disintegrating agent, a binder, a lubricant, a glidant, a sweetener, a flavoring agent or a coloring agent. In addition, the tablets may be coated in order to improve stability, taste, convenience for administration, appearance and the like.

Examples The present invention will be described in more detail with reference to the following examples but should not be considered as limiting the scope of the present invention.

Examples 1-3: Preparation of solid dispersions with various polymers 6 g of pranlukast were mixed with 9 g of each of the polymers, respectively, indicated in the following Table 1 and solid dispersions were made using a melt flow meter at 200 ° C.

Table 1 Comparative examples 1-6: Preparation of solid dispersions for various polymers Solid dispersions were made as in Examples 1-3 except that the polymers shown in the following Table 2 were used.

Table 2 Examples 4-15: Preparation of solid dispersions with different polymer contents Solid dispersions were made as in Examples 1-3 after mixing 1 g of pranlukast and the polymers indicated in the following Table 3.

Table 3 Experimental example 1: Measurement of the solubility of solid dispersions made with various polymers 50 mg of each of the solid dispersions made in Examples 1-3 and Comparative Examples 1-6 were dissolved in 30 ml of water using ultrasonic wave for 30 min, centrifuged, filtered using a 0.45 filter. pm and then the amount of pranlukast contained in the solution was measured. The results are shown in the following Table 4.

Table 4 Experimental example 2: Measurement of the solubility of solid dispersions made with various polymers The amount of pranlukast contained in the solution made in Examples 4-15 was measured as in Experimental Example 1. The results are shown in the following Table 5.

Table 5 As shown in the above Table 5, the solubility of the pranlukast was excellent within the range according to the present invention.

EXPERIMENTAL EXAMPLE 3 Comparison of the solubility between solid dispersions made with the spray-drying method and the present invention A solid dispersion was made with the spray-drying method as described in Korean Patent No. 10-0381834 (Spray-dried Product). To 10 I of a solvent mixture consisting of methylene chloride and methanol at a ratio of 4: 1 was added 100 g of pranlukast and 150 g of hydroxypropyl cellulose. The mixture was dissolved by stirring at 40 ° C. The spray drying was carried out at a speed of 70 ml / min. The temperature of the inlet air was 100 ° C, the temperature of the air outlet was 45 ° C and the atomizing air pressure was 5 atm.

Table 6 As shown in Table 6, the solid dispersion made in Example 1 showed a significant increase in solubility compared to that of the pranlukast powder product in bulk and spray-dried; that is, it showed an increase of more than 250 times compared to that of powder pranlukast in bulk and more than 10 times compared to that of the spray-dried product.

Experimental example 4: Comparison of the solid dispersion of the present invention with the spray-dried product and Onon® powder The solid dispersion of the present invention was compared to the solid dispersion made with the spray-drying method (hereinafter referred to as the 'spray-dried product') as described in Korean Patent No. 10-0381834 and the Powdered Onon® product, commercially available. (1) Comparison of bioavailability in rats Absorption tests were performed on rats (4 rats per group) to examine the bioavailability of the solid dispersion by hot melt for pranlukast and the spray-dried product.

As shown in Table 7, each of the powders was suspended in water by the addition of 0.5% carboxymethylcellulose and Tween 80 and pranlukast was then orally administered to the rats in the experiment at a concentration of 20 mg / kg. At 15 min, 30 min, 60 min, 2 hr, 4 hr, 6 hr, 8 hr after the administration described, respectively, blood was collected from the rats. Blood serum was collected after centrifugation and the amount of pranlukast in blood was examined using HPLC-MASS.

As shown in Table 8, the solid dispersion made in Example 1 showed a significant increase in bioavailability as compared to Onon® powder and the spray-dried product when the same amounts were administered; that is, it showed an increase of 2.9 times compared to that of Onon® powder and an increase of 1.7 times compared to that of the spray-dried product. That is, the solid dispersion -produced in the Example presents an equivalent pharmaceutical efficacy when only one third of the dosage suggested by the original supplier is administered, which is why a significant reduction in production costs is expected.

Table 7 Table 8 (2) Comparison of types of possible formulations As shown in Table 9, the solid dispersion of the present invention has a relatively high apparent bulk density and therefore could be prepared in the same type of formulation (capsule No. 3) as the product made using Onon® in dust. However, the spray-dried product prepared with conventional technology has a bulk volume of filling powder that is approximately 6 times larger in size and therefore can not be prepared in the same type of formulation (capsule No. 3). This is because the spray-dried product is not well disintegrated and therefore contains a large amount of disintegrating agent.

Table 9 (3) Comparison of the dissolution speed of the final products The dissolution rates of the products in the presence of an artificial intestinal fluid (pH 6.8) at 37 ° C were compared at a speed of 100 rpm and the results are shown in the following Table 10 and in FIG. 2.

Table 10 Experimental example 5: Measurement of XRD (X-ray diffraction) The X-ray diffraction of pranlukast powder in bulk and of a solid dispersion of pranlukast obtained by the hot melt method (8XHF22, Mac Science, Japan) were measured.

As can be clearly seen in FIGs. 3a and 3b that the bulk crystalline powder pranlukast in Fig. 3b is converted into a solid dispersion of amorphous pranlukast without a crystalline peak between pranlukast and the polymer in Fig. 3a. Formulation example: Preparation of capsules The composition of the present invention can be used in the types of general formulations, such as tablets, powders, capsules, syrups and the like, In the case of capsules, in particular those having the same dosage form as the Onon® product. commercially available. can be made using the composition of the present invention based on the composition shown in the following Table applying the conventional method.

Table 11 Industrial application As set forth above, the present invention provides a composition of a solid dispersion of pranlukast with improved bioavailability and a method of making the solid dispersion by a hot melt process using a composition comprising (a) pranlukast and (b) al less a water-soluble polymer selected from the group consisting of a polyvinyl pyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol, whereby highly improved dissolution rate and bioavailability values are obtained with with respect to the values of the products made with the conventional method so that even a lower quantity of the drug has an equivalent pharmaceutical efficacy. In addition, the present invention makes it possible to simplify the processing method due to the relative ease of obtaining the formulations. In addition, the solid dispersion of the present invention is prepared without the use of any organic solvent during the manufacturing process and therefore allows to eliminate public concerns concerning a possible environmental contamination, as well as the fact that the final product will not contain solvent organic.

All the aforementioned documents are fully incorporated in this document as a reference.

Although the present invention is described in detail with reference to the foregoing embodiments, it is not intended to limit the scope of the present invention thereto. It is evident from the foregoing that it is possible for a person skilled in the art to make variations and modifications without departing from the essential concept of the present invention.

Claims (9)

CLAIMS:

1. A solid dispersion of pranlukast, CHARACTERIZED BECAUSE it is prepared by hot melting of pranlukast and a water-soluble polymer.

2. A composition of a solid dispersion of pranlukast, CHARACTERIZED BECAUSE it comprises pranlukast and a water-soluble polymer with a vitreous transition temperature of 100-200 ° C.

3. The composition of a solid dispersion of pranlukast according to clause 2, CHARACTERIZED BECAUSE said polymer is selected from the group formed by a copolymer of vinyl acetate of polyvinylpyrrolidone and polyvinylpyrrolidone and polyvinylalcohol.

4. The composition of a solid dispersion of pranlukast according to clause 2 or clause 3, CHARACTERIZED BECAUSE the weight ratio of polymer and pranlukast is in the range of 0,: 1 to 10: 1.

5. A method for preparing a solid dispersion of pranlukast, CHARACTERIZED BECAUSE it comprises hot melting of pranlukast and a polymer with a vitreous transition temperature of 100-200 ° C.

6. The method for preparing a solid dispersion of pranlukast according to clause 5, CHARACTERIZED BECAUSE said method further comprises the steps of: (a) mix pranlukast and a water-soluble polymer with a vitreous transition temperature of 100-200 ° C by hot melt, and (b) obtaining a solid dispersion by cooling and spraying the molten mixture.

7. The method for preparing a solid dispersion of pranlukast according to clause 5 or clause 6, CHARACTERIZED BECAUSE the weight ratio of polymer and pranlukast is in the range of 0.1: 1 to 10: 1.

8. The method for preparing a solid dispersion of pranlukast according to clause 5 or clause 6, CHARACTERIZED BECAUSE said melting temperature is found in the range between 100 and 200 ° C.

9. The method for preparing a solid dispersion of pranlukast according to clause 5 or clause 6, CHARACTERIZED BECAUSE said polymer is selected from the group formed by a copolymer of vinylacetate of polyvinylpyrrolidone and vinylacetate, polyvinylpyrrolidone and polyvinylalcohol.