WO2006049433A1 - Solid dispersion composition of pranlukast with improved bioavailibility and the method of preparing the solid dispersion - Google Patents

Solid dispersion composition of pranlukast with improved bioavailibility and the method of preparing the solid dispersion Download PDF

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Publication number
WO2006049433A1
WO2006049433A1 PCT/KR2005/003686 KR2005003686W WO2006049433A1 WO 2006049433 A1 WO2006049433 A1 WO 2006049433A1 KR 2005003686 W KR2005003686 W KR 2005003686W WO 2006049433 A1 WO2006049433 A1 WO 2006049433A1
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Prior art keywords
pranlukast
solid dispersion
polymer
present
polyvinylpyrrolidone
Prior art date
Application number
PCT/KR2005/003686
Other languages
French (fr)
Inventor
Joon-Gyo Oh
Yong Ho Oh
Ho Chul Shin
Ji Sun Jung
Key-An Um
Dong Sun Min
Nam Kyu Lee
Ju Young Lee
Guang-Jin Im
Tae Kon Kim
Jeong Tae Kim
Woo Jae Jang
Dong Chul Shin
Woong-Sik Kim
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Sk Chemicals Co., Ltd.
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Application filed by Sk Chemicals Co., Ltd. filed Critical Sk Chemicals Co., Ltd.
Priority to MX2007005427A priority Critical patent/MX2007005427A/en
Priority to JP2007540251A priority patent/JP5232472B2/en
Publication of WO2006049433A1 publication Critical patent/WO2006049433A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to novel pranlukast solid dispersion compositions with improved solubility and dissolution rate, as well as enhanced bioavailability, methods for their preparation and the use of these compositions.
  • 4-oxo-8-(4-(4-phenylbutoxy)benzoyl-amino)-2-(tetrazol-5-yl)-4H-l-benzopyran hemihydrate is a compound having a strong antagonistic activity against leukotriene C4(LTC4) and leukotriene D4(LTD4) and thus has been used as a therapeutic agent for treating bronchial asthma and allergic rhinitis.
  • LTC4 leukotriene C4
  • LTD4 leukotriene D4
  • WO publication 1996/41628 discloses granules containing pranlukast, a process for producing the granules and method of lowering cohesiveness of pranlukast.
  • lowering the cohesiveness of pranlukast it provides a process for easier formulation comprising: dissolving a saccharide, a water-soluble polymer, and a surfactant in purified water, suspending pranlukast, and manufacturing granules via spray dry method thereby improving cohesiveness of pranlukast.
  • JP Unexamined Publication Hei 8/73353 discloses a process about formulations comprising pranlukast and polyvinylpyrrolidone or ⁇ - cyclodextrin.
  • WO publication 1999/04790 discloses a method for preparing a water-soluble pharmaceutical composition containing a benzopyran aerosol with improved inhalation efficiency via surface modification (Pharmaceutical Research 1998, 15, 1748-1752).
  • Korean Pat. No. 10-389606 only provides a formulation method via im ⁇ provement in physical properties on surface and the pranlukast powder was spray-dried after it was suspended and thus there were still limitations in the method that the crys- tallinity of pranlukast was maintained, as confirmed in X-ray diffraction analysis, and its dissolution rate was also not improved.
  • JP Unexamined Publicatoion Hei 8/73353 relates to liquid preparations such as eyedrops, nasal drops, or injections, etc., which use polyvinylpyrrolidone or b - cyclodextrin as a dissolution adjuvant.
  • WO Publication 1999/04790 relates to liquid preparations such as a water-soluble pranlukast solution containing a surfactant or a pranlukast suspension containing a water-soluble polymer.
  • these preparations have extremely low concentration of pranlukast and thus a few hundred milliliters of the preparation is needed per each dose for normal adequate amount of administration.
  • the preparations with increased solubility by adjusting pH are highly likely to be precipitated due to the presence of gastric acid when administered orally.
  • Solid dispersion means a mixture where at least one active ingredient is uniformly dispersed in a solid polymer or an inactive carrier, and the rate of oral absorption can be increased by improving the in vivo as well as in vitro dissolution properties of a drug.
  • Korean Pat. No. 10-0381834 discloses a method to improve dissolution properties and oral absorption rate by manufacturing a pranlukast solid dispersion which was prepared by dissolving pranlukast in a mixed solution of dichloromethane and methanol followed by drying. This was a remarkable technology in that it was the first method to manufacture pranlukast solid dispersion and also enabled a relatively high dissolution rate.
  • spray-drying method which essentially requires the use of an organic solvent, and therefore there was a risk that the solvent may be remained and also the risk of environmental pollution due to the use of an organic solvent.
  • the spray-drying product obtained as a result was too bulky to be formulated in the form of capsules and was thus prepared in tablets.
  • hydroxypropylmethylcellulose which was used to increase dissolution rate of pranlukast, is a polymer generally used as a matrix when manu ⁇ facturing slow-release tablets, and its dissolution rate becomes slowed when it is added about 1.5 times of that of a drug to be administered thus requiring the use of a disin ⁇ tegrating agent in large amount. Therefore, when a disintegrating agent is added in large amount in manufacturing tablets, there are required additional processes such as moisture-proof coating, moisture-proof packaging, etc., when prescription is given to a patient thereby increasing the production cost.
  • the inventors of the present invention have made extensive efforts to solve the drawbacks of the conventional methods, and as a result, they have succeeded in manu ⁇ facturing an amorphous pranlukast solid dispersion via 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 dry method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.
  • the present invention provides a pranlukast solid dispersion composition
  • a pranlukast solid dispersion composition comprising (a)pranlukast and (b)at least one water-soluble polymer selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer ( Plasdone O ), polyvinylpyrrolidone and polyvinylalcohol.
  • the present invention provides a method for manufacturing a pranlukast solid dispersion by means of a hot-melting process using the pranlukast solid dispersion composition in the above.
  • an improved pranlukast solid dispersion composition and a method for manufacturing a solid dispersion of the same.
  • the present invention relates to a pranlukast solid dispersion manufactured by a hot-melting process using a composition comprising (a)pranlukast and (b)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 dry method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.
  • a composition comprising (a)pranlukast and (b)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 dry method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.
  • the present invention relates to a method for preparing a pranlukast solid dispersion by hot-melting of pranlukast and a polymer with a glass transition temperature of 100 - 200 °C .
  • the present invention designs a solid dispersion via a hot-melting process, wherein pranlukast and a polymer with glass transition temperature of 100 - 200 °C are hot-melted, whereby pranlukast can be dissolved in large amount at the drug absorption area of intestinal tract.
  • 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 polyvinylpyrrolidone -vinylacetate copolymer(Plasdone O ), polyvinylpyrrolidone( Povidone() and polyvinylalcohol, which can be then hot-melted to manufacture a solid dispersion.
  • Pranlukast has a disadvantage that it cannot be stably melted without being decomposed in the course of manufacturing a solid dispersion via a hot-melting process because its decomposition temperature and melting temperature are very close to each other.
  • pranlukast is melted after mixing with the water-soluble polymer of the present invention its melting temperature becomes lowered and comelted thus not requiring increase of the temperature to about 230 °C , a melting temperature of a drug.
  • the pharmaceutical polymer to be used in the present invention is endowed with a sufficient plasticity at a temperature of below 200 °C and it may not be carbonized by the heat to be applied.
  • Plasticity of a polymer is closely related with glass transition temperature(Tg).
  • the pharmaceutical polymer of the present invention which is suitable for hot-melting process for manufacturing a solid dispersion should not be carbonized at 200 °C. Further, to improve workability such as simplification in formulation and manu ⁇ facturing process, Tg should be higher than 50 °C so that the required plasticity is attained at a working temperature of 100 - 200 °C. In addition, to improve solubility as well as workability, it is preferable that Tg is higher than 100 °C and the water-soluble polymers which meet the above requirement are as follows.
  • water-soluble polymers examples include polyvinylpyrrolidones (Povidone).
  • the contents of pranlukast and the pharmaceutical polymer being a weight ratio of the pharmaceutical polymer with reference to that of pranlukast, are preferable to be in the range of from 0.1 : 1 to 10 : 1, more preferably from 0.5 : 1 to 5 : 1. If the weight ratio is less than 0.1 there will be no improvement in bioavailability. In contrast, if the weight ratio exceeds 10 it will result in increase in the amount of a daily dose thus raising a problem in formulation.
  • the pranlukast solid dispersion of the present invention may contain other con ⁇ ventional active ingredients such as a surfactant, a preservative, a complexing agent, electrolytes, and other active ingredients in addition to the above essential constituents.
  • active ingredients to be used along with pranlukast are steroids, a bronchodilator, a cough suppressant and an expectorant and the like.
  • the manufacture of pranlukast solid dispersion via a hot-melting process is not limited to a certain process and herein below is one representing example of the manu ⁇ facturing process.
  • the method of manufacturing solid dispersion composition via hot-melting process has the advantages over spray-drying method as follows.
  • the hot-melting process of the present invention does not use any organic solvent and thus the resulting product of solid dispersion does not contain any organic solvent remnant in it and also the above problems raised due to the presence of organic solvents. Further, the volume of the resulting product of solid dispersion is relatively small and thus it is easy to handle. Still further, the melted composition is made into a final product by instantly filling it into capsules and without going through the processes such as tableting and moisture-proof coating.
  • the pranlukast solid dispersion composition of the present invention can be formulated into a pharmaceutical dosage form containing a therapeutically effective amount of a drug.
  • a drug for example, they can be formulated in the forms of oral preparations such as tablets, capsules, granules, and dry granules; and pharma ⁇ ceutically administerable preparations such as eyedrops, nasal sprays or inhaling preparation.
  • oral preparations such as tablets, capsules, granules, and dry granules
  • pharma ⁇ ceutically administerable preparations such as eyedrops, nasal sprays or inhaling preparation.
  • the convenience and commercial value in approval/authorization it is most preferable that the preparations be prepared in capsules, and these capsule preparations can be formulated by using the conventional manufacturing method using an excipient suitable for capsules.
  • oral preparations formulated in tablets they can be manufactured by using the conventional tableting technology using the conventional ingredients or excipients.
  • excipients include a diluent, a disintegrating agent, a binder, a lubricant, a glidant, a sweetener, a flavoring agent or a dyeing agent.
  • tablets can be coated in order to improve stability, flavor, conveniences in administration, ap ⁇ pearances, and the like.
  • FlG. 1 shows a graph comparing the solubility of a solid dispersion manufactured by hot-melting process , a solid dispersion manufactured by the spray-drying method disclosed in Korean Pat. No. 10-0381834, and the commercially available Onon O powder;
  • FTG. 2 shows a graph comparing the dissolution rate of capsules manufactured by hot-melting process, spray dry tablets manufactured by the spray dry method disclosed in Korean Pat. No. 10-0381834, and the commercially available Onon O capsules ;
  • FTGs. 3 and 4 show the results of X-ray diffraction for hot melt solid dispersion and pranlukast bulk powder.
  • Examples 1 - 3 Manufacturing of Solid Dispersions for Various Polymers
  • 6g of pranlukast was mixed respectively with 9g each of the polymers in the following Table 1, and solid dispersions were manufactured by using Melt-Flow
  • Example 1 As shown in Table 6, the solid dispersion manufactured in Example 1 showed a significant increase in solubility as compared to those of pranlukast bulk powder and spray-drying product; i.e., it showed a more than 250 folds of increase compared to that of pranlukast bulk powder and more than 10 folds compared to that of spray- drying product.
  • each of the powders was suspended in water by adding 0.5 % carboxymethyl cellulose and Tween 80, and then pranlukast was administered orally to the experimental rats with a concentration of 20 mg/ kg. 15 min , 30 min, 60 min, 2 hr, 4 hr, 6 hr, 8 hr after the above administration, respectively, blood was collected from the rats. The blood serum was collected after centrifugation and the amount of pranlukast in blood was examined by using HPLC-MASS.
  • the solid dispersion manufactured in Example 1 showed a significant increase in bioavailabililty as compared to those of Onon O powder and spray-drying product when administered with the same amount; i.e., it showed a 2.9 fold increase compared to that of Onon O powder and a 1.7 fold increase compared to that of spray-drying product. That is, the solid dispersion manufactured in Example can exhibit equivalent pharmaceutical efficacy when administered with only one third of the dosage of the original manufacturer it is expected to greatly reduce production cost.
  • the solid dispersion of the present invention has a relatively high bulk density and was thus able to be prepared in the same formulation type (capsule No. 3) as the product manufactured by using Onon O powder.
  • the spray-drying product prepared by using the conventional technology has a bulky volume of filling powder which is about 6 times greater in size and thus it cannot be prepared in the same formulation type (capsule No. 3). This is because the spray- drying product is not well disintegrated and thus contains a large amount of a disin ⁇ tegrating agent.
  • composition of the present invention can be used in general types of for ⁇ mulations such as tablets, powders, capsules, syrups and the like.
  • for ⁇ mulations such as tablets, powders, capsules, syrups and the like.
  • those having the same dosage form as the commercially available Onon O can be manufa ctured by using the composition of the present invention based on the composition shown in the following Table 11 by using the con ⁇ ventional method.
  • the present invention provides a pranlukast solid dispersion composition with improved bioavailability and a method of manufacturing the solid dispersion via hot melting process using the composition comprising (a)pranlukast and (b)at least one water-soluble polymer selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol, thereby providing greatly improved dissolution rate and bioavailability over those manufactured by the conventional method so that even a smaller amount of dose of the drug has equivalent pharmaceutical efficacies.
  • the present invention can simplify the manufacturing method due to the relative easiness in formulations.
  • the solid dispersion of the present invention is prepared by not using any organic solvent during the manufacturing process and thus it can eliminate the public worries on the possibility of environmental pollution as well as the organic solvent will not be contained in the final product.

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

Description
SOLID DISPERSION COMPOSITION OF PRANLUKAST WITH IMPROVED BIOAVAILIBILITY AND THE METHOD OF PREPARING THE SOLID
DISPERSION
Technical Field
The present invention relates to novel pranlukast solid dispersion compositions with improved solubility and dissolution rate, as well as enhanced bioavailability, methods for their preparation and the use of these compositions.
Background Art
Pranlukast, a
4-oxo-8-(4-(4-phenylbutoxy)benzoyl-amino)-2-(tetrazol-5-yl)-4H-l-benzopyran hemihydrate, is a compound having a strong antagonistic activity against leukotriene C4(LTC4) and leukotriene D4(LTD4) and thus has been used as a therapeutic agent for treating bronchial asthma and allergic rhinitis. However, because the pranlukast is very slightly soluble in water and has a relatively low bioavailability when orally administered, it has been administered in large amount thus not being economical. Therefore, there has been a long-felt need to develop a novel formulation and pharmaceutical technology which can resolve the above problems.
In fact, various kinds of researches have been conducted on pranlukast for the past few decades considering its usefulness as a therapeutic drug. For example, WO publication 1996/41628 (Korean Pat. No. 10-389606) discloses granules containing pranlukast, a process for producing the granules and method of lowering cohesiveness of pranlukast. In lowering the cohesiveness of pranlukast, it provides a process for easier formulation comprising: dissolving a saccharide, a water-soluble polymer, and a surfactant in purified water, suspending pranlukast, and manufacturing granules via spray dry method thereby improving cohesiveness of pranlukast.
In another example, JP Unexamined Publication Hei 8/73353 discloses a process about formulations comprising pranlukast and polyvinylpyrrolidone or β- cyclodextrin.
In yet another example, WO publication 1999/04790 discloses a method for preparing a water-soluble pharmaceutical composition containing a benzopyran aerosol with improved inhalation efficiency via surface modification (Pharmaceutical Research 1998, 15, 1748-1752).
[11] However, Korean Pat. No. 10-389606 only provides a formulation method via im¬ provement in physical properties on surface and the pranlukast powder was spray-dried after it was suspended and thus there were still limitations in the method that the crys- tallinity of pranlukast was maintained, as confirmed in X-ray diffraction analysis, and its dissolution rate was also not improved.
[12] JP Unexamined Publicatoion Hei 8/73353 relates to liquid preparations such as eyedrops, nasal drops, or injections, etc., which use polyvinylpyrrolidone or b - cyclodextrin as a dissolution adjuvant.
[13] WO Publication 1999/04790 relates to liquid preparations such as a water-soluble pranlukast solution containing a surfactant or a pranlukast suspension containing a water-soluble polymer. However, these preparations have extremely low concentration of pranlukast and thus a few hundred milliliters of the preparation is needed per each dose for normal adequate amount of administration. Further, the preparations with increased solubility by adjusting pH are highly likely to be precipitated due to the presence of gastric acid when administered orally. Still further, in JP Unexamined Publication Hei 8/73353 and WO Publication 1999/04790, the dissolution or bioavailability was not very high because the crystallinity of pranlukast was maintained as in Korean Pat. No. 10-389606.
[14] One way of improving the rate of oral absorption for water-insoluble drugs such as pranlukast is to prepare a solid dispersion. Solid dispersion means a mixture where at least one active ingredient is uniformly dispersed in a solid polymer or an inactive carrier, and the rate of oral absorption can be increased by improving the in vivo as well as in vitro dissolution properties of a drug.
[15] There are various methods to prepare a solid dispersion: coprecipitation, co- evaporation, freeze drying, spray drying, cogrinding, etc. (J. PHARM. ScL 1993, 82, 32-38).
[16] Korean Pat. No. 10-0381834 discloses a method to improve dissolution properties and oral absorption rate by manufacturing a pranlukast solid dispersion which was prepared by dissolving pranlukast in a mixed solution of dichloromethane and methanol followed by drying. This was a remarkable technology in that it was the first method to manufacture pranlukast solid dispersion and also enabled a relatively high dissolution rate. However, it employed spray-drying method, which essentially requires the use of an organic solvent, and therefore there was a risk that the solvent may be remained and also the risk of environmental pollution due to the use of an organic solvent. Further, the spray-drying product obtained as a result was too bulky to be formulated in the form of capsules and was thus prepared in tablets. In case of formulating it in tablets, hydroxypropylmethylcellulose, which was used to increase dissolution rate of pranlukast, is a polymer generally used as a matrix when manu¬ facturing slow-release tablets, and its dissolution rate becomes slowed when it is added about 1.5 times of that of a drug to be administered thus requiring the use of a disin¬ tegrating agent in large amount. Therefore, when a disintegrating agent is added in large amount in manufacturing tablets, there are required additional processes such as moisture-proof coating, moisture-proof packaging, etc., when prescription is given to a patient thereby increasing the production cost. In addition, it originally obtained an approval for the item according to the Korean Pharmaceutical Law to be prepared in the form of capsules and it was later developed in tablets based on the approval, but to obtain an approval for the above item to be manufactured in tablets there was required a considerable amount of time and could not expect much commercial benefits although it is acknowledge as a substitute.
[17] The information disclosed in this Background of the Invention section is only for enhancement of understanding of the background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art that is already known to a person skilled in the art.
[18]
Disclosure
[19]
[20] The inventors of the present invention have made extensive efforts to solve the drawbacks of the conventional methods, and as a result, they have succeeded in manu¬ facturing an amorphous pranlukast solid dispersion via 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 dry method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.
[21] Therefore, in one aspect, the present invention provides a pranlukast solid dispersion composition comprising (a)pranlukast and (b)at least one water-soluble polymer selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer ( Plasdone O ), polyvinylpyrrolidone and polyvinylalcohol.
[22] In another aspect, the present invention provides a method for manufacturing a pranlukast solid dispersion by means of a hot-melting process using the pranlukast solid dispersion composition in the above.
[23]
[24] In an embodiment of the present invention, there is provided an improved pranlukast solid dispersion composition and a method for manufacturing a solid dispersion of the same.
[25] More particularly, the present invention relates to a pranlukast solid dispersion manufactured by a hot-melting process using a composition comprising (a)pranlukast and (b)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 dry method, thus enabling to obtain the equivalent pharmaceutical effects with less amount of a drug.
[26] In another embodiment of the present invention, there is provided a simplified manufacturing process due to the easiness of the formulation.
[27] In yet another embodiment of the present invention, there is provided a final phar¬ maceutical product which is free of any remaining organic solvent because no organic solvent is used in the manufacturing process of the present invention. This can also eliminate the public worries on the possibility of environmental pollution.
[28] In a further embodiment of the present invention, there is provided a pranlukast solid dispersion composition which has improved bioavailability.
[29] In a still further embodiment of the present invention, there is provided a method for manufacturing a pranlukast solid dispersion using the pranlukast solid dispersion composition with improved bioavailability.
[30] The present invention is described further as set forth hereunder.
[31] The present invention relates to a method for preparing a pranlukast solid dispersion by hot-melting of pranlukast and a polymer with a glass transition temperature of 100 - 200 °C .
[32] In order to increase dissolution and bioavailability of a water-insoluble drug such as pranlukast by manufacturing a solid dispersion it is important to determine the kinds of carriers and their content ratio which can maintain a relatively high dissolution rate at the area of drug absorption. In this respect, the present invention designs a solid dispersion via a hot-melting process, wherein pranlukast and a polymer with glass transition temperature of 100 - 200 °C are hot-melted, whereby pranlukast can be dissolved in large amount at the drug absorption area of intestinal tract.
[33] To attain the desirable pharmaceutical 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 polyvinylpyrrolidone -vinylacetate copolymer(Plasdone O ), polyvinylpyrrolidone( Povidone() and polyvinylalcohol, which can be then hot-melted to manufacture a solid dispersion.
[34] Pranlukast has a disadvantage that it cannot be stably melted without being decomposed in the course of manufacturing a solid dispersion via a hot-melting process because its decomposition temperature and melting temperature are very close to each other. However, if pranlukast is melted after mixing with the water-soluble polymer of the present invention its melting temperature becomes lowered and comelted thus not requiring increase of the temperature to about 230 °C , a melting temperature of a drug.
[35] The pharmaceutical polymer to be used in the present invention is endowed with a sufficient plasticity at a temperature of below 200 °C and it may not be carbonized by the heat to be applied.
[36] If the conventional cellulose-based polymers such as hydroxypropyl cellulose and hydroxypropyl methylcellulose are applied to pranlukast there would occur a de¬ composition of active ingredients at a melting temperature and thus it is very difficult to perform a melting process while maintaining the pharmaceutical effects. That is, it lacks in plasticity and is carbonized at the melting temperature of a drug thus unabling to manufacture the solid dispersion of the present invention.
[37] Plasticity of a polymer is closely related with glass transition temperature(Tg). The pharmaceutical polymer of the present invention which is suitable for hot-melting process for manufacturing a solid dispersion should not be carbonized at 200 °C. Further, to improve workability such as simplification in formulation and manu¬ facturing process, Tg should be higher than 50 °C so that the required plasticity is attained at a working temperature of 100 - 200 °C. In addition, to improve solubility as well as workability, it is preferable that Tg is higher than 100 °C and the water-soluble polymers which meet the above requirement are as follows.
[38] Examples of the water-soluble polymers include polyvinylpyrrolidones (Povidone
O , ISP and BASF, Tg= 155 °C ), polyvinylpyrrolidone vinylacetate copolymers ( Plasdone O , ISP, Kollidone( VA64(, BASF, Tg=105 °C ), polyvinylalcohols(Tg=180 - 190 °C ), polyacrylate copolymers(Carbopol(, GoodRich, Tg=IOO - 105 °C ) and the like.
[39] The contents of pranlukast and the pharmaceutical polymer, being a weight ratio of the pharmaceutical polymer with reference to that of pranlukast, are preferable to be in the range of from 0.1 : 1 to 10 : 1, more preferably from 0.5 : 1 to 5 : 1. If the weight ratio is less than 0.1 there will be no improvement in bioavailability. In contrast, if the weight ratio exceeds 10 it will result in increase in the amount of a daily dose thus raising a problem in formulation.
[40] The pranlukast solid dispersion of the present invention may contain other con¬ ventional 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 to be used along with pranlukast are steroids, a bronchodilator, a cough suppressant and an expectorant and the like.
[41] The manufacture of pranlukast solid dispersion via a hot-melting process is not limited to a certain process and herein below is one representing example of the manu¬ facturing process.
[42] Pranlukast (10 g) and Plasdone O S-630 (15 g) are accurately weighed, added into
PE bag and then mixed together. 5 g of a mixture of pranlukast and a polymer is introduced through a funnel into Melt-Flow-Indexer (CSI 127C, CSI Co.), which is preset at 150 - 200 °C. In 3 min, the melted mixture is forcefully discharged from the Melt-Flow-Indexer by using a 1 kg weight. Thus obtained melted product is placed in a cold room and then pulverized by using a mortar and a pestle to obtain hot- melting solid dispersion of a drug-polymer.
[43] The method of manufacturing solid dispersion composition via hot-melting process has the advantages over spray-drying method as follows.
[44] First, in spray-drying method it is essential to use an organic solvent and high pressure which is harmful to workers, raises the problem of environmental pollution, and also the organic solvent may remain in the final product. Second, the spray-drying product prepared by spray-drying method is too bulky to be formulated and thus there is required an additional process of tableting.
[45] In contrast, the hot-melting process of the present invention does not use any organic solvent and thus the resulting product of solid dispersion does not contain any organic solvent remnant in it and also the above problems raised due to the presence of organic solvents. Further, the volume of the resulting product of solid dispersion is relatively small and thus it is easy to handle. Still further, the melted composition is made into a final product by instantly filling it into capsules and without going through the processes such as tableting and moisture-proof coating.
[46] The pranlukast solid dispersion composition of the present invention can be formulated into a pharmaceutical dosage form containing a therapeutically effective amount of a drug. For example, they can be formulated in the forms of oral preparations such as tablets, capsules, granules, and dry granules; and pharma¬ ceutically administerable preparations such as eyedrops, nasal sprays or inhaling preparation. The convenience and commercial value in approval/authorization, it is most preferable that the preparations be prepared in capsules, and these capsule preparations can be formulated by using the conventional manufacturing method using an excipient suitable for capsules.
[47] As for oral preparations formulated in tablets, they can be manufactured by using the conventional tableting technology using the 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 dyeing agent. Besides, tablets can be coated in order to improve stability, flavor, conveniences in administration, ap¬ pearances, and the like.
[48]
Description Of Drawings
[49] [50] The aforementioned aspect and other features of the present invention will be explained in the following detailed description, taken in conjunction with the ac¬ companying drawings, wherein:
[51] FlG. 1 shows a graph comparing the solubility of a solid dispersion manufactured by hot-melting process , a solid dispersion manufactured by the spray-drying method disclosed in Korean Pat. No. 10-0381834, and the commercially available Onon O powder;
[52] FTG. 2 shows a graph comparing the dissolution rate of capsules manufactured by hot-melting process, spray dry tablets manufactured by the spray dry method disclosed in Korean Pat. No. 10-0381834, and the commercially available Onon O capsules ; and
[53] FTGs. 3 and 4 show the results of X-ray diffraction for hot melt solid dispersion and pranlukast bulk powder. [54]
Best Mode
[55] [56] The present invention is described in greater detail with reference to the following examples hereunder but it should not be construed as limiting the scope of the present invention.
[57] Examples 1 - 3 : Manufacturing of Solid Dispersions for Various Polymers [58] 6g of pranlukast was mixed respectively with 9g each of the polymers in the following Table 1, and solid dispersions were manufactured by using Melt-Flow
Indexer at 200 °C.
[59]
[Table 1]
Figure imgf000008_0001
[60] [61] Comparative Examples 1 - 6 : Manufacturing of Solid Dispersions for Various Polymers
[62] Solid dispersions were manufactured same as in Examples 1 - 3 except the polymers shown in the following Table 2.
[63]
[Table 2]
Figure imgf000009_0001
[64] [65] Examples 4 - 15 : Manufacturing of Solid Dispersions According to Different Content of Polymers
[66] Solid dispersions were manufactured same as in Examples 1 - 3 after mixing 1 g of pranlukast and polymers in the following Table 3. [67]
[Table 3]
Figure imgf000010_0001
[68] [69] Experimental Example 1 : Measurement of Solubility for Solid Dispersions Manufactured for Various Polymers
[70] 50 mg each of solid dispersions manufactured in Examples 1 - 3 and Comparative Examples 1 - 6 was dissolved in 30 mL of water by using ultrasonic wave for 30 min, centrifuged, filtered using 0.45 μ m filter, and then the amount of pranlukast contained in the solution was measured. The results are shown in the following Table 4.
[71]
[Table 4]
Figure imgf000011_0001
[72] [73] Experimental Example 2 : Measurement of Solubility for Solid Dispersions Manufactured for Various Polymers
[74] The amount of pranlukast contained in the solution manufactured in Examples 4 15 was measured same as in Experimental Example 1. The results are shown in the following Table 5.
[75]
[Table 5]
Figure imgf000012_0001
[76] As shown in the above Table 5, the solubility of the pranlukast was excellent within the range according to the present invention. [77] Experimental Example 3 : Solubility Comparison between Solid Dispersions Manufactured by Spray-Drying Method and the Present Invention [78] Solid dispersion was manufactured by spray-drying method as disclosed in Korean Pat. No. 10-0381834 (Spray-Drying Product). To a 10 L mixed solvent consisting of methylene chlorideand methanol in the ratio of 4 : 1 were added 100 g of pranlukast and 150 g of hydroxypropyl cellulose. The mixture was dissolved by stirring at 40 °C. Spray-drying was performed at the rate of 70 mL/min. The temperature of inlet air was 100 °C, the temperature of exhaust air was 45 °C, and the atomizing air pressure was 5 atm.
[79]
[Table 6]
Figure imgf000012_0002
[80] As shown in Table 6, the solid dispersion manufactured in Example 1 showed a significant increase in solubility as compared to those of pranlukast bulk powder and spray-drying product; i.e., it showed a more than 250 folds of increase compared to that of pranlukast bulk powder and more than 10 folds compared to that of spray- drying product.
[81] Experimental Example 4 : Comparison of the Solid Dispersion of the Present Invention with Spray-Drying Product and Onon( Powder [82] The solid dispersion of the present invention was compared with the solid dispersion manufactured by spray dry method (hereinafter referred to as ' spray-drying product ' ) as disclosed in Korean Pat. No. 10-0381834 and the Onon( powder, which is available in commercial market.
[83] (1) Comparison of Bioavailability in Rats [84] Absorption test was performed using rats (4 rats per group) to examine the bioavailabililty of hot melt solid dispersion for pranlukast and spray-drying product.
[85] As shown in Table 7, each of the powders was suspended in water by adding 0.5 % carboxymethyl cellulose and Tween 80, and then pranlukast was administered orally to the experimental rats with a concentration of 20 mg/ kg. 15 min , 30 min, 60 min, 2 hr, 4 hr, 6 hr, 8 hr after the above administration, respectively, blood was collected from the rats. The blood serum was collected after centrifugation and the amount of pranlukast in blood was examined by using HPLC-MASS.
[86] As shown in Table 8, the solid dispersion manufactured in Example 1 showed a significant increase in bioavailabililty as compared to those of Onon O powder and spray-drying product when administered with the same amount; i.e., it showed a 2.9 fold increase compared to that of Onon O powder and a 1.7 fold increase compared to that of spray-drying product. That is, the solid dispersion manufactured in Example can exhibit equivalent pharmaceutical efficacy when administered with only one third of the dosage of the original manufacturer it is expected to greatly reduce production cost.
[87]
[Table 7]
Figure imgf000013_0001
[88] [89] [Table 8]
Figure imgf000014_0001
[90] [91] (2) Comparison of Possible Types of Formulations [92] As shown in Table 9, the solid dispersion of the present invention has a relatively high bulk density and was thus able to be prepared in the same formulation type (capsule No. 3) as the product manufactured by using Onon O powder. However, the spray-drying product prepared by using the conventional technology has a bulky volume of filling powder which is about 6 times greater in size and thus it cannot be prepared in the same formulation type (capsule No. 3). This is because the spray- drying product is not well disintegrated and thus contains a large amount of a disin¬ tegrating agent.
[93]
[Table 9]
Figure imgf000014_0002
[94] [95] (3) Comparison of Dissolution Rate of Final Products [96] Dissolution rates of products were compared in the presence of an artificial intestinal fluid (pH 6.8) at 37 °C at the rate of 100 rpm and the results are shown in the following Table 10 and HG. 2.
[97] [Table 10]
Figure imgf000015_0001
[98] Experimental Example 5 : Measurement of XRD(X-RAY DIFFRACTION) [99] The X-ray diffractions were measured for pranlukast bulk powder and pranlukast solid dispersion by method of hot-melting process (M18XHF22, Mac Science, Japan ).
[100] From the FIGs. 3 and 4, it is now clear that the crystalline pranlukast bulk powder in FIG. 4 is converted into an amorphous pranlukast solid dispersion without a crystalline peak between pranlukast and a polymer in FIG. 3.
[101] Formulation Example : Preparation of Capsules [102] The composition of the present invention can be used in general types of for¬ mulations such as tablets, powders, capsules, syrups and the like. In the event of capsules, in particular, those having the same dosage form as the commercially available Onon O can be manufa ctured by using the composition of the present invention based on the composition shown in the following Table 11 by using the con¬ ventional method.
[103]
[Table 11]
Figure imgf000015_0002
[104]
Industrial Applicability
[105]
[106] As stated above, the present invention provides a pranlukast solid dispersion composition with improved bioavailability and a method of manufacturing the solid dispersion via hot melting process using the composition comprising (a)pranlukast and (b)at least one water-soluble polymer selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol, thereby providing greatly improved dissolution rate and bioavailability over those manufactured by the conventional method so that even a smaller amount of dose of the drug has equivalent pharmaceutical efficacies. Further, the present invention can simplify the manufacturing method due to the relative easiness in formulations. In addition, the solid dispersion of the present invention is prepared by not using any organic solvent during the manufacturing process and thus it can eliminate the public worries on the possibility of environmental pollution as well as the organic solvent will not be contained in the final product.
[107] AU documents mentioned herein are incorporated herein by reference in their entirety.
[108] Even though 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 many variations and modifications may be made by a person having an ordinary skill in the present field without departing from the essential concept of the present invention.
[109]

Claims

Claims
[1] A pranlukast solid dispersion prepared by hot-melting of pranlukast and a water- soluble polymer.
[2] A pranlukast solid dispersion composition which comprises pranlukast and a water-soluble polymer with a glass transition temperature of 100 - 200 °C .
[3] The pranlukast solid dispersion composition according to claim 2, wherein said polymer is selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol.
[4] The pranlukast solid dispersion composition according to claim 2 or claim 3, wherein the weight ratio of polymer against pranlukast is in the range of 0.1 : 1 to 10 : 1.
[5] A method for preparing a pranlukast solid dispersion by hot-melting of pranlukast and a polymer with a glass transition temperature of 100 - 200 °C .
[6] The method for preparing a pranlukast solid dispersion according to claim 5, wherein said method further comprises steps of:
(a) mixing pranlukast and a water-soluble polymer with a glass transition temperature of 100 - 200 °C by hot-melting, and
(b) obtaining a solid dispersion by cooling and pulverizing the melted mixture. [7] The method for preparing a pranlukast solid dispersion according to claim 5 or claim 6, wherein the weight ratio of polymer against pranlukast is in the range of
0.1 : 1 to 10 : 1. [8] The method for preparing a pranlukast solid dispersion according to claim 5 or claim 6, wherein said melting temperature is in the range of 100 - 200 °C. [9] The method for preparing a pranlukast solid dispersion according to claim 5 or claim 6, wherein said polymer is selected from the group consisting of polyvinylpyrrolidone vinylacetate copolymer, polyvinylpyrrolidone and polyvinylalcohol.
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