JP2009506027A - Pharmaceutical composition of pranlukast solid dispersion with improved initial dissolution rate and method for producing the same - Google Patents

Abstract

    The present invention relates to a pharmaceutical composition of a pranlukast solid dispersion having an improved initial dissolution rate and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition of a pranlukast solid dispersion produced by heating and mixing an anticoagulant having an HLB in a predetermined range with a pranlukast solid dispersion. The initial dissolution rate of pranlukast was improved by resolving the serious problem of pranlukast solid dispersion adhering to the capsule wall. Compared with the pharmaceutical composition, when the same volume is administered, the bioavailability can be improved because the in vivo absorption concentration (Cmax) and the maximum absorption concentration (AUC) are excellent.

Description

  The present invention relates to a pharmaceutical composition of a pranlukast solid dispersion having an improved initial dissolution rate and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition of a pranlukast solid dispersion produced by heating and mixing an anticoagulant having an HLB in a predetermined range with a pranlukast solid dispersion. The initial dissolution rate of pranlukast was improved by resolving the serious problem of pranlukast solid dispersion adhering to the capsule wall. Compared with the pharmaceutical composition, when the same volume is administered, the bioavailability can be improved because the in vivo absorption concentration (Cmax) and the maximum absorption concentration (AUC) are excellent.

化学式１ Planluca which is 4-oxo-8- [4- (4-phenylbutoxy) benzoyl-amino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate represented by the following chemical formula 1 Stroke is a compound having a strong antagonistic effect on leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and is therefore used as a therapeutic agent to treat bronchial asthma and allergic rhinitis.

Chemical formula 1

  However, the pranlukast is poorly soluble in water and has low bioavailability when administered orally. Therefore, it is necessary to administer a large amount of the pranlukast. There is an urgent need to develop a formulation.

  Therefore, various studies have been conducted on pranlukast in consideration of pharmacological usefulness. Patent Document 1 (International Publication No. 1996/41628) and Patent Document 2 (Korea Patent No. 10-389606) disclose granules containing pranlukast and a method for producing the same. According to the invention, in order to improve the cohesiveness of pranlukast, the step of dissolving saccharides, a water-soluble polymer and a surfactant in purified water, the step of suspending pranlukast, and the granulation by spray drying method A manufacturing process is disclosed.

  However, the invention provides only a formulation method by improving the physical properties of the surface, and pranlukast is suspended and then spray dried to maintain the crystallinity of pranlukast and improve its dissolution characteristics Not.

  Patent Document 3 (Japanese Patent Laid-Open No. 8-73353) discloses a liquid preparation such as eye drops, nasal drops or injections containing pranlukast and polyvinylpyrrolidone or β-cyclodextrin as a solubilizing agent. . Patent Document 4 (International Publication No. 1999/04790) discloses a water-soluble pharmaceutical composition containing a benzopyran derivative as a main component, and furthermore, planurka having improved inhalation efficiency by surface modification. Research has been conducted on strike powder aerosols [Non-Patent Document 1 (Pharmaceutical Research 1998, 15, 1748-1752)]. This relates to liquid pharmaceutical compositions such as a pranlukast aqueous solution containing a surfactant and a pranlukast suspension containing a water-soluble polymer.

  However, the formulations presented in Patent Document 3 (Japanese Patent Application Laid-Open No. 8-73353) and Patent Document 4 (International Publication No. 1999/04790) have very low concentrations of pranlukast. Several hundred ml is needed. Furthermore, formulations with increased solubility by adjusting pH are more likely to coagulate with gastric acid upon oral administration. Furthermore, as disclosed in Patent Document 2 (Korean Patent No. 10-389606), the crystallinity of pranlukast is maintained, so that the dissolution rate and the bioavailability were low.

  On the other hand, one way to improve oral absorption is to prepare a solid dispersion. Solid dispersion means a mixture in which at least one active ingredient is evenly dispersed in a solid polymer or inert carrier, and the oral absorption rate is improved by improving the dissolution characteristics of the drug in vitro and in vivo. Can be increased.

  There are various methods for producing the solid dispersion, such as coprecipitation, co-evaporation, lyophilization, spray drying, mixed pulverization, etc. [Non-Patent Document 2 (J. PHARM. Sci. 1993, 82, 32-38) ].

  Patent Document 5 (Korean Patent No. 10-0381834) discloses a pranlukast solid dispersion which improves the dissolution characteristics and oral absorption rate by dissolving pranlukast in a mixed solution of dichloromethane and methanol. .

  Although the invention was a remarkable technique in terms of allowing the first method of producing pranlukast solid dispersion and a relatively high dissolution rate, a spray that basically requires the use of an organic solvent. There is a risk of using an organic solvent, and therefore there is a risk of environmental pollution due to the use of the organic solvent.

  Furthermore, the resulting spray-dried product was so large that it could not be formulated into capsules and was prepared only for tablets. The original product was approved in capsule form and was subsequently developed as a tablet. However, the approval process may be complex or impossible. Moreover, even if approved, it was difficult to be recognized as a substitute, and many commercial benefits could not be expected.

  Furthermore, the tablet manufactured according to Patent Document 5 (Korean Patent No. 10-0381834) also has the following problems, which are obvious to those skilled in the art of the present invention.

  Hydroxypropylmethylcellulose used to increase the solubility of pranlukast is a component commonly used as a matrix in the manufacture of sustained release tablets. When hydroxypropylmethylcellulose is administered in excess (about 1.5 times the drug), its solubility becomes dull and therefore requires the use of large amounts of disintegrant. Therefore, additional processing such as moisture-proof coating or moisture-proof packaging is required, resulting in increased manufacturing costs.

  In order to overcome the disadvantages, the inventor of the present invention heat-melted at least one water-soluble polymer selected from the group consisting of pranlukast and polyvinylpyrrolidone vinyl acetate copolymer, polyvinylpyrrolidone and polyvinyl alcohol. Presents a method for producing an amorphous pranlukast solid dispersion (Patent Document 6 [Korean Patent Application No. 2004-89455]). Compared with the conventional spray drying method, the dissolution rate and bioavailability of pranlukast are remarkably improved, and even if a small amount of drug is administered, the same medicinal effect can be obtained.

  However, when the pharmaceutical composition prepared with the solid dispersion is encapsulated, the water-soluble polymer and the gelatin capsule adhere to each other in the solution, thus delaying the initial dissolution. Therefore, the above-described invention has a serious problem that the maximum plasma concentration is lowered because the time to reach the medicinal concentration becomes longer and the disappearance rate is higher than the absorption rate of the drug. Further, the problem of adhesion between the water-soluble polymer and gelatin cannot be solved sufficiently even if a large amount of disintegrant is used, and therefore there is a problem in commercializing the solid dispersion.

International Publication No. 1996/41628 Korean Patent No. 10-389606 Japanese Unexamined Patent Publication No. 8-73353 International Publication No. 1999/04790 Korean Patent No. 10-0381834 Korean Patent Application 2004-89455 Pharmaceutical Research 1998, 15, 1748-1752 J. PHARM. Sci. 1993, 82, 32-38

  The inventor of the present invention has made a lot of efforts to solve the disadvantages of the conventional method, and as a result, by heating and mixing the anticoagulant with a predetermined HLB and the pranlukast solid dispersion, pranlukast The present invention has been completed by solving the problem of the solid dispersion adhering to the capsule wall and further discovering that the initial dissolution rate and in-vivo utilization efficiency are improved.

  That is, according to the present invention, particularly when an anticoagulant such as polyethylene glycol having an HLB of 10 to 40 is used, the initial dissolution behavior, in vivo utilization efficiency and Cmax can be remarkably improved.

  Accordingly, it is an object of the present invention to provide a pharmaceutical composition of pranlukast solid dispersion and a method for producing the same which improve the problem that the pranlukast solid dispersion adheres to the capsule wall.

  In one aspect, the present invention relates to an anticoagulant having a HLB of 10 to 40 and a solid or semi-solid at room temperature with respect to 100 parts by weight of pranlukast solid dispersion. A pharmaceutical composition of a pranlukast solid dispersion is provided.

  In another aspect, the present invention provides (a) a pranlukast solid dispersion and an anticoagulant that has a HLB of 10-40 and is solid or semi-solid at room temperature in the range of 40-90 ° C. And (b) a method for producing a pharmaceutical composition of a pranlukast solid dispersion comprising the steps of cooling and granulating the mixture.

  Hereinafter, various embodiments of the present invention will be described.

  According to the present invention, an anticoagulant having an HLB in a predetermined range is heated and mixed with the pranlukast solid dispersion, and then granulated and encapsulated to obtain a pharmaceutical composition of the pranlukast solid dispersion. Adhering to the capsule wall can be prevented, and the initial dissolution rate of pranlukast can be improved. Furthermore, the pharmaceutical composition of the present invention increases the absorption concentration (Cmax) and the maximum absorption concentration (AUC) in vivo even when the same volume is administered as compared with the existing formulation technology of pranlukast, The bioavailability is improved.

  The pharmaceutical composition of a pranlukast solid dispersion according to the present invention comprises a pranlukast solid dispersion and an anticoagulant having an HLB in a predetermined range.

  The pranlukast solid dispersion is prepared with crystalline pranlukast using a water-soluble polymer and spray-drying method or heat-melting method, preferably heat-melting method, and has an amorphous structure with improved solubility. .

  The anticoagulant has 10 to 40 HLB (hydrophobic lipophilic balance). When an anticoagulant having an HLB of less than 10 is used, the hydrophilicity is small and the aggregation phenomenon is not improved. The anticoagulant is preferably a solid or semi-solid at room temperature in consideration of processability and influence on the capsule.

  Specifically, the anticoagulant is one or a mixture of two or more selected from polyethylene glycol group, polyethylene glycol fatty acid ester derivative group, polysorbate group, poloxamer group, sucrose fatty acid ester group and sodium lauryl sulfate. However, it is not limited to this. In general, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 3350, polyethylene glycol 4000, and the like can be used as the polyethylene glycol group, preferably polyethylene glycol 1500 or as a main component. Gelucire (registered trademark) (Gattefossa) consisting of a fatty acid ester of polyethylene glycol 1500 can be used. As the polysorbate group, one of polysorbate 61 or polysorbate 65 that is solid at room temperature can be used. As the poloxamer group, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407 can be used. As the sucrose fatty acid ester, a saturated or unsaturated fatty acid having 14 to 20 carbon atoms can be used. In particular, sucrose stearic acid, sucrose oleic acid, sucrose palmitic acid, sucrose myristic acid and sucrose lauric acid can be used for this purpose.

  The anticoagulant is at least one of the types described above, and the amount used is 0.1 to 10 parts by weight with respect to 100 parts by weight of the pranlukast solid dispersion. If the amount of anticoagulant used is less than 0.1 parts by weight, non-uniformity and undesirable deviations in product quality can be caused. On the other hand, when the amount exceeds 10 parts by weight, the sustained release time of the drug becomes very long, and side effects can be caused on the intestinal cells by overdosing the surfactant.

  The pharmaceutical composition of the pranlukast solid dispersion according to the invention may further contain pharmaceutically acceptable additives such as diluents, disintegrants, binders and lubricants.

  The pharmaceutical composition of the pranlukast solid dispersion of the present invention having the above-mentioned characteristics is produced by heating and mixing the pranlukast solid dispersion and the anticoagulant, cooling and granulating, and encapsulating.

  The pranlukast solid dispersion uses a water-soluble polymer, and the crystalline pranlukast is produced into an amorphous pranlukast with improved solubility by a spray drying method or preferably a heat melting method.

  When the pranlukast solid dispersion and the anticoagulant are mixed, the temperature is adjusted in the range of 40 to 90 ° C., which means that the solid or semi-solid anticoagulant is sufficient for the pranlukast solid dispersion. It is important to get wet or coated. When the said temperature is less than 40 degreeC, since an anticoagulant and a pranlukast solid dispersion do not fully contact, the desired aggregation prevention effect cannot be acquired. On the other hand, when the temperature exceeds 90 ° C., the pranlukast solid dispersion and the anticoagulant are overheated, which may cause instability. In addition, normal hot water (around 90 ° C.) is insufficient for formulation, and a special heater must be used instead, thus requiring additional heating equipment, and thus manufacturing costs. Increases and the merchantability decreases.

  The cooling temperature is preferably 20-30 ° C. After thorough mixing and cooling, it is granulated into 20-200 mesh, preferably 60-200 mesh particles. At this time, if it is less than 200 mesh, the water penetration into the composition is low, so that the disintegration is delayed. On the other hand, when the particle size exceeds 60 meshes, it takes a relatively long time until the drug dissolves in the solution after disintegration.

  The granulated pranlukast solid dispersion pharmaceutical composition does not adhere to the capsule wall after encapsulation. As a result, unlike the existing case, the initial dissolution rate of the drug is improved without using a disintegrant, and the bioavailability and bioavailability are improved even when a small amount of drug is administered.

Best Mode The present invention will be described in further detail on the basis of the following examples, which are merely illustrative of the present invention and should not be limited to the scope of the present invention.

Examples 1-3: Production of a pharmaceutical composition of a pranlukast solid dispersion using an anticoagulant Solid pranlukast is melted with copovidone, a kind of water-soluble polymer, and pranlukka A strike solid dispersion was produced, and it was confirmed by XRD (X-ray diffraction method) that the produced pranlukast solid dispersion was amorphous.

  Granules were prepared by mixing 6 g of the pranlukast solid dispersion and 0.06 g of the anticoagulant shown in Table 1 below at 60 ° C. for 30 minutes using a double-jacketed beaker. This was cooled to room temperature, sieved using a 20 mesh sieve, and then a pharmaceutical composition of granular pranlukast solid dispersion was produced.

  Lubricant was added to the pharmaceutical composition of the pranlukast solid dispersion, mixed well, and then filled into capsules using a manual capsule filler.

Comparative Examples 1-3: Preparation of a pharmaceutical composition of a pranlukast solid dispersion using a super disintegrant Using the same pranlukast solid dispersion used in Examples 1-3 above, Three kinds of super disintegrants shown in Table 2 which are widely used were mixed to prepare a pharmaceutical composition of pranlukast solid dispersion. After adding a lubricant to this and mixing, the capsules were filled in the same manner as in Examples 1-3.

Comparative Example 4: Production of a pharmaceutical composition of a pranlukast solid dispersion without using a disintegrant. The same pranlukast solid dispersion used in Examples 1 to 3 and a lubricant were mixed. The capsules were filled in the same manner as in Examples 1 to 3, but no anticoagulant and disintegrant were used.

Comparative Example 5: Commercial Pranlukast Product Ona Pharmaceutical (Korea) Onon (Registered Trademark) Capsules (Containing 225 mg of Pranlukast per Capsule) and the Pharmaceuticals of Pranlukast Solid Dispersion The compositions were compared.

Comparative Examples 4 to 15: Preparation of a pharmaceutical composition of pranlukast solid dispersion with various additions of anticoagulant 1 g of pranlukast solid dispersion identical to that used in Examples 1-3 above And an anticoagulant having a ratio shown in Table 3 below were mixed at 60 ° C., and then a pharmaceutical composition of a granular pranlukast solid dispersion was produced in the same manner as in Examples 1 to 3.

Experimental Example 1: Measurement of dissolution rate over time A capsule manufactured in Examples 1 to 15 and Comparative Examples 1 to 4 and a commercially available ONON (registered trademark) capsule of Comparative Example 5 were heated to A dissolution test was conducted with an elution solvent having a pH of 6.8 and stirring for 60 minutes at a speed of 50 rpm. The solubility for each time zone was analyzed by HPLC and determined by the following mathematical formula 1. The results are shown in Table 4 below.

前記Ｃは１カプセル当りプランルカストの重量（ｍｇ）である。

C is the weight (mg) of pranlukast per capsule.

Experimental Example 2: Observation of disintegration aspect by pH condition Using a dissolution tester (paddle method, 50 rpm), the disintegration aspect of the capsule produced in Example 4 and Comparative Example 1 was observed for 60 minutes under the following pH condition. The results are shown in Table 5 below.

  It can be seen that at pH 1.2, 4.0 and distilled water, the capsule of Example 4 is disintegrated at a rate three times faster than the capsule of Comparative Example 1.

Experimental Example 4: Measurement of bioavailability The capsule produced in Example 4 and Comparative Example 1 (containing 100 mg of pranlukast) was orally administered to six healthy adults, and then the plasma concentration of the drug was measured by LC- Analysis by Mass was performed, and the bioavailability was determined as shown in Table 6 below.

  As shown in Table 6, when the capsule of Example 4 in which the dissolution rate in the 15 minute range was improved by 70% or more was administered, compared with the capsule of Comparative Example 1 in which the dissolution rate in the 30 minute range was less than 20%. , Cmax and ACU increased 1.5-fold and Tmax shortened.

  As described above, the present invention has solved the problem that when an existing disintegrant is used for pranlukast, the pranlukast solid dispersion adheres to the capsule and the initial dissolution rate and Cmax are lowered.

  Furthermore, the present invention provides a pharmaceutical composition of a pranlukast solid dispersion that can increase the initial dissolution rate and improve the bioavailability and bioavailability even by administering less than half of the existing product. Offer things. Therefore, the pharmaceutical composition of pranlukast solid dispersion according to the present invention exhibits excellent antagonism against leukotriene even when a smaller amount of drug is administered.

The graph which compared the elution pattern of the capsule by Comparative Examples 1-4 and a commercially available ONON (trademark) capsule is shown. The graph which compared the elution pattern of the capsule by Examples 1-3 is shown. The graph which compared the elution pattern of the capsule by Example 1, the comparative example 1, and the comparative example 5 (commercially available ONON (trademark) capsule) is shown. The graph which compared the plasma density | concentration of the pranlukast by the time passage after the capsule administration by Example 4 and the comparative example 1 is shown.

Claims (6)

  Pranlukast comprising 100 to 10 parts by weight of pranlukast solid dispersion and containing 0.1 to 10 parts by weight of anticoagulant having HLB of 10 to 40 and solid or semi-solid at room temperature A pharmaceutical composition of a solid dispersion.   2. The pranlukast solid dispersion according to claim 1, wherein the pranlukast solid dispersion has an amorphous structure produced by spray-drying or heat-melting a crystalline pranlukast using a water-soluble polymer. A pharmaceutical composition of a solid dispersion.   3. The pranlukast solid dispersion according to claim 2, wherein the pranlukast solid dispersion has an amorphous structure in which crystalline pranlukast is manufactured using a water-soluble polymer by a heat melting method. The pharmaceutical composition of the body.   The anticoagulant is one or a mixture of two or more selected from the group consisting of polyethylene glycol group, polyethylene glycol fatty acid ester derivative group, polysorbate group, poloxamer group, sucrose fatty acid ester group and sodium lauryl sulfate. The pharmaceutical composition of pranlukast solid dispersion according to claim 1, characterized in that   The anticoagulant is one or a mixture of two or more selected from the group consisting of polyethylene glycol group, fatty acid ester derivative group of polyethylene glycol, lauryl macrogol glyceride and sodium lauryl sulfate. A pharmaceutical composition of a pranlukast solid dispersion according to claim 3, characterized in that it is characterized in that (A) a step of mixing a pranlukast solid dispersion with an anticoagulant having an HLB of 10 to 40 and being solid or semi-solid at room temperature while adjusting to a range of 40 to 90 ° C., and (b) ) A method for producing a pharmaceutical composition of a pranlukast solid dispersion, comprising the steps of cooling and granulating the mixture.

Images