KR101476096B1 - Pharmaceutical composition comprising celecoxib with improved solubility - Google Patents

Abstract

Disclosed is a pharmaceutical composition containing a celecoxib vehicle including celecoxib, an absorption regulating agent, and a dispersing agent, wherein the pharmaceutical composition is characterized to have a particle size of celecoxib of the celecoxib vehicle is 1 μm (D90) or less.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING CELECOXIB WITH IMPROVED SOLUBILITY [0002]

The present invention relates to a pharmaceutical composition of celecoxib having improved solubility. More particularly, the present invention relates to a pharmaceutical composition comprising a celecoxib, a dispersing agent and an absorption controlling agent, and a celecoxib vehicle having a particle size of 1 m or less.

(4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide) It is reported that heterocycle derivative compounds can prevent or treat COX-2 mediated disease states such as rheumatoid arthritis, osteoarthritis, pain, Alzheimer's disease and colon cancer.

[Chemical Formula 1]

However, since celecoxib exhibits extremely low solubility, it is known that it is difficult to obtain a satisfactory bioavailability when it is used as a solid preparation. Therefore, in formulating celecoxib, measures are needed to compensate for the low solubility and the resulting decrease in bioavailability. Also, when formulated into a solid formulation such as tablets or capsules due to the low solubility of celecoxib, rapid dissolution and dispersion in the gastrointestinal tract is not achieved. Further, since celecoxib has electrostatic characteristics, cohesiveness, low bulk density, low compressibility and poor fluidity, it is difficult to prepare a composition having uniformity. As described above, due to low solubility, celecoxib is not only difficult to produce a uniform mixture, but also has ineffective release and elution, resulting in lower bioavailability.

In this regard, Korean Patent No. 501034 discloses a pharmaceutical composition having a particle size distribution wherein the D90 of the particles in the longest dimension of the celecoxib particles is 200 mu m or less. However, in this document, the solubility is increased by differentiating particles of celecoxib. Thus, there is a limitation in increasing the solubility and bioavailability only by controlling the particle size.

Korean Patent No. 793668 discloses a celecoxib drug substance present as an amorphous celecoxib. This document discloses a complex of Celecoxib crystallization inhibitor comprising amorphous celecoxib particles or celecoxib drug substance which are intimately bound to one or more crystallization inhibitors such as polymers.

Korean Patent No. 1237646 relates to a solid dispersion containing celecoxib in which celecoxib is amorphous and has excellent dissolution rate and long-term storage stability, and thus can be applied to solid pharmaceutical compositions for oral use Lt; RTI ID = 0.0 > celecoxib < / RTI >

Korean Patent Laid-Open Publication No. 2013-69484 discloses a celecoxib-containing solid dispersion comprising celecoxib, a water-soluble polymer carrier and a surfactant, and a process for producing the same. The solid dispersion of celecoxib disclosed in this document shows that the water solubility and dissolution rate of celecoxib, which is a poorly soluble drug, is increased, the bioavailability is remarkably improved upon oral administration, and recrystallization to a crystalline form is minimized, .

Korean Patent Publication No. 2013-124113 provides a eutectic mixture comprising celecoxib or a pharmaceutically acceptable salt thereof and poloxamer. The above document is to provide a eutectic mixture with improved solubility by adding poloxamer to celecoxib or a pharmaceutically acceptable salt thereof.

However, the above-mentioned documents are merely obtained by increasing the solubility of the celecoxib particles by differentiating or forming a eutectic mixture, and the effect of increasing the solubility or increasing the bioavailability is unsatisfactory as compared with existing commercial products. Particularly, when the solubility is increased by conventional means, unlike the expectation, it is impossible to achieve the same bioavailability as existing commercial formulations due to the fact that there is no effect of actually increasing the bioavailability in vivo or it is extremely weak, It was considered impossible to achieve equivalent bioavailability while reducing the dose.

On the other hand, currently available medicines including celecoxib may increase the risk of serious cardiovascular thrombosis, myocardial infarction and stroke when administered to a subject in need thereof, and may cause gastric or intestinal bleeding, ulceration and perforation It is known that it can increase the risk of serious gastrointestinal adverse reactions, including.

Accordingly, the present inventors have found that, in providing a pharmaceutical composition comprising celecoxib, a celecoxib vehicle composed of an absorption controlling agent and a dispersing agent significantly improves solubility and bioavailability, and furthermore surprisingly, depending on the dose of celecoxib Resulting in increased cardiovascular side effects or gastrointestinal side effects, leading to the present invention.

Korean Patent No. 501034 Korean Patent No. 793668 Korean Patent No. 1237646 Korean Patent Publication No. 2013-69484 Korea Patent Publication No. 2013-124113

A celecoxib vehicle having improved solubility and bioavailability of celecoxib in which wettability is improved and particle re-aggregation is inhibited, and a high solubility in vivo as well as high bioavailability in vivo It is an object of the present invention to provide a pharmaceutical composition.

It is another object of the present invention to provide a pharmaceutical composition in which a cardiovascular side effect or gastrointestinal side effect, which is known to increase with the dose of celecoxib, is less than that of a commercially available drug.

As a means for solving the above problem, the present invention provides a pharmaceutical composition comprising a celecoxib vehicle consisting of celecoxib, a dispersing agent and an absorption regulator.

In addition, in the pharmaceutical composition, the celecoxib vehicle contains a phospholipid as an absorption controlling agent, and as a dispersing agent, sodium docusate, sodium lauryl sulfate, poloxamer, polysorbate, polyethylene glycol, sorbitan Ester, polyoxylated castor oil, and polyoxyethylene stearate.

According to the pharmaceutical composition comprising the celecoxib vehicle according to the present invention, the solubility and bioavailability of the celecoxib are improved, the wettability of the celecoxib is improved, and the re-aggregation of the particles is suppressed, Can be provided.

Particularly, according to the pharmaceutical composition comprising the celecoxib vehicle according to the present invention, the expression of the cardiovascular side effect or the gastrointestinal side effect which is increased according to the dose of celecoxib is less than the existing commercial formulation.

In addition, the celecoxib vehicle of the present invention can be used to form various pharmaceutical compositions and can be formulated into various formulations.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a photograph comparing wettability and dispersibility of the examples according to the present invention and the comparative examples. Fig.

The term " celecoxib vehicle " in the present invention means a vehicle containing an absorption controlling agent and a dispersing agent together with celecoxib, specifically, a state in which the substance is dispersed or dissolved in a solvent, Is removed and only the solid content remains.

In particular, the celecoxib vehicle of the present invention achieves the effect of decreasing the particle size of the celecoxib unit and increasing the solubility by the dispersing agent, and showing the result that the bioavailability is enhanced by the absorption controlling agent. That is, the cerecoxib vehicle of the present invention has higher bioavailability than the celecoxib composition having the same solubility and particle size as the celecoxib particles contained in the celecoxib vehicle.

Hereinafter, the present invention will be described in detail.

Celecoxib is a poorly soluble drug, and its solubility has a direct effect on bioavailability. In order to improve the solubility of the drug, a conventional commercial preparation (Celebrex capsule, Pfizer Korea) It contains a cocksive.

On the other hand, the dissolution of a drug is a process in which after the drug particles are brought into contact with the solvent, the surface of the drug particles is wetted in the solvent, and thereafter the drug molecules are diffused from the drug particles into the surface diffusion layer around the drug particles. In the dissolution of such a drug, the poorly soluble drug lowers the wettability of the drug surface upon contact with the solvent due to the hydrophobic property of the drug, thereby lowering the dissolution rate and solubility of the drug. Further, even if the drug molecule is wetted, the drug particles again aggregate with each other before the drug molecules diffuse from the drug particle into the surface diffusion layer, thereby reducing the surface area of the drug, which causes the drug to dissolve, thereby lowering the dissolution rate and solubility. Therefore, the dissolution rate and solubility of the drug can be improved by inhibiting the wettability of the poorly soluble drug and the re-aggregation of the poorly soluble drug particle.

The celecoxib vehicle of the present invention comprises a dispersing agent for enhancing the wettability of celecoxib and inhibiting re-aggregation, characterized in that the size of the celecoxib particles is 1 m (D90) or less.

The dispersing agent may be selected from, but not limited to, sodium docusate, sodium lauryl sulfate, poloxamer, polysorbate, polyethylene glycol, sorbitan ester or polyoxylated castor oil.

Such celecoxib vehicles have increased solubility due to particle size reduction, and the inventors have found that satisfactory bioavailability can not be achieved by simply increasing solubility based on particle size reduction. Therefore, in the present invention, through the so-called celecoxib vehicle, it has been attempted to increase the solubility of celecoxib and the actual bioavailability in vivo.

Specifically, in the present invention, a celecoxib vehicle consisting of a dispersant, an absorption controlling agent and celecoxib is used.

That is, according to the study of the present inventors, no matter how much the celecoxib is pulverized, the solubility increase rate is lower than that of the celecoxib vehicle unless it contains a dispersant such as a celecoxib vehicle. This is because celecoxib is re-agglomerated immediately upon crushing by the hydrophobicity of celecoxib.

Furthermore, when only celecoxib and a dispersant were included, the solubility-increasing effect was somewhat satisfactory, but the actual bioavailability was not satisfactory. Accordingly, preparation of celecoxib vehicle by adding an absorption modifier to the celecoxib vehicle resulted in satisfactory results in both increased solubility and increased bioavailability.

That is, the oral bioavailability of the celecoxib vehicle is increased by the phospholipid, an absorption regulating agent contained in the celecoxib vehicle. A phospholipid is a lipid containing phosphorus, which is an amphoteric substance in which polar and non-polar moieties are present in one molecule. It is one of the main components constituting the biological membrane and is one of digestive components secreted in the gastrointestinal tract of the living body.

The phospholipid that can be included in the celecoxib vehicle of the present invention includes, but is not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and the like. Be in

In the celecoxib vehicle of the present invention, the dispersing agent may be used in an amount of 0.01 to 1 part by weight based on 1 part by weight of celecoxib, and 0.01 to 1 part by weight based on 1 part by weight of the celecoxib.

Such a celecoxib vehicle can be administered to a patient as a preparation in which the celecoxib drug is formulated into a liquid form preparation by mixing with a pharmaceutically acceptable solvent to reduce the dose of celecoxib, as well as a pharmaceutically acceptable preparation process And can be formulated into granules, capsules, and tablets. The celecoxib vehicle of the present invention prepared in a variety of formulations, such as liquid or solid formulations, exhibits higher celecoxib solubility and bioavailability than the commercially available Celebrex capsules (Korean Pfizer).

In addition, a similar solubility is observed in a vehicle of the present invention containing a composition comprising celecoxib and a dispersant of 1 m (D90) or less and celecoxib of 1 m or less (D90), but when measuring the bioavailability thereof, The bioavailability of the sieve vehicle is higher. That is, it can be confirmed that the oral bioavailability of the celecoxib vehicle is increased by the phospholipid, an absorption regulating agent contained in the celecoxib vehicle.

In particular, surprisingly, according to the present invention, it is possible to reduce the expression of cardiovascular side effects or gastrointestinal side effects which are increased according to the dose of celecoxib.

Hereinafter, the present invention will be described by way of examples. It should be noted, however, that the following embodiments do not limit the scope of the present invention as an exemplary embodiment of the present invention, and various modifications may be made within the scope of the present invention.

Examples 1 to 5

Cerechoxic vehicle (25% w / v) was prepared using water as a solvent according to the prescription described in Table 1 below. First, the thickening agent and the dispersing agent were added to the water and dispersed, then celecoxib was added, and phospholipid, which is an absorption controlling agent, was added. Thereafter, a celecoxib vehicle was prepared using a bead grinder. The celecoxib contained in the thus prepared celecoxib vehicle was confirmed to have a particle size of about 0.9 mu m (D90).

Example No. Celecoxib Incrementer Dispersant Absorption regulator Solubility
(μg / ml) One 1 part by weight 0.5 parts by weight of white sugar 0.05 part by weight of docusate sodium 0.05 part by weight phospholipid 153 2 1 part by weight 0.5 part by weight < tb > 0.05 part by weight of docusate sodium 0.05 part by weight phospholipid 154 3 1 part by weight 0.5 part by weight of white sugar,
0.5 part by weight < tb > 0.05 part by weight of docusate sodium 0.05 part by weight phospholipid 152 4 1 part by weight 0.5 part by weight of white sugar,
0.5 part by weight < tb > 0.05 part by weight of docusate sodium,
Sodium lauryl sulfate 0.05 part by weight 0.05 part by weight phospholipid 155 5 1 part by weight 0.5 part by weight of white sugar,
0.5 part by weight < tb > 0.05 part by weight of docusate sodium,
Sodium lauryl sulfate 0.05 part by weight 0.5 parts by weight phospholipid 154

Comparative Examples 1 to 17

The celecoxib composition was prepared in the same manner as in the above example, using water as a solvent and following the prescription described in Table 2 below. Comparative Examples 1 to 11 include a dispersing agent but not an absorption controlling agent, Comparative Examples 12 to 16 do not contain both a dispersing agent and an absorption controlling agent, and Comparative Example 17 is a commercial formulation.

Comparative Example No. Celecoxib Incrementer Dispersant Absorption regulator Solubility
(μg / ml) One 1 part by weight 0.5 parts by weight of white sugar 0.05 part by weight of docusate sodium 151 2 1 part by weight 0.5 parts by weight of white sugar Sodium lauryl sulfate 0.05 part by weight 150 3 1 part by weight 0.5 parts by weight of white sugar Poloxamer 0.05 part by weight 146 4 1 part by weight 0.5 parts by weight of white sugar Polysorbate 0.05 part by weight 141 5 1 part by weight 0.5 parts by weight of white sugar Polyethylene glycol 0.05 part by weight 138 6 1 part by weight 0.5 parts by weight of white sugar Sorbitan ester 0.05 part by weight 145 7 1 part by weight 0.5 parts by weight of white sugar 0.05 parts by weight of polyoxyl-hardened castor oil 144 8 1 part by weight 0.5 parts by weight of white sugar 0.05 parts by weight of polyoxyethylene stearate 146 9 1 part by weight 0.5 part by weight < tb > 0.05 part by weight of docusate sodium 155 10 1 part by weight 0.5 part by weight of hydroxypropyl cellulose 0.05 part by weight of docusate sodium 139 11 1 part by weight 0.5 part by weight povidone 0.05 part by weight of docusate sodium 138 12 1 part by weight 0.5 parts by weight of white sugar - - 12 13 1 part by weight 0.5 part by weight < tb > - - 15 14 1 part by weight HPC 0.5 part by weight - - 9 15 1 part by weight 0.5 part by weight povidone - - 8 16 1 part by weight 0.5 part by weight of white sugar,
0.5 part by weight < tb > - - 11 17 Commercially available products (Celebrex capsules, Pfizer Korea) 3

Experimental Example 1 - Solubility test

The solubility test was carried out using the examples, comparative examples and commercially available formulations. The solubility test method is as follows.

After adding each of the example, comparative example and commercial formulation to water, the mixture was stirred at 37 ° C for 24 hours and centrifuged at 12,000 rpm to obtain a supernatant. The supernatant was analyzed as follows to determine the solubility by measuring the concentration of celecoxib.

[Analytical Conditions - Liquid Chromatography]

Column type: Lichrospher 100, RP-18 (5 m, 250 mm x 4.6 mm)

- Mobile phase: Acetonitrile: pH 6.0 Buffer = 55:45 (v / v)

- Column temperature: 20-25 ° C

- detector: ultraviolet absorptiometer, 251 nm

- Flow rate: 1.0 mL / min

- Injection amount: 10 μl

- Collection time: 15 minutes

The experimental results are shown together in Table 1 above. As can be seen from Table 1, the celecoxib vehicle of the present invention containing a dispersing agent and an absorption controlling agent is remarkably superior in solubility to a celecoxib composition not containing a dispersing agent and an absorption controlling agent.

Example 6

[Celecoxib vehicle-containing suspension]

After adding 50 g of white sugar and 30 g of hyphromel to 1,200 g of water, 4 g of sodium disuccinate as a dispersant and 7 g of sodium laurylsulfate were added and dissolved (if necessary, heated). 200 g of celecoxib was added thereto, and 11 g of phospholipid as an absorption controlling agent was added thereto. The suspension was prepared by pulverizing the celecoxib particle size of the celecoxib vehicle to about 0.3 mu m (D90) using a bead pulverizer.

Example 7

[Tablets containing celecoxib]

22 g of sodium lauryl sulfate was added to the celecoxib vehicle-containing suspension prepared in Example 6 to spray-dry 273 g of lactose in a fluidized bed granulator, and then dried. 25 g of microcrystalline cellulose, 86 g of crospovidone and 10 g of colloidal silicon dioxide were added to the dried product, and then 7 g of magnesium stearate was added thereto, and the mixture was filtered and purified using a rotary tablet machine. The defined weight of the tablet thus prepared is 725 mg.

Comparative Example 18

50 g of white sugar and 30 g of hyphromelose were added to 1,200 g of water, 4 g of docusate sodium as a dispersant and 7 g of sodium laurylsulfate were added to dissolve (if necessary, heated) and 200 g of celecoxib was added. The suspension was pulverized to a particle size of about 0.3 mu m (D90) using a bead pulverizer to prepare a suspension.

EXPERIMENTAL EXAMPLE 2 - Evaluation of bioavailability

(Celebrex Capsule, Korea Pfizer) were orally administered to rats (n = 3) in an amount corresponding to 5 mg / kg as celecoxib, respectively, to determine the bioavailability (%) Were evaluated.

At this time, tablets containing celecoxib were suspended in an appropriate amount of water and then orally administered to rats.

division Example 6
(Suspension) Example 7
(refine) Comparative Example 18 Commercial product AUC (ng · h / ml) 6293 6205 5281 4401 Bioavailability (%) 143 141 120 100

As a result of the evaluation, it can be confirmed that a celecoxib vehicle containing a phospholipid as an absorption regulator exhibits a higher bioavailability than a comparative example having a similar particle size and a commercially available product.

Experimental Example 3 - Wettability and dispersibility test

Comparative Example 16 and celecoxib vehicle (Example 4) were placed in water, stirred using a propeller type stirrer at 100 rpm for 15 minutes, and left standing for 1 minute to confirm wettability and dispersibility. The test results are shown in Fig.

Claims (4)

Celecoxib;
An absorption modifier selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol; And
A dispersant selected from the group consisting of docusate sodium, sodium lauryl sulfate, poloxamer, polysorbate, polyethylene glycol, sorbitan esters, and polyoxyl-
Wherein the particle size of the celecoxib is less than or equal to 1 m (D90). ≪ Desc / Clms Page number 13 >
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