KR101770403B1 - Solid dispersion of celecoxib having improved solubility and method for preparing the same - Google Patents

Abstract

The present invention relates to a celecoxib solid dispersion having improved solubility and a process for producing the same. More particularly, the present invention relates to a celecoxib composition comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorbent carrier, And 25 to 75 parts by weight of a water penetration enhancer, wherein the dissolution rate of celecoxib is remarkably improved.
The celecoxib solid dispersion of the present invention has an effect of significantly increasing the solubility of celecoxib and not only can improve the bioavailability, but also the celecoxib in the solid dispersion does not change into a crystalline form even when stored for a long period of time, And exhibits an effect of having excellent stability by maintaining the shape.

Description

TECHNICAL FIELD The present invention relates to a solid dispersion of celecoxib having improved solubility and a method for preparing the solid dispersion of celecoxib having improved solubility,

The present invention relates to a celecoxib solid dispersion having improved solubility and a process for producing the same. More particularly, the present invention relates to a celecoxib composition comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorbent carrier, And 25 to 75 parts by weight of a water penetration enhancer, wherein the dissolution rate of celecoxib is remarkably improved.

Attempts have been made to improve their solubility in the use of sparingly soluble materials as medicaments. Amorphization is known as a physicochemical method for such attempts. The amorphization method is a method of breaking down the crystal structure of the material to a minute level down to the molecular level. One form of this amorphization method is a solid dispersion. The solid dispersion contains a substance dispersed at a molecular level in the solid, and the so-called solid is in a state dissolved in the solid. In the solid dispersion, since the dispersed substances are not in contact with each other, crystallization hardly occurs, and stability of the substance in an amorphous state is generally improved.

As a method for producing the solid dispersion, there may be mentioned a solvent method (Chem. Pharm. Bull., 34 (8), 3408 (1986)) in which a substance and a water-soluble polymer are dissolved in an appropriate solvent to remove the solvent, (See J. Pharm. Sci., 59, 937 (1970)), a mixed pulverization method in which a substance and a water-soluble polymer are mixed and ground using a ball mill or the like (see Pharmaceutical Sciences, 45 (4), 291 1985), a spray drying method in which a drug and a water-soluble polymer solution are spray-dried (see Chem. Pharm. Bull., 44 (3), 568 (1996)).

On the other hand, the selective cyclooxygenase-2 (COX-2) inhibitors can be usefully used for the prevention or treatment of diseases of inflammation and pain. Celecoxib is known as a representative example of the above-mentioned selective cyclooxygenase-2 (COX-2) inhibitor and is used as an active ingredient of Celebrex available from Pharmacia Corporation. 1, which has the structure of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol- 1-yl] benzenesulfonamide as in Example 1, and cyclooxygenase- ), Thereby being useful for the treatment and / or prevention of COX-2 mediated diseases.

[Chemical Formula 1]

Methods for making celecoxib are disclosed in U.S. Patent No. 5,466,823, U.S. Patent No. 5,892,053, and the like. U.S. Patent No. 5,466,823 describes 1,5-diarylpyrazole compounds as being useful in the treatment of inflammation and inflammation related disorders, as well as general dosage formulations of such 1,5-diarylpyrazole compounds , Wherein such dosage formulations include preparations which can be administered orally, such as tablets and capsules.

Celecoxib is characterized by the absence of side effects associated with the inhibition of cyclooxygenase-1, which can occur in conventional non-steroidal anti-inflammatory agents. Therefore, there is a need for a form suitable for preparing a pharmaceutical composition for rapid onset oral administration which rapidly alleviates pain through selective inhibition of cyclooxygenase-2. However, since celecoxib exhibits very low solubility, especially in an aqueous medium, it is not dissolved and dispersed so that it is rapidly absorbed in the gastrointestinal tract upon oral administration. For this reason, the absolute bioavailability of celecoxib is only about 30%, and the relatively low bioavailability of celecoxib is mainly due to poor availability of the gastrointestinal tract in an acidic environment. Thus, there is a need to improve the low water solubility of celecoxib and the low dissolution rate in the gastrointestinal tract.

Celecoxib has problems in formulating into a rapid onset dosage form due to cohesion, low volume density, low compressibility, and factors associated with crystal structure. Celecoxib having a crystalline form that tends to form a long tacky needle shape is a non-uniformly mixed composition containing an undesirably large and insoluble celecoxib agglomerate that tends to separate and agglomerate during mixing with other materials . Thus, it is difficult to prepare a celecoxib-containing pharmaceutical composition having the desired composition uniformity. In addition, celecoxib requires relatively high doses, resulting in handling problems resulting from the low bulk density of celecoxib in the preparation of the celecoxib composition. Accordingly, there is a need to address a number of problems associated with the preparation of compositions and dosage forms comprising celecoxib, in particular oral dosage capable units.

Accordingly, the present inventors have conducted various studies to develop a pharmaceutical method capable of improving the low water solubility of celecoxib. As a result, they have found that a celecoxib solid dispersion consisting of celecoxib, a phospholipid, an adsorbent carrier and a moisture permeation enhancer The inventors have found that the solubility of celecoxib can be remarkably improved and the dissolution can be increased, thus completing the present invention.

Accordingly, an object of the present invention is to provide a celecoxib solid dispersion comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorptive carrier and 25 to 75 parts by weight of a moisture permeation enhancer.

Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of a pain or an inflammatory disease containing a celecoxib solid dispersion as an active ingredient.

Another object of the present invention is to provide a method for preparing a mixed solution comprising: (a) preparing a mixed solution by mixing celecoxib, a phospholipid, an adsorbent carrier, and a moisture permeation enhancer; And (b) drying the mixed solution, wherein the mixing is carried out by mixing 100 parts by weight of celecoxib, 5 to 200 parts by weight of phospholipid, 100 to 300 parts by weight of an adsorbent carrier, And 25 to 75 parts by weight of a water penetration enhancer.

In order to accomplish the above object, the present invention provides a celecoxib solid dispersion comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorbent carrier and 25 to 75 parts by weight of a moisture permeation enhancer Provide sieve.

In order to accomplish still another object of the present invention, the present invention provides a pharmaceutical composition for the prevention and treatment of pain or inflammatory diseases containing the celecoxib solid dispersion as an active ingredient.

According to another aspect of the present invention, there is provided a method of preparing a mixed solution comprising: (a) preparing a mixed solution by mixing celecoxib, a phospholipid, an adsorbent carrier, and a moisture permeation enhancer; And (b) drying the mixed solution, wherein the mixing is carried out by mixing 100 parts by weight of celecoxib, 5 to 200 parts by weight of phospholipid, 100 to 300 parts by weight of an adsorbent carrier, And 25 to 75 parts by weight of a water penetration enhancer.

Hereinafter, the present invention will be described in detail.

The present invention provides a celecoxib solid dispersion comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorbent carrier and 25 to 75 parts by weight of a moisture permeation enhancer.

The term "solid dispersion" used in the present invention means a form in which a phospholipid and celecoxib are bonded by an intermolecular bonding, that is, a surface modification, and the wettability of the celecoxib is increased by surface modification The solubility and the dissolution rate of the celecoxib can be further increased. In particular, the present invention is characterized in that celecoxib is present in an amorphous form in the solid dispersion by the surface modification of the phospholipid and the celecoxib. As used herein, the term "amorphous" means that celecoxib is not precipitated as crystals. Since celecoxib is a poorly soluble drug, when it is precipitated by crystals, it is not absorbed by the gastrointestinal tract and the bioavailability is significantly lowered. In the present invention, since celecoxib is amorphous in the solid dispersion, the solubility of celecoxib is remarkably increased, and thus the bioavailability can be remarkably improved. In addition, amorphous celecoxib present in the solid dispersion retains its amorphous form, and thus has excellent storage stability.

According to one embodiment of the present invention, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), and X-ray diffractometry are used to confirm the crystallographic change of the celecoxib solid dispersion containing celecoxib, phospholipid, adsorbent carrier and moisture penetration enhancer As a result of performing diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), it was confirmed that the inherent crystalline characteristic of celecoxib disappeared and changed to an amorphous form.

In the present invention, the phospholipid is a substance used to maintain the amorphous form of celecoxib through intermolecular interaction with celecoxib, and is preferably selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, diacylglycerophosphoethanolamine, phosphatidylserine, phosphatidyl Inositol, phosphatidylglycerol, phosphatidic acid, lysophospholipid and egg or soybean phospholipid, preferably phosphatidylcholine, but is not limited thereto.

In the present invention, the phospholipid is contained in an amount of 5 to 200 parts by weight, preferably 10 to 150 parts by weight, more preferably 50 to 150 parts by weight, and most preferably, But it is not limited thereto. If the content of the phospholipid is less than 5 parts by weight, the celecoxib may not be stabilized and a considerable amount of the crystalline celecoxib may remain. If the content exceeds 200 parts by weight, the formulation may become excessively tacky, The phospholipid may aggregate and precipitate.

The solid dispersion comprising only celecoxib and phospholipid exhibits a very sticky shape and thus is difficult to prepare as a powdered solid dispersion. Therefore, the solid dispersion of the present invention is characterized by including an adsorptive carrier in order to complete the formulation as a solid preparation.

In the present invention, the adsorptive carrier may be at least one selected from the group consisting of magnesium aluminum silicate, magnesium aluminometasilicate (Neusilin US2, UFL2), colloidal silicon dioxide, Attapulgite microcrystalline May be at least one selected from the group consisting of microcrystalline cellulose (trade name: Avicel 101, 102), lactose, hydroxypropylcellulose lowsubstituted, bentonite and kaolin, May be magnesium metasilicate aluminate, but is not limited thereto.

The adsorbent carrier contained in the solid dispersion of the present invention is contained in an amount of 100 to 300 parts by weight, preferably 150 to 250 parts by weight, and most preferably 200 parts by weight based on 100 parts by weight of the celecoxib But is not limited thereto. When the content of the adsorptive carrier is less than 100 parts by weight, the adsorbable amount is too small to form a powdered formulation. When the content of the adsorptive carrier is more than 300 parts by weight, it is difficult to control the release rate of celecoxib It is economically undesirable and an additional removal process may be required, resulting in a complicated manufacturing process.

In the present invention, the moisture permeation enhancer is used for absorbing moisture to promote dissolution of the celecoxib, and may be selected from the group consisting of croscamellose sodium, sodium starch glycolate, pregelatinized starch Pregelatinized starch, microcrystalline cellulose, crospovidone, cross-linked povidone, polyvinylpyrrolidone, PVP, Povidone, hydroxypropylcellulose, lowsubstituted, CL, Kollidone CL, alginic acid, Carboxymethylcellulose calcium salt and sodium salt, colloidal silica collidal silica, guar gum, magnesium alumimum silicate, Methylcellulose, powdered cellulose, starch, and sodium alginate. And wherein the at least one selected from the group consisting of, preferably, may be a cross-house Carmelo sodium is not limited thereto.

In the present invention, the moisture permeation enhancer is contained in an amount of 25 to 75 parts by weight, preferably 30 to 70 parts by weight, more preferably 40 to 60 parts by weight, and most preferably 50 parts by weight per 100 parts by weight of celecoxib But is not limited thereto.

When the moisture permeation enhancer contained in the solid dispersion according to the present invention is less than 25 parts by weight, the solubility of the celecoxib may decrease. When the amount of the water-penetration enhancer exceeds 75 parts by weight, the volume of the solid dispersion becomes unnecessarily large, May become too high.

The solid dispersion prepared according to the present invention can be used as it is for oral administration as it is, and the solid dispersion prepared in the present invention can be used as a pharmaceutically acceptable excipient, a disintegrant, a binder, a colorant, a stabilizer, Granules, capsules, tablets and the like can be prepared by adding the above-mentioned additives, etc. In order to make the form of the tablets into a coating tablets, they may contain a plasticizer and a plasticizer according to a conventional method.

The present invention also provides a pharmaceutical composition for the prevention and treatment of pain or inflammatory diseases containing the solid dispersion as an active ingredient.

The pharmaceutical composition according to the present invention may be formulated into a suitable form together with the above solid dispersion alone or in combination with a pharmaceutically acceptable carrier, and may further contain an excipient or a diluent. &Quot; Pharmaceutically acceptable " as used herein refers to a nontoxic composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans.

The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, it may contain various drug delivery materials used for oral administration to peptide preparations. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, etc. in addition to the above components. Other pharmaceutically acceptable carriers and preparations can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).

The composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration Lt; / RTI >

The pharmaceutical composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the administration route as described above.

In the case of a preparation for oral administration, the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, . For example, an oral preparation can be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and then processing the mixture into a granular mixture. Examples of suitable excipients include, but are not limited to, sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose and the like, fillers such as gelatin, polyvinylpyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

In the case of a preparation for parenteral administration, it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa., 1995, which is a commonly known formulary for all pharmaceutical chemistries.

 The total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses. In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. Preferably, the preferred total dosage of the pharmaceutical composition of the present invention is from about 0.01 μg to about 10,000 mg, most preferably from 0.1 μg to 500 mg (TFG 100 nM = 134.33 μg / kg, TFMG 100 nM = 137.015 μg / kg. < / RTI > However, the dosage of the pharmaceutical composition may be determined depending on various factors such as the formulation method, administration route and frequency of treatment, as well as the patient's age, body weight, health condition, sex, severity of disease, diet and excretion rate, It will be possible to determine the appropriate effective dose of the composition of the present invention by those of ordinary skill in the art in view of this point. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.

The present invention also relates to the use of a compound of formula I as defined above for the manufacture of a medicament for the treatment of inflammatory bowel diseases, diabetic eye diseases, peritonitis, osteomyelitis, meningitis, meningitis, encephalitis, pancreatitis, traumatic shock, bronchial asthma, rhinitis, sinusitis, otitis media, Inflammatory bowel disease, fibrosis, stroke, bronchitis, bronchiolitis, hepatitis, nephritis, arthritis, gout, spondylitis, lighter syndrome, nodular polyarteritis, hypersensitivity vasculitis, ruggenic granulomatosis, rheumatoid multiple myalgia, arthritic cell arthritis, , Non-arthritic rheumatism, bursitis, hay fever, suppurative (tennis elbow), Charcot's joint, hemarthrosis, Henoch-Schlenstein purpura, hypertrophic osteoarthritis, Surcoilosis, hemochromatosis, sickle cell and other hemochromatosis, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, terminal < RTI ID = 0.0 & Chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute respiratory distress syndrome, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute respiratory distress syndrome, acute respiratory distress syndrome, acute respiratory distress syndrome, Lung injury, acute lung injury, and broncho-pulmonary dysplasia. The present invention also provides a pharmaceutical composition comprising the same.

The present invention also provides a method for preparing a mixed solution comprising: (a) preparing a mixed solution by mixing celecoxib, a phospholipid, an adsorbent carrier, and a moisture permeation enhancer; And (b) drying the mixed solution, wherein the mixing is performed by mixing 100 parts by weight of celecoxib, 5 to 200 parts by weight of phospholipid, 150 to 250 parts by weight of an adsorbent carrier, And 25 to 75 parts by weight of a water penetration enhancer.

In the present invention, the type of the solvent for preparing the mixed solution is not particularly limited. Preferably, the solvent is an organic solvent which can be taken orally and has excellent volatility, for example, acetone, ethanol, or methylene chloride The species can be selected and used appropriately, but is not limited thereto.

In the present invention, the method of drying the solvent is not particularly limited. For example, spray drying using a spray dryer, fluidized bed granulator, CF granulator, vacuum dryer or the like may be used, Can be used.

The celecoxib solid dispersion of the present invention has an effect of significantly increasing the solubility of celecoxib and not only can improve the bioavailability, but also the celecoxib in the solid dispersion does not change into a crystalline form even when stored for a long period of time, And exhibits an effect of having excellent stability by maintaining the shape.

FIG. 1 shows the results of measurement of the amount of celecoxib dispersed in the celecoxib-phosphatidylcholine solid dispersion with increasing content of phosphatidylcholine.
FIG. 2 shows the morphological changes of nucilin US2 or celecoxib-phosphatidylcholine-nucilin US2 solid dispersion according to stirring time (Nucillin US2 was added for 5 minutes (a), 10 minutes (b) or 15 (C) Photo observed after stirring, celecoxib-phosphatidylcholine-nucilin US2 stirred for 5 minutes (d), 10 minutes (e) or 15 minutes (f)
Fig. 3 shows the results of evaluating changes in the amount of dispersion of the celecoxib solid dispersion depending on the type of water penetration enhancer or diluent.
Fig. 4 shows the results of evaluation of dissolution characteristics of the pure celecoxib itself and the celecoxib solid dispersion (SD: solid dispersion)
FIG. 5 is a diagram showing differential scanning calorimetry (DSC) results of (a) nucilin US2, (b) phosphatidylcholine, (c) croscarmellose sodium (CCS) or (d) physical mixtures.
Figure 6 shows the differential scanning calorimetry of (a) celecoxib, (b) celecoxib + phosphatidylcholine, (c) celecoxib + phosphatidylcholine + nucilin US2 or (d) celecoxib + phosphatidylcholine + nucilin US2 + Croscarmellos sodium (DSC) results.
FIG. 7 is a graph showing powder X-ray diffraction results of (a) celecoxib, (b) phosphatidylcholine, (c) nucilane US2 or (d) Croscarmellose sodium.
Fig. 8 is a graph showing the results of a comparison between the powder X (c) of celecoxib, celecoxib + phosphatidylcholine, celecoxib + phosphatidylcholine + nucilin US2 or d) celecoxib + phosphatidylcholine + nucilin US2 + Croscarmellos sodium - line diffraction pattern.
Fig. 9 is a schematic diagram of the hydrogen bonding structure of celecoxib and phosphatidylcholine.
FIG. 10 is a graph showing the results of (a) Celecoxib, (b) Celecoxib + Phosphatidylcholine, (c) Celecoxib + Phosphatidylcholine + Nucilin US2, (d) Celecoxib + Phosphatidylcholine + Nucillin US2 + Croscarmellos sodium or ) FT-IR spectrum of the physical mixture.

Hereinafter, the present invention will be described in detail.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

<Experimental Method>

1. Reagents

Celecoxib (CLC) was purchased from Dong-Gwang Pharmaceutics (Seoul, Korea), and neucilin (Neusilin® US2, Magnesium alumino metasilicate) was purchased from Woo-Shin Medics (Seoul, Korea). Phosphatidylcholine (PC) was purchased from Lipoid (Seoul, Koera). Sodium starch glycolate, Lactose and Croscarmellose sodium were purchased from WonPoong pharmaceutical company (Seoul, Korea). Crospovidone was purchased from BASF (Cleveland, Ohio, USA). Mannitol and Dextrose were purchased from Daejung chemicals & metal Co., Seoul, Korea. Methanol and ethanol were purchased from Burdick and Jackson (Muskegon, MI, USA) as HPLC grade.

2. Preparation of solid dispersion

Solid dispersions of celecoxib and phosphatidylcholine were prepared by solvent evaporation method using ethanol. The composition of the solid dispersion was prepared with different proportions of components. Celecoxib and phosphatidylcholine were respectively quantified and added to ethanol, followed by stirring using a magnetic stirrer (Varomag, Erweka, Germany). When the celecoxib-phosphatidylcholine mixture became amorphous, it was placed in a petridish, and the fume food was hot-air dried using a dryer.

3. Preparation of solid dispersion with adsorbing material added

An adsorbing material was added to prepare a solid dispersion. Celecoxib and phosphatidylcholine were quantified and added to ethanol, followed by stirring using a magnetic stirrer. After the celecoxib-phosphatidylcholine mixture became amorphous, adsorbent material (Neusilin® US2) was added and mixed. The mixture was placed in a petri dish and the ethanol was evaporated using a dryer in the hood. The dried powder was filtered using a sieve of 100 mu m size. All experimental procedures were carried out at room temperature.

4. Evaluation of Adsorption of Celecoxib and Phosphatidylcholine

Celecoxib (100 mg) and phosphatidylcholine (150 mg) were placed in a screw capped glass vial and dissolved in 10 ml of ethanol. 200 mg of adsorbing material (Neusilin® US2) was then added to the vial and mixed. Samples were taken at 5, 10, and 15 minutes after stirring to observe the change of adsorption of celecoxib and phosphatidyl on Neusilin®, and they were placed on slide glass and cover glass and examined by optical microscope light microscopy, S38, Microscopes INC., St. Louis, MO, USA) and image analysis software (ScopePhoto, Hangzhou, China).

5. Preparation of solid dispersion containing adsorbent and water penetration enhancer or diluent

Solid dispersions were prepared using three types of water penetration enhancers (croscarmellose sodium, starch glycolate sodium, crospovidone) and diluents (lactose, mannitol, dextrose). To obtain a solid dispersion having a particle size of a certain size, a dried solid dispersion was sieved using a sieve having a size of 100 mu m. All experimental procedures were carried out at room temperature.

6. Quantitative evaluation of dispersed celecoxib in solid dispersion

After a certain amount of powder was dispersed in water (2 ml), the mixture was stirred for 12 hours (room temperature, 24 ° C) using a magnetic stirrer, and centrifuged at 5,000 rpm for 10 minutes (Gyrogen 1580 MGR, Korea). After centrifugation, 100 쨉 l of Centrifuge tube supernatant was diluted with 900 쨉 l of methanol. The diluent was then filtered through a syringe filter (0.45 μm PVDF) and the amount of drug dispersed in each sample was determined using HPLC.

7. Evaluation of hygroscopicity of solid dispersion

 A solid dispersion sample with added moisture penetration enhancer (croscarmellose sodium, starch glycolate sodium, crospovidone) and adsorbent material (Neusilin® US2) was prepared. The capillary tube was filled with a solid dispersion sample and a pure moisture permeation enhancer sample to a height of 5 cm. The filter paper was adhered to the bottom of the tube to prevent leakage of the sample. A capillary tube was vertically placed in the water to which methylene blue had been added to measure the time for the water to rise to 5 cm height.

 8. High Performance Liquid Chromatographic Analysis (HPLC) of Celecoxib

The amount of drug in each sample was analyzed by high performance liquid chromatography (YL-9100 HPLC system, Young Lin, Korea). The column used was a C18 column (250 x 4.6 mm, 5 μm, Agilent) and a mobile phase with a methanol-water mixture (75:25, v / v%). The flow rate was set to 1.26 ml / min, and the ultraviolet ray measurement wavelength was set to 250 nm. The retention time of the celecoxib peak was about 4.6 minutes.

9. In vitro dissolution test

The dissolution test was carried out using 900 ml of purified water and an elution apparatus (EDT-08LX, Electrolab) according to USP dissolution Apparatus II (paddle method) (37 ± 0.5 ° C, 100 rpm). The dissolution test was carried out using pure celecoxib as a control group and a solid dispersion (corresponding to 30 mg of celecoxib) as an experimental group. 2 ml of sample was extracted from the eluate at 5, 10, 20, 40, 60, 90, 120, 180, 240 and 300 minutes after the start of elution and 2 ml of fresh eluate was added to each vessel to maintain the initial volume Respectively. Samples were filtered with a 0.45 μm PVDF syringe filter and analyzed by high performance liquid chromatography.

10. Differential Scanning Calorimetry (DSC)

DSC analysis of the samples was performed using a differential scanning calorimeter (STA S-1000, Sinco, Korea). Each 5 mg sample was placed on an aluminum pan and a thermogram of each sample was obtained while heating from 30 ° C to 350 ° C at a rate of 10 ° C / min.

11. Powder X-ray diffraction (XRD)

The X-ray diffraction pattern of the pure celecoxib and the solid dispersion was evaluated using an X-ray diffractometer (D8 Advance, Bruker, Germany). X-ray diffraction results were obtained with a scan speed of 6 deg / min and a scan range of 0.02 steps of 3 - 40 ° (2 θ).

12. Fourier Transform Infrared Spectroscopy

2 mg of pure drug and solid dispersion sample were mixed with 200 mg of KBr and made into a pellet. The spectrum corresponding to each sample was measured using a Fourier transform infrared spectrophotometer (MB-100 BOMEM, Hartmann & Braun, Canada) .

<Experimental Results>

1. Measurement of celecoxib dispersion amount with increase of phosphatidylcholine content

The solubilities of the Celecoxib (CLC) solid dispersion formulations prepared using phosphatidylcholine (PC) are shown in Table 1 and FIG.

As shown in Table 1 and FIG. 1, it was confirmed that the water solubility of the drug increases as the content of phosphatidylcholine contained in the celecoxib solid dispersion increases. F5, the saturation solubility of the formulation, showed a 430-fold increase in the amount of the pure drug compared to the pure drug containing pure celecoxib alone.

On the other hand, it was observed that the turbidity of the dispersed solution increases as the content of phosphatidylcholine increases. It is believed that this phenomenon is caused by aggregation of phospholipids (Dahim et al., 1998; Ickenstein et al., 2006).

Centrifugation was carried out at 5000 rpm or 10000 rpm for 10 minutes to determine the appropriate centrifugation rpm for separating the drug particles from the undissolved phosphatidylcholine mixture. The drug was better separated at 5000 rpm, and the longer the centrifugation time and the higher the rpm, the more flocculated particles flocculated on the bottom, resulting in a decrease in the amount of drug particles being separated (Table 2).

Therefore, in the subsequent experiments, centrifugation was carried out using a rotation number of 5000 rpm in order to separate the drug particles from the supernatant. Therefore, the supernatant was firstly diluted with methanol, filtered through a 0.45 μm PVDF filter, and analyzed by HPLC. Celecoxib formulated with phosphatidylcholine showed a sticky shape even after drying. This has served as a difficulty to prepare celecoxib oral solid preparations. Thus, it was confirmed that it is necessary to use an adsorptive carrier to powder the celecoxib formulation.

2. Preparation of dispersion using adsorbent carrier

In order to use Nucilin US2 (Neusilin US2) with a size of 100 μm or less, Nucillin US2 was screened using a sieve with 100 μm pore size. Nucillin US2 was stirred at 1000 rpm for 5, 10 or 15 minutes using a magnetic bar in order to disperse US2 in a mixture of celecoxib and phosphatidylcholine. The shape of nucilin US2 was then observed using a microscope.

The results are shown in Fig.

As shown in Fig. 2, the shape of the mixture agitated for 15 minutes was not significantly different from that of the mixture agitated for 10 minutes. Thus, in the subsequent experiments, stirring was carried out for 10 minutes to prepare a dispersion of celecoxib, phosphatidylcholine and nucilin US2.

3. Evaluation of the amount of dispersion of the celecoxib formulation containing the adsorptive carrier

Nucillin US2, one of the powerful adsorbents, was used in this experiment because of its strong adsorption capacity. 100 mg of nucilin US2 adsorbed only a small amount in celecoxib and phosphatidylcholine solid dispersion, while 200 mg and 300 mg of nucilin US2 showed excellent adsorption capacity. Thus, 200 mg of nucilane was used in subsequent experiments.

Although Nucillin US2 was well suited to prepare a powdered formulation by adsorbing the sticky celecoxib-phosphatidylcholine solid dispersion very well, solubility in distilled water of the solid dispersion formulation adsorbed using Nucillin US2 was significantly (Table 3).

Nuclide US2 is a porous particle with a very large pore diameter of about 1 μm. Therefore, most phosphatidylcholine and celecoxib are absorbed into the macropores of nucilin US2 and become deeply embedded in the silicate channel (Gumaste, Pawlak, et al. 2013). This phenomenon is considered to be a cause of low solubility of celecoxib in the solid dispersion prepared by using Nucillin US2.

4. Evaluation of dispersion amount of celecoxib solid dispersion containing adsorbent, water penetration enhancer or diluent

All water penetration enhancers and diluents are well absorbed and very hydrophilic. Moisture penetration enhancers and diluents are expected to have different effects on the solubility of the drug, depending on the type of water penetration enhancer and diluent, since they exhibit different water uptake, wicking degree and swelling power.

Table 4 and Fig. 3 show the solubilities of the celecoxib solid dispersion using various kinds of water penetration enhancers and diluents.

It is known that croscamellose sodium (CCS) and sodium starch glycolate (SSG) have excellent swelling and wicking ability. Among them, SSG has a swelling power superior to CCS. Therefore, the high swelling power of SSG may result in an increase in the viscosity of the dispersion. The high viscosity of the SSG can cause instability of the dispersant, resulting in a decrease in solubility. Further, there may arise a problem that stirring becomes more difficult as the viscosity of the mixture increases. Therefore, in the subsequent experiments, CCS was used in the preparation of the solid dispersion.

As can be seen from Fig. 3, the solid dispersions prepared with celecoxib, phosphatidylcholine, nucilin US2 and CCS were found to be very good in solubility.

5. In vitro dissolution test

The dissolution profiles of the pure celecoxib itself and the solid dispersion (SD) are shown in Fig. The dissolution experiment was carried out using distilled water.

As shown in Fig. 4, it was confirmed that the solubility output of the solid dispersion according to the present invention was eluted at an increased ratio and amount as compared with the conventional celecoxib tablets, and these results were remarkably prominent at the initial stage . Approximately 7% of the celecoxib was released from the solid dispersion within 300 minutes, but only 0.2% of the drug was released in the case of the pure celecoxib formulation.

The increased uptake of celecoxib is believed to be due not only to the formation of the inclusion complex and to the decrease in the crystallinity of the product, but also to the dissolution rate enhanced by phosphatidylcholine.

6. Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry was carried out by determining the melting point of crystalline forms and solid dispersions of celecoxib, phosphatidylcholine, nucilane, croscarmellose sodium (CCS) and physical mixtures thereof.

The results are shown in Fig. 5 and Fig.

As shown in Figs. 5 and 6, the celecoxib showed a peak at 163.19 캜, and the nucylline US2 showed a peak at 219.06 캜. However, phosphatidylcholine, CCS, physical mixtures and solid dispersions did not show any peak in DSC studies. The absence of any peak in the solid dispersion means that it is present in an amorphous form.

7. Powder X-ray diffraction (XRPD)

Powder X-ray diffractometry was performed to investigate the crystal structure of the sample.

The results are shown in FIGS. 7 and 8. FIG.

As can be seen in Fig. 7a, XRPD results of the celecoxib itself showed peaks at 2 &thetas; values of 5.3 DEG, 10.7 DEG, 16.1 DEG and 21.5 DEG, which are the same as those known as the detection peak of the celecoxib crystal type (Dolenc et al., 2009; Gupta & Bansal 2005; Homayouni et al., 2014). On the other hand, as shown in Fig. 7B, pure phosphatidylcholine has peaks at 2 [theta] values of 4.0 [deg.], 6.5 [deg.], 8.0 [deg.] And 14.7 [deg.], Which is the same as that known as the detection peak of the phosphatidylcholine crystal form.

However, in the case of the solid dispersion of celecoxib and phosphatidylcholine, peaks observed in pure celecoxib or phosphatidylcholine were not detected (Fig. 8B). A weakly observed intensity of the detection peak of celecoxib in the solid dispersion not containing phosphatidylcholine means that the crystallinity of the celecoxib is reduced in the solid dispersion.

On the other hand, as shown in Figs. 8C and 8D, the fact that different crystalline peaks appear in the solid dispersion having different compositions indicates that the celecoxib detection peak is changing, which means that the crystalline peak is changed from amorphous to amorphous do.

The above results show correlation with the results of differential scanning calorimetry of Example 6, showing that the solid dispersion exhibits an amorphous form. As can be seen in FIG. 9B, the peak of celecoxib in the solid dispersion of celecoxib-phosphatidylcholine is observed because the stability of the solid dispersion sample containing the carrier in a small amount decreases, and the celecoxib is recrystallized from amorphous. It is thought that it has become.

8. Fourier Transform Infrared Spectroscopy (FT-IR)

The FT-IR analysis results of each sample are shown in Fig.

The results of the FT-IR analysis of the celecoxib showed 3338 and 3232 cm ^-1 (NH stretching vibration of SO 2 NH 2 group), 1347 and 1165 cm ^-1 (S = O asymmetric and symmetric stretching), and 1230 cm ^-1 stretching) (Dolenc et al. 2009; Gupta & Bansal 2005; Homayouni et al. 2014). In the case of phosphatidylcholine, a band was observed at 1253 cm ^-1 (P = O stretching).

When a celecoxib-phosphatidylcholine solid dispersion is produced, a hydrogen bond is formed between the celecoxib and the phosphatidylcholine molecule as shown in Fig. These defects can be observed as characteristic bands in FT-IR analysis.

When the NH 2 group of celecoxib and the phosphoric acid group of phosphatidylcholine form a hydrogen bond, as shown in FIGS. 10A and 10B, the peak shifts to a higher side, and in particular, the P = O bond Is shifted to the higher side. On the other hand, the peak of the S = O bond which does not participate in the hydrogen bond shows no change.

In addition, the following Table 5, and wave values of the NH2 group of, as can be seen in Figure 10, celecoxib (a), (b), (c) and (d) (3338 - 3339 - 3343 - 3349 cm - ¹ ), it can be said that the solid dispersion is more uniformly produced and the hydrogen bonding is more stabilized.

The celecoxib solid dispersion of the present invention has an effect of significantly increasing the solubility of celecoxib and not only can improve the bioavailability, but also the celecoxib in the solid dispersion does not change into a crystalline form even when stored for a long period of time, And it is excellent in industrial applicability because of its excellent stability.

Claims (8)

A celecoxib solid dispersion comprising 100 parts by weight of celecoxib, 5 to 200 parts by weight of a phospholipid, 100 to 300 parts by weight of an adsorptive carrier and 25 to 75 parts by weight of a water penetration enhancer,
Wherein said phospholipid is phosphatidylcholine,
Wherein the adsorptive carrier is at least one selected from the group consisting of magnesium aluminosilicate, magnesium metasilicate alumina, colloidal silicon dioxide, attapulgite, microcrystalline cellulose, lactose, low substituted hydroxypropyl cellulose, bentonite and kaolin,
Characterized in that the moisture permeation enhancer is croscarmellose sodium or sodium starch glycolate.
delete delete delete The solid dispersion according to claim 1, wherein the celecoxib in the solid dispersion is amorphous.
The composition according to claim 1, further comprising at least one additive selected from the group consisting of a pharmaceutically acceptable excipient, a colorant, a flavoring agent, a diluent, a sweetener and a glidant, which does not have a carrier function of the solid dispersion. sieve.
A pharmaceutical composition for the prevention and treatment of pain or inflammatory diseases containing the solid dispersion of claim 1 as an active ingredient.
(a) preparing a mixed solution by mixing celecoxib, a phospholipid, an adsorbent carrier, and a moisture permeation enhancer; And
(b) drying the mixed solution. In the method for producing the solid dispersion of celecoxib,
The mixture is mixed with 100 parts by weight of celecoxib, 5 to 200 parts by weight of phospholipids, 100 to 300 parts by weight of an adsorbent carrier and 25 to 75 parts by weight of a moisture permeation enhancer,
Wherein said phospholipid is phosphatidylcholine,
Wherein the adsorptive carrier is at least one selected from the group consisting of magnesium aluminosilicate, magnesium metasilicate alumina, colloidal silicon dioxide, attapulgite, microcrystalline cellulose, lactose, low substituted hydroxypropyl cellulose, bentonite and kaolin,
Wherein the moisture permeation enhancer is croscarmellose sodium or sodium starch glycolate. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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