KR20200014076A - Celecoxib solid dispersion having improved dissolution rate, oral absorption and method for producing the same - Google Patents

Abstract

The present invention relates to a celecoxib solid dispersion having an improved dissolution rate, and a method for manufacturing the same. More specifically, by using cremophor, which is a nonionic surfactant, a dissolution rate, an oral absorption rate, efficacy, skin compatibility, and biodegradability are improved and toxicity is reduced compared to celecoxib products using conventional anionic surfactants which cause abnormalities in the stomach and kidneys, thereby being expected to be usefully utilized in the celecoxib drug treatment field.

Description

Celecoxib solid dispersion having improved dissolution rate, oral absorption and method for producing the same}

The present invention relates to a celecoxib solid dispersion having improved dissolution rate and oral absorption rate and a method for preparing the same. More specifically, to improve the low dissolution rate and oral absorption rate of celecoxib, cremophor, which is a nonionic surfactant, is used. The present invention relates to a celecoxib solid dispersion having improved side effects such as dissolution rate, oral absorption rate, toxicity and skin disease induction, and a preparation method thereof.

Selective cyclooxygenase-2 (COX-2) inhibitors may be usefully used for the prevention or treatment of diseases of inflammation and pain. Celecoxib is known as a representative example of the selective cyclooxygenase-2 (COX-2) inhibitor, and is used as an active ingredient of Celebrex, which is commercially available from Pharmacia Corporation.

Celecoxib has a 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide structure, and cyclooxygenase-2 (COX- By selectively inhibiting 2), it can be usefully used for the treatment and / or prevention of COX-2 mediated diseases.

Celecoxib is characterized by the absence of side effects associated with the inhibitory action of cyclooxygenase-1, which may occur in conventional nonsteroidal anti-inflammatory agents. Therefore, there is a need for a form suitable for preparing a pharmaceutical composition for rapid onset oral administration to rapidly alleviate pain through selective inhibitory action of cyclooxygenase-2. However, celecoxib exhibits very low solubility, especially in aqueous media, so it does not dissolve and disperse well for quick absorption into 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 solubility in the acidic environment of the gastrointestinal tract. Therefore, low water solubility of celecoxib requires improvement of low dissolution rate and low oral absorption rate in the gastrointestinal tract.

Among various methods to ameliorate this problem, the use of surfactants is one of the most successful strategies for improving the dissolution rate and oral absorption rate of poorly soluble drugs. Surfactants are compounds that have a hydrophilic part that is easily soluble in water and a hydrophobic part that is easily soluble in oil.When the surfactant is dissolved in water, the surfactant molecules gather together at a concentration above the critical micelle concentration to form a micelle structure. As the molecules melt into this structure, they are solubilized. In addition, celecoxib commercially available Celebrex® (Celebrex®, Pfizer) improved the low dissolution rate and oral absorption rate of celecoxib by using a surfactant called sodium lauryl sulfate.

Korean Patent Registration No. 10-1237646 relates to the above problems, using the sodium lauryl sulfate and fluidized bed granulator to produce a celecoxib-solid dispersion with improved dissolution rate and oral absorption, but sodium lauryl sulfate is anion As a type of surfactant, it can be irritating when ingested and can cause abnormalities in the stomach and kidneys. Inhalation may also cause irritation, coughing and shortness of breath in the respiratory tract, and skin irritation may result in dry and rashes of the skin during continuous contact. Therefore, the use of nonionic surfactants having superior toxicity, efficacy, skin compatibility, and biodegradability instead of sodium lauryl sulfate is required.

The present invention has been made to solve the above problems, the present inventors have conducted a variety of studies, when the preparation of celecoxib solid dispersion using a nonionic surfactant, solubility of conventional celecoxib It was confirmed that it can be significantly improved to increase the dissolution rate and oral absorption rate, the present invention was completed based on this.

It is an object of the present invention to provide a celecoxib solid dispersion comprising celecoxib and a nonionic surfactant.

Another object of the present invention is to provide a method for producing celecoxib solid dispersion comprising the following steps.

(a) dissolving celecoxib, nonionic surfactant, and hydroxypropylmethylcellulose in an aqueous solution;

(b) stirring the solution dissolved in step (a) in a high speed stirrer to prepare a suspension;

(c) mixing microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and talc; And

(d) spray-drying the suspension of step (b) to the mixture of step (c).

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the above object, the present invention provides a celecoxib solid dispersion comprising celecoxib and a nonionic surfactant.

In one embodiment of the present invention, the nonionic surfactant is Cremophor EL, Cremophor RH40, Cremophor RH40, Labrasol, Soluplus, Poloxamer 188 (Poloxamer 188). ), Poloxamer 407, Lotto sugar ester L-1695 (Ryoto sugar ester L-1695), Lotto sugar ester P-1670, Span 80 (Span 80), Labrafil M 1944 CS (Labrafil M 1944 CS), Plerol Oleique CC497, Transcutol HP, and Labrafac PG.

In another embodiment of the present invention, the nonionic surfactant may be Cremophor EL or Cremophor RH40.

In one embodiment of the present invention, the celecoxib may have 5.0 to 30.0 wt% and the nonionic surfactant may have 0.5 to 15.0 wt%.

In another embodiment of the present invention, the solid dispersion is microcrystalline cellulose 40.0-70.0 wt%, lactose 10.0-40.0 wt%, hydroxypropylmethylcellulose 0.5-5.0 wt%, crospovidone 0.5-10.0 wt%, colloidal dioxide 0.1 to 5.0% by weight of silicon, and 0.1 to 5.0% by weight of talc may be further included.

In another embodiment of the invention, celecoxib in the solid dispersion may be present in amorphous form.

In another embodiment of the present invention, the average particle size of the solid dispersion may be 100 to 500 μm.

The present invention also provides a method for producing a celecoxib solid dispersion comprising the following steps.

(a) dissolving celecoxib, nonionic surfactant, and hydroxypropylmethylcellulose in an aqueous solution;

(b) stirring the solution dissolved in step (a) in a high speed stirrer to prepare a suspension;

(c) mixing microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and talc; And

(d) spray-drying the suspension of step (b) to the mixture of step (c).

In the case of celecoxib solid dispersion according to the present invention, by using a nonionic surfactant, dissolution rate, oral absorption rate, toxicity, Improved efficacy, skin compatibility, and biodegradation are expected to be useful in the field of celecoxib drug treatment.

1 is celecoxib (CXB), Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example 3 (CXB: Cre-RH = 1: electron micrograph of 0.5) is shown.
2 shows celecoxib (CXB), additive mixtures, excipients and celecoxib and additive mixtures, Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25 ), And the results of confirming the differential scanning calorimeter pattern of Experimental Example 3 (CXB: Cre-RH = 1: 0.5).
Figure 3 shows the results of confirming the dissolution rate of celecoxib solid dispersion, pure celecoxib and commercially available formulations prepared with nonionic surfactant other than Cremophor RH (Cre-RH).
Figure 4 shows the results of confirming plasma concentration profiles after oral administration of celecoxib (CXB), commercial product (Celebrex®), and Experimental Example 3 (CXB: Cre-RH) in the animal model will be.

Hereinafter, the present invention will be described in detail.

The present inventors have studied to improve the low dissolution rate and oral absorption rate of celecoxib. When preparing celecoxib solid dispersion using a nonionic surfactant, the solubility of celecoxib was remarkably improved to improve the dissolution rate and oral rate. The present invention has been completed by confirming that the absorption can be increased.

Thus, the present invention provides a celecoxib solid dispersion comprising celecoxib and a nonionic surfactant.

In the present invention, celecoxib is a 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide) compound represented by the following Chemical Formula 1, and cyclo By selectively inhibiting oxygenase-2 (COX-2), it can be usefully used for the prevention or treatment of COX-2 mediated diseases.

[Formula 1]

As used herein, the term "solid dispersion" refers to a form in which a water-soluble polymer, a surfactant, and celecoxib are intermolecular bonds, that is, a surface modification, and the wettability of celecoxib by surface modification ) Can further increase the solubility, dissolution rate and oral absorption of celecoxib. In particular, in the present invention, celecoxib is present in an amorphous (amorphous) form in the solid dispersion by surface modification with a water-soluble polymer and a surfactant.

As used herein, the term "amorphous" means that celecoxib does not precipitate as a crystal. Since celecoxib is a poorly soluble drug, it is not absorbed in the gastrointestinal tract when precipitated as crystals, so that the bioavailability is significantly reduced. In the present invention, since celecoxib is amorphous in the solid dispersion, the solubility of celecoxib is markedly increased, and thus bioavailability can be significantly improved. In addition, the amorphous celecoxib present in the solid dispersion retains the amorphous form as it is, and has excellent storage stability characteristics.

The term "surfactant" used in the present invention is a material used to effectively combine the water-soluble polymer and celecoxib, the preferred type of surfactant used in the present invention may be a nonionic surfactant.

Nonionic surfactants used in the present invention have the advantages of effectiveness (efficiency), efficiency (efficiency), toxicity (dermatological compatibility), biodegradability, etc. Among the nonionic surfactants, anionic surfactants, and cationic surfactants, nonionic surfactants were considered first.

At this time, the nonionic surfactants used in the present invention are Cremophor EL, Cremophor RH40, Labrasol, Soluplus, Poloxamer 188 (Poloxamer 188). Poloxamer 407, Lotto Sugar Ester L-1695, Ryoto Sugar Ester P-1670, Span 80, Labrafil M 1944 CS (Labrafil M 1944 CS), Pleol Oleique CC497, Transcutol HP and Labrafac PG, preferably Cremo Pore El (Cremophor EL) or Cremophor RH40 can be used, most preferably Cremophor RH40.

In preparing the celecoxib solid dispersion of the present invention, it may further include an additive. More specifically, the additive used in the present invention may be at least one selected from the group consisting of hydroxypropylmethylcellulose, microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and talc, celecoxib solid dispersion In the preparation, the preferred addition content including celecoxib and cremophore is 5.0 to 30.0% by weight of celecoxib, 0.5 to 15.0% by weight of cremophore, 40.0 to 70.0% by weight of microcrystalline cellulose, 10.0 to 40.0 of lactose Wt%, hydroxypropylmethylcellulose 0.5-5.0 wt%, crospovidone 0.5-10.0 wt%, colloidal silicon dioxide 0.1-5.0 wt%, and talc 0.1-5.0 wt%.

The additive used in the celecoxib solid dispersion of the present invention may use an additive commonly used in the pharmaceutical field. For example, white sugar, lactose, mannitol, dextrin, cellulose, starch, gelatinized starch, corn starch, polyvinylpinolidone, croscarmellose sodium, sodium starch glycolate, magnesium stearate can be used, but are not limited thereto. It is not.

The formulation of the pharmaceutical composition may be in various forms, but preferably in the form of granules, tablets or capsules, these formulations may be prepared according to methods commonly used in the pharmaceutical field. For example, tablets and capsules can be prepared by filling the celecoxib solid dispersion into tablets and capsules (using additives, if necessary).

The average particle size of the solid dispersion in the present invention may be 100 to 500 μm, preferably 150 μm, but is not limited thereto.

In one embodiment of the present invention, by saturation solubility in various oils and surfactants in order to find the best solubilizing agent for celecoxib, it was confirmed that cremophor is the best solubilizing agent for celecoxib (see Example 2). As a result of confirming the physical / chemical properties of the solid dispersion prepared using the cremophor as a solubilizer, it was confirmed that granules having improved flowability and compressibility were formed. In addition, by confirming that the amorphous state through the thermal transition (thermal transition), it was confirmed in detail that the solid dispersion of the present invention can be effective in improving solubility and bioavailability (see Examples 3 and 4).

In addition, in another embodiment of the present invention, the celecoxib solid dispersion of the present invention was compared with commercially available products, and the superior effect of celecoxib elution was confirmed. Was confirmed (see Examples 5 and 6).

According to the above results, the celecoxib solid dispersion according to the present invention has improved dissolution rate, toxicity, efficacy, skin compatibility, and biodegradability as compared with the conventional solid dispersion, and thus may be usefully used in the field of celecoxib drug treatment. It is expected to be able.

In another aspect of the present invention, the present invention provides a method for producing a celecoxib solid dispersion comprising the following steps.

(a) dissolving celecoxib, a nonionic surfactant, and hydroxypropylmethylcellulose in an aqueous solution, stirring in a high speed stirrer to prepare a suspension;

(b) mixing microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and talc with a fluid bed granulator; And

(c) spray-drying the suspension of step (a) to the mixture of step (b).

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

EXAMPLE

Example 1 Experiment Preparation and Experiment Method

1-1. Experiment preparation

Celecoxib (CXB) and Span 80 are used by Cadila Pharmaceutical Ltd. (Ahmedabad, India) and Sigma Chemical Co. Purchased from St. Louis, USA, and the Cremophor RH40 (Cre-RH), Poloxamer 188, Poloxamer 407, and Soluplus were purchased from BASF ( Ludwigshafen, Germany) as a sample. In addition, Labrac PG, Labrafil M 1944 CS, Labrasol, Labrasol, Plurol Oleique CC497 and Transcutol HP Purchased from Gattefosse (St Priest, France), Lotto sugar ester L-1695 and Lotto sugar ester P-1670 were manufactured by Mitsubishi-Kasei Chemical Co. Heweten 101 (microcrystalline cellulose) and Pharmatose 200M (Lactose) were purchased from JRS Pharma (Rosenberg, Germany) and DMV-Fonterra Excipients (Goch, Germany), respectively.

1-2. Celecoxib Solubility Measurement

Cremophor RH (Cre-RH), Labrafac PG, Labrafil M 1944 CS, Labrasol, Pleol Oleique CC497, Poloxamer 188, Poloxamer 407, Lotto Sugar Ester L-1695, Lotto Sugar Ester P-1670, Soluplus The solubility of celecoxib (CXB) was measured in various solubilizers, including Span 80, SPAN 80, and Transcutol HP.

More specifically, excess celecoxib (CXB) (10 mg) was added to each 5% solubilizer solution (1 mL) and mixed for 2 days in a rotating mixer (at room temperature), at 3000 rpm. The supernatant was taken by centrifugation. The supernatant was appropriately diluted with methanol, and the concentration of celecoxib (CXB) was analyzed by HPLC at 250 nm.

The solubility of celecoxib (CXB) in 5% of each solubilizer solution was then quantitated using an HPLC system equipped with a UV detector (Agilent Technologies 1100, Santa Clara, USA). In this case, a column was used as a reverse-phase C18 column (Aegispak; 5 μm, 4.6 × 150 mm; Korea), and a flow rate of 1.25 mL / min and a mobile phase (methanol: distilled water = 75: 25 Isocratic eluted, and the test was carried out at a 30 ° C. column oven temperature and a wavelength of 250 nm.

1-3. Preparation of Solid Dispersions

The preparation of a solid dispersion (SDG) containing celecoxib (CXB) was used with a Mini-Glatt fluid-bed granulator (Binzen, Germany).

More specifically, 1, 2.5, 5 g of Cremophor RH (Cre-RH) and 2.5 g of HPMC at 50 ° C. are dissolved in 250 mL of distilled water, and the solution is then 4,000 to 8,000 using a high speed stirrer. While stirring at a rotational speed of rpm, 10 g of celecoxib (CXB) was slowly added and suspended to obtain a homogeneous solution. The resulting solution was mixed with 60 g of microcrystalline cellulose, 30 g of lactose, 3 g of crospovidone, 1.5 g of colloidal silicon dioxide (1.5 g), and 3 g of talc (talc) through a fluidized bed granulator. , Spray-drying the suspension, Experimental Example 1 (CXB: Cre-RH = 1: 0.1) shown in Table 1, Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example 3 (CXB: A solid dispersion (SDG) of Cre-RH = 1: 0.5) was obtained.

At this time, the operating conditions of the Granulation process are as follows:

Inlet air temperature: 70-80 ° C .;

Spray rate of celecoxib suspension: 2-5 mL / min

Product bed temperature: 25-35 ° C .; And

Atomization pressure: 2.0-3.0 bar.

In addition, a celecoxib solid dispersion was prepared in the same manner as the method for preparing a solid dispersion, using a nonionic surfactant other than Cremophore RH (Cre-RH).

division ingredient Experimental Example One 2 3 4 5 6 7 8 9 chief ingredient Celecoxib 10 g Nonionic surfactant Cremophor
RH40) 1 g 2.5g 5 g - - - - - - Cremophor EL
EL) - - 5 g - - - - - Labrasol - - - 5 g - - - - Soluplus - - - - 5 g - - - Poloxamer 407 - - - - - 5 g - - Lotto sugar ester P-1670 - - - - - - 5 g - Lotto sugar ester L-1695 (Ryoto sugar ester L-1695) - - - - - - - 5 g additive Microcrystalline cellulose 60 g Lactose 30 g Hydroxypropyl
Methylcellulose 2.5g Crospovidone 3 g Colloidal
Silicon dioxide 1.5 g Talc 3 g Total weight 101 g 102.5 g 105 g

1-4. Scanning Electron Microscopy (SEM)

Celecoxib (CXB), Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example 3 (CXB: Cre-RH = 1: 0.5 ) Morphology was observed by scanning electron microscopy (SEM, Hitachi S-4300 SE scanning electron microscopy) (Tokyo, Japan).

At this time, each sample was mounted on a carbon film, sputtered with platinum before the observation, and the voltage was set to 15 kV.

1-5. Differential Scanning Calorimeter (DSC)

Celecoxib (CXB), physical mixture with excipients, additive and celecoxib mixture, Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), and thermal transition of Experimental Example 3 (CXB: Cre-RH = 1: 0.5) was observed with a TA Q1000 differential scanning calorimeter (DSC) (Leatherhead, UK). More specifically, each sample (5 mg) was weighed into an aluminum pan, crimped with lid, and then the pretreated sample was heated at 40 ° C. at a heating rate of 10 ° C./min under a dry nitrogen flow rate of 20 mL / min. Scanning was carried out at ℃ to 200 ℃.

1-6. Dissolution Study

Dissolution rate evaluation was performed according to the paddle method described in US Pharmacopoeia 24 (Apparatus II). More specifically, first, celecoxib (CXB), Celebrex (Celebrex®), and the celecoxib solid dispersions of Experimental Examples 1 to 9 of Table 1 above, pH 1.2 elution test solution (adjusted with 0.1 N HCl) 900 mL Into, and stirred at 37.0 ± 0.5 ° C and 50 rpm. Thereafter, 3 mL of the elution test solution was taken at predetermined and predetermined times (5, 10, 15, 30, 45, 60, 90, 120 min), filtered through a membrane filter (0.2 μm pore size), and analyzed by HPLC.

1-7. In vivo Oral Pharmacokinetic (PK) Experiment

Celecoxib fine powder, celecoxib in vivo oral pharmacokinetic study with respect to the solid dispersion granules and marketed celecoxib product by taking the 5mg / kg to male SD (Spraque Dawley) rats in fasted condition (fasted condition) (dose ) Investigated.

More specifically, the rats used in the experiments remained fasted overnight, after which anesthesia was followed by intubation of the polyethylene tube into the femoral artery for blood sampling.

After recovery from surgery, celecoxib (celecoxib micropowder, celecoxib solid dispersion granules and commercial celecoxib product) consisting of the three formulations was orally administered to rats at a dose of 5 mg / kg. After drug administration, 100 μl of blood samples were collected from the intubated femoral artery cannula at 0, 15, 30, 60, 120, 180, 240, 360, 480, 1440 and 2880 minutes and the resulting plasma stored at −20 ° C. It was.

Simple sample preparation was performed by deproteinizing with 100 μL of a methanol solution containing IS. After vortex-mixing, centrifugation was performed at 12,000 g for 10 minutes at 4 ° C., and the supernatant was analyzed for celecoxib analysis. Obtained.

For analysis of celecoxib, the LC-MS / MS system is a modified liquid chromatography consisting of Agilent HPLC and Agilent 6460 QQQ mass spectrometers equipped with ESI + Agilent Jet Stream ion source (Agilent Technologies, Santa Clara, CA, USA) Liquid chromatography tandem mass spectrometry (LC-MS / MS) bioassay was performed.

Example  2. according to solubilizer Celecoxib  Solubility Check

Cremophor RH (Cre-RH), Labrac PG, Labrafil M 1944 CS, Labrasol, Labole Ole according to Examples 1-2 above Plurol Oleique CC497, Poloxamer 188, Poloxamer 407, Loto Sugar Ester L-1695 (Ryoto sugar ester L-1695), Lotto Sugar Ester P-1670 -1670), solubilization of celecoxib was confirmed in various solubilizers, including Soluplus, Span 80, and Transcutol HP.

As a result, as shown in Table 2 below, the solubility of celecoxib (CXB) in the Cremophore RH (Cre-RH) 5% solution was 1434.69 ± 16.44 μg / mL, pure pure selecock of 1.98 ± 0.13 μg / mL. Approximately 724-fold increase compared to the sieve solubility, Labrasol, Soluplus, Poloxamer 407, Loto Sugar ester P-1670, Lotto Sugar Easter L High solubility was recorded in -1695 (Ryoto sugar ester L-1695) in the order of 1024.06 ± 27.85, 823.10 ± 30.71, 622.37 ± 22.03, 407.48 ± 0.55, 329.31 ± 7.22 μg / mL.

Nonionic surfactant Celecoxib Saturated Solubility (μg / mL) Purified water (not used) 1.98 ± 0.13 Cremophor EL
(Cremophor EL) 1493.26 ± 19.17 Cremophor RH40 1434.69 ± 16.44 Labrasol 1024.06 ± 27.85 Soluplus 823.10 ± 30.7 Poloxamer 407 622.37 ± 22.03 Lotto Sugar Easter P-1670
(Ryoto sugar ester P-1670) 407.48 ± 0.6 Lotto Sugar Easter P-1670
(Ryoto sugar ester L-1695) 329.31 ± 7.22 Span 80
(Span 80) 290.64 ± 157.8 Peleol Olleeck CC497
(Labrafil M 1944 CS) 284.27 ± 21.3 Pleole oleek cc497
(Plurol Oleique CC497) 93.58 ± 12.2 Transcutol HP
(Transcutol HP) 44.84 ± 27.1 Poloxamer 188
(Poloxamer 188) 25.00 ± 13.3 Poloxamer 188
(Labrafac PG) 8.00 ± 2.7

Among the solubilizers used in the above experiments, the most efficient cremophor RH (Cre-RH) is known to improve drug absorption by increasing cell membrane fluidity, and also Lotto Sugar Easter P- 1670 (Ryoto sugar ester P-1670) and Lotto sugar ester L-1695 are also known to enhance drug absorption.

Therefore, in order to improve the dissolution rate and bioavailability of celecoxib (CXB), a solubilizer capable of improving solubilization of the drug while well solubilizing celecoxib (CXB) is required. This suggests that Cremophore RH (Cre-RH), which has the best solubilization efficiency, may be the best celecoxib solid dispersion solubilizer.

Thus, in the following examples, the characteristics of the celecoxib solid dispersion using Cremophor RH (Cre-RH) as an optimal solid dispersion solubilizer were analyzed.

Example  3. Celecoxib  solid Dispersion  Check particle size and shape

The morphological characteristics of celecoxib and celecoxib solid dispersions were observed through well fluid bed granulation.

As a result, as shown in Figure 1, in the SEM image, it was confirmed that pure celecoxib (CXB) has an average size of 5 ㎛ of the needle-shaped, this needle-shaped celecoxib (CXB) is insufficient dispersibility It is known to cause flowability and compressibility.

Experimental Example 1 (CXB: Cre-RH = 1: 0.1) prepared using celecoxib (CXB), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example 3 (CXB: Cre-RH = 1: 0.5) was found to have a spherical average size of 150 μm, because the material used through the fluid bed granulation agglomerates to increase in size and has a spherical shape. Since the granulated aggregates have improved flowability and compressibility compared to fine powders, the granules were well prepared through SEM measurement.

Example  4. Celecoxib  solid Dispersion  Crystallinity Check

In order to confirm the crystallinity of celecoxib in the celecoxib solid dispersion according to the present invention, the crystal of celecoxib was confirmed using a differential scanning calorimeter according to Example 1-5. More specifically, celecoxib, additive mixture, celecoxib and additive mixture, Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example The DSC thermal image of 3 (CXB: Cre-RH = 1: 0.5) was confirmed.

As a result, as shown in Fig. 2, the endothermic pattern of the DSC peak of celecoxib (CXB) was observed at 162-163 ° C (also observed in the additive mixture and celecoxib (CXB)). However, celecoxib in Experimental Example 1 (CXB: Cre-RH = 1: 0.1), Experimental Example 2 (CXB: Cre-RH = 1: 0.25), Experimental Example 3 (CXB: Cre-RH = 1: 0.5) Melting point of (CXB) was not observed because celecoxib (CXB) is in amorphous form in the solid dispersion.

Therefore, the amorphous state of celecoxib (CXB) is expected to contribute to the improvement of solubility and bioavailability.

Example  5. Celecoxib  solid Dispersion  Dissolution rate confirmation

Dissolution test method 2 (paddle method) for celecoxib (CXB), celecrex (Celebrex®) and the celecoxib solid dispersions of Experimental Examples 1 to 9 of Table 1 according to Examples 1-6. It was carried out according to the comparative analysis for each dissolution rate.

As a result, as shown in Figure 3, compared with pure celecoxib, it was confirmed that the dissolution rate of celecoxib of the celecoxib solid dispersion using a nonionic surfactant prepared according to the present invention significantly increased. there was.

In addition, compared to the commercially available Celebrex®, Experimental Example 3 (SDG (CXB: Cre-RH = 1: 0.5)), that is, a celecoxib solid dispersion using cremopor in a nonionic surfactant It was confirmed specifically that the dissolution rate of celecoxib increased significantly.

Example  6. Identification of pharmacokinetics in animal models

Pharmacokinetic (PK) studies were conducted in rats to confirm improved drug uptake of celecoxib (CXB) from solid dispersion.

Products Celecoxib (CXB) Commercially available
(Marketed product) Experimental Example 3
(CXB: Cre-RH = 1: 0.5) AUCinf (µg / h / mL) 5.8 ± 1.9 25.5 ± 3.8 30.0 ± 5.4 Cmax (μg / mL) 0.3 ± 0.1 1.6 ± 0.3 1.6 ± 0.1 Tmax (h) 6.5 ± 3.0 3.3 ± 1.0 7.5 ± 1.0 T1 / 2 (h) 8.9 ± 3.1 4.9 ± 1.1 8.7 ± 2.4

As a result, as shown in Fig. 4 and Table 3, plasma concentrations of celecoxib (CXB) from Experimental Example 3 (CXB: Cre-RH = 1: 0.5) compared to pure celecoxib (CXB) at all time points ( The plasma concentration was much higher. After oral administration of Experimental Example 3 (CXB: Cre-RH = 1: 0.5), Cmax and AUCinf were 1.6 ± 0.1 μg / mL and 30.0 ± 5.4 μg · h / mL, respectively, and Cmax and AUCinf of pure CXB were 0.3 ± 0.1 μg. 5 and 6 fold increase compared to / mL and 5.8 ± 1.9 μg · h / mL, respectively. This is due to the solubilization of celecoxib (CXB) by Cremophor RH (Cre-RH) (Table 2) and improved dissolution rate (FIG. 3). The AUCinf of the marketed product and Experimental Example 3 (CXB: Cre-RH = 1: 0.5) were almost the same at 25.5 ± 3.8 and 30.0 ± 5.4 μg · h / mL, but the anionic surfactant used in the commercially available formulation was Unlike phosphorus SLS, the solid dispersion of the present invention used a nonionic surfactant. Nonionic surfactants are preferred among several types of surfactants because of their effectiveness, efficiency, toxicity, dermatological compatibility, biodegradability and the like.

Therefore, in the solid dispersion system used in the present invention, the use of nonionic surfactants, Cremophor RH (Cre-RH) as a solubilizer, may improve the bioavailability of celecoxib (CXB). It was found to be an effective way.

The above description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (11)

A celecoxib solid dispersion comprising celecoxib and a nonionic surfactant.
The method of claim 1, wherein the nonionic surfactant is Cremophor EL, Cremophor RH40, Labrasol, Soluplus, Poloxamer 188 (Poloxamer 188) , Poloxamer 407, Lotto Sugar Ester L-1695, Lotto Sugar Ester P-1670, Span 80, Labrafil M 1944 CS (Labrafil M 1944 CS), Pleol Oleique CC497, Transcutol HP, and Lafrapak PG, which is at least one selected from the group consisting of Solid dispersion.
The solid dispersion of claim 2, wherein the nonionic surfactant is Cremophor EL or Cremophor RH40.
The solid dispersion according to claim 1, wherein the celecoxib has 5.0 to 30.0 wt% and the nonionic surfactant has 0.5 to 15.0 wt%.
The method of claim 1, wherein the solid dispersion is 40.0 to 70.0% by weight of microcrystalline cellulose, 10.0 to 40.0% by weight of lactose, 0.5 to 5.0% by weight of hydroxypropylmethylcellulose, 0.5 to 10.0% by weight of crospovidone, colloidal silicon dioxide 0.1 to 5.0 wt%, and talc 0.1 to 5.0 wt%, solid dispersion.
The solid dispersion according to claim 1, wherein celecoxib in the solid dispersion is amorphous.
The solid dispersion of claim 1, wherein the average particle size of the solid dispersion is 100 μm to 500 μm.
A method for preparing celecoxib solid dispersion comprising the following steps:
(a) dissolving celecoxib, nonionic surfactant, and hydroxypropylmethylcellulose in an aqueous solution;
(b) stirring the solution dissolved in step (a) in a high speed stirrer to prepare a suspension;
(c) mixing microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and talc; And
(d) spray-drying the suspension of step (b) to the mixture of step (c).
The method of claim 8, wherein the solid dispersion is celecoxib is 5.0 to 30.0% by weight, nonionic surfactant is 0.5 to 15.0% by weight, microcrystalline cellulose 40.0 to 70.0% by weight, lactose 10.0 to 40.0% by weight, hydroxy And 0.5 to 5.0 weight percent propylmethylcellulose, 0.5 to 10.0 weight percent crospovidone, 0.1 to 5.0 weight percent colloidal silicon dioxide, and 0.1 to 5.0 weight percent talc.
The method of claim 8 or 9, wherein the nonionic surfactant is Cremophor EL, Cremophor RH40, Labrasol, Soluplus, Poloxamer 188 (Poloxamer 188), Poloxamer 407, Lotto Sugar ester L-1695, Lotto Sugar ester P-1670, Span 80, At least one selected from the group consisting of Labrafil M 1944 CS, Plaurol Oleique CC497, Transcutol HP, and Labrafac PG. Characterized by the method.
The method of claim 10, wherein the nonionic surfactant is Cremophor EL or Cremophor RH40.

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