KR102002906B1 - Tablet comprising Celecoxib - Google Patents

Abstract

The present invention relates to tablets containing celecoxib, which is smaller in size than conventional celecoxib oral preparations and has excellent convenience for taking, and even when stored for a long time, there is no change in the dissolution rate and an equivalent therapeutic effect can be expected , It is produced in tablet form, has a high productivity, and reaches the maximum drug concentration of blood quickly, resulting in rapid efficacy.

Description

Tablets comprising Celecoxib Tablet comprising Celecoxib < RTI ID = 0.0 >

The present invention relates to tablets comprising celecoxib. Specifically, the present invention provides a tablet for oral administration, which is small in size compared to conventional celecoxib oral preparations, has excellent convenience of taking, has no change in dissolution rate even after prolonged storage, can be expected to have an equivalent therapeutic effect, The present invention also relates to a method for preparing the same.

Celecoxib is the generic name of the chemical name 4- [5 (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, I have.

(I)

A selective cyclooxygenase -2 (COX-2) Celebrex ^® (Pfizer), is the largest share of the market with no arthritis present in the gastrointestinal disorder is sold in the form of capsules include a celecoxib inhibitor as an active ingredient of It is occupied.

Celecoxib can be administered in a formulation containing large amounts (100 to 400 mg). However, due to the physical and chemical properties peculiar to celecoxib, it is difficult to prepare tablets small enough to be easily taken. For example, celecoxib is a material with electrostatic properties, low compressibility and cohesive, low density.

Due to such properties, it is difficult to prepare tablets having desirable characteristics.

In addition, in order to reduce the mass of the tablet, the solubility of the celecoxib is low because the excipient must be used in a limited amount to promote rapid drug release.

Celecoxib has been conventionally developed as a capsule because of its physical and chemical properties. However, in the case of these capsules, not only the volume is high but also the manufacturing cost is high, and the disintegration and dissolution rate depends on the dissolution degree of the gelatin constituting the capsule, and when it is stored in the external environment such as moisture and temperature There is a problem that the disintegration and dissolution rate may be further delayed or the pattern may be changed.

On the other hand, Korean Patent Registration No. 0501034 discloses a pharmaceutical composition which can be orally administrated containing celecoxib as an active ingredient. However, when the tablets are manufactured according to the above patent documents, the volume of the finished tablets is very large and the convenience of taking the tablets is deteriorated.

Accordingly, the inventors of the present invention have conducted studies to overcome the problems of the prior art, and have found that the composition of the present invention has a smaller size than the conventional composition, and therefore has excellent convenience for taking, and even when stored for a long period of time, The present invention has been accomplished on the basis of tablets which are manufactured in a tablet form, have a high productivity, and can quickly reach drug concentrations at the highest blood levels and exhibit rapid drug efficacy.

Korean Registered Patent No. 0501034

An object of the present invention is to provide a celecoxib tablet having improved convenience and stability and high productivity.

In order to solve the above problems, the present invention provides a pharmaceutical composition comprising: (1) a dosage form containing a minimum amount of excipient to reduce administration volume to improve convenience of use; (2) (4) tablets having desirable tablet characteristics, and a method for producing the tablets. Hereinafter, the present invention will be described in detail.

Celecoxib With high content  Containing tablets

The present invention provides a tablet comprising a therapeutically effective amount of 50-70% by weight of celecoxib or a pharmaceutically acceptable salt thereof and 5-20% by weight of a cellulosic excipient.

In the present invention, celecoxib or a pharmaceutically acceptable salt thereof may be used as a celecoxib free base or any pharmaceutically acceptable salt thereof. Preferably, a celecoxib free base can be used. Celecoxib or a pharmaceutically acceptable salt thereof can be synthesized directly by a known preparation method or can be purchased commercially.

In the present invention, celecoxib or a pharmaceutically acceptable salt thereof is contained in a pharmacologically effective amount, and the amount thereof may vary depending on the condition, body weight, etc. of the patient to be treated. Specifically, celecoxib or a pharmaceutically acceptable salt thereof may be administered at about 10 to 1000 mg, preferably 100 to 400 mg, more preferably 100 to 200 mg .

In the present invention, celecoxib or a pharmaceutically acceptable salt thereof may be contained in an amount of 50 to 70% by weight, and preferably 60 to 70% by weight based on the total weight of the tablet. Since the active ingredient celecoxib or a pharmaceutically acceptable salt thereof is contained in a high content in the tablet and may contain various excipients in a minimum amount, the tablets of the present invention are smaller than conventional celecoxib oral preparations (capsules) And thus, the convenience of taking the patient can be greatly increased.

The "cellulosic excipient" included in the tablets of the present invention can overcome the tableting disturbance during tabletting and accelerate the disintegration rate of tablets. Preferred cellulosic excipients are powdered cellulose, low substituted hydroxypropylcellulose, microcrystalline cellulose colloidal silicon dioxide (e.g., prosolve), lactose hydrate, microcrystalline cellulose (e.g. microcellular), lactose hydrate, cellulose Tosse) and mixtures thereof.

The above-mentioned "powdered cellulose" includes amorphous cellulose. For example, it may be composed of 45 wt% crystalline form and 55 wt% amorphous form. The average particle size of the powdered cellulose is preferably 30 to 180 m, more preferably 40 to 80 m.

The "low-substituted hydroxypropyl cellulose" preferably has a degree of substitution of about 0.2. The degree of substitution means the average number of hydroxypropyl groups per anhydroglucose ring of cellulose. The low-substituted hydroxypropyl cellulose may have a content of hydroxypropoxy groups of about 5 to 16% by weight, and preferably 9 to 13% by weight. The average particle size of the low-substituted hydroxypropyl cellulose is preferably 35 to 75 μm, more preferably 50 to 60 μm.

The term "microcrystalline cellulose colloidal silicon dioxide" means a silicified microcrystalline cellulose in which colloidal silicon dioxide particles are dispersed thinly on the microcrystalline cellulose surface to form monoparticles. Preferably, 98% by weight of microcrystalline cellulose and 2% by weight of colloidal silicon dioxide can be used. In addition, the average particle size of the microcrystalline cellulose colloidal silicon dioxide is preferably 40 to 130 μm, more preferably 90 to 130 μm.

The above-mentioned "lactose hydrate-microcrystalline cellulose" refers to a monoparticle-containing excipient comprising 75% by weight of lactose hydrate and 25% by weight of microcrystalline cellulose by spray-drying lactose hydrate and microcrystalline cellulose.

Refers to a monoparticle-containing excipient containing 75% by weight of lactose hydrate and 25% by weight of powdered cellulose by spray-drying the lactose hydrate and the powdered cellulosic powder.

In the present invention, the cellulose-based excipient may be contained in an amount of 5 to 20% by weight, and preferably 6 to 12% by weight based on the total weight of the tablet. Exceeding the above range may result in a penile disorder or a problem with the dissolution rate of celecoxib.

In addition, the cellulosic excipient may be used as an extragranular excipient mixed with a granule comprising celecoxib or a pharmaceutically acceptable salt thereof.

The tablets of the present invention may further comprise water-soluble excipients. The "water-soluble excipient" used in the present invention means a water-soluble diluent. Water-soluble excipients are one or more compounds that can increase the density of the tablet to obtain the mass of the desired tablet, and can improve electrostatic and cohesive properties. Preferred water-soluble excipients may be selected from lactose hydrates, sorbitol, mannitol, xylitol, maltodextrin and mixtures thereof.

In the present invention, the water-soluble excipient may be contained in an amount of 8 to 30% by weight, preferably 10 to 16% by weight, based on the total weight of the tablet.

The tablets of the present invention may further comprise surfactants, disintegrants, binders and glidants commonly used in the art.

The "surfactant" used in the tablets of the present invention may be one or more compounds capable of increasing the wettability and solubility of the celecoxib. Preferred surfactants may be selected from sodium lauryl sulfate, polysorbate, poloxamer, polyethylene oxide, and mixtures thereof. However, the present invention is not limited thereto. In the present invention, the surfactant may be contained in an amount of 1 to 5% by weight based on the total weight of the tablet.

The "disintegrant" used in the tablets of the present invention has the effect of expanding upon contact with water to disrupt the tablet in the gastrointestinal tract. Preferred disintegrants may be selected from crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, starch, sodium starch glycolate, low substituted hydroxypropylcellulose and mixtures thereof. However, the present invention is not limited thereto. In the present invention, the disintegrant may be contained in an amount of 2 to 12% by weight based on the total weight of the tablet.

The "binder" used in the tablets of the present invention is one or more compounds that can increase the density of granules and increase the granulation with more fluid granules. Preferred binding agents may be selected from povidone, hypromellose, hydroxypropylcellulose, gelatinized starch, and mixtures thereof. However, the present invention is not limited thereto. In the present invention, the binding agent may be contained in an amount of 1 to 6% by weight based on the total weight of the tablet.

The "lubricant" used in the composition of the present invention has such effects as improving fluidity from a tablet machine die, preventing adhesion to punches and dies, and reducing resistance when discharging tablets from a tablet machine. Preferred lubricants may be selected from talc, sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide and mixtures thereof. However, the present invention is not limited thereto. In the present invention, the lubricant may be contained in an amount of 1 to 5% by weight based on the total weight of the tablets.

The tablets of the present invention contain a high content of celecoxib or a pharmaceutically acceptable salt thereof in an amount of 50 to 70% by weight and can contain small amounts of various excipients to produce small-sized tablets, The convenience of taking can be greatly increased. In addition, the tablets of the present invention can minimize the penile disorder and exhibit an elution pattern comparable to that of conventional celebrex capsules (Celebrex).

Celecoxib With high content  Process for preparing tablets containing

The production method of the present invention can produce celecoxib tablets by the wet granulation method. Specifically, the method of manufacture of the present invention comprises the steps of: (a) preparing a granulate from a mixture comprising a therapeutically effective amount of celecoxib or a pharmaceutically acceptable salt thereof and a water-soluble excipient; And (b) subjecting the mixture comprising the granule and the cellulose-based excipient.

The step (a) may be carried out by further adding a surfactant, a binder, and a disintegrating agent to produce a wet granulated product. About 50 to about 70 weight percent of celecoxib or a pharmaceutically acceptable salt thereof, about 8 to 30 weight percent of a water-soluble excipient, about 1 to 5 weight percent of a surfactant, about 1 to 6 weight percent of a binder, By weight, and about 1 to 6% by weight of a disintegrant is mixed to obtain a powdery mixture. In addition, the mixture may be re-combined and granulated with water or a surfactant aqueous solution to form granules. The granules are dried and milled and used in subsequent steps.

The step (b) may further include adding a disintegrant and a glidant, wherein the disintegrant and the glidant are added after the cellulose-based excipient is further added to the granules. Based on the total weight of the tablet, about 5 to 20% by weight of the cellulose-based excipient, about 1 to 6% by weight of the disintegrant, and about 1 to 5% by weight of the lubricant may be used.

The cellulose-based excipient, the water-soluble excipient, the surfactant, the disintegrant, the binder and the glidant used in the production method of the present invention are mentioned in this specification.

In addition, the tablet of the present invention can be film coated, and the film composition can be contained in an amount of 1 to 5% by weight based on the total weight of the tablet.

The present invention provides a tablet for oral administration which is superior in easiness of taking the tablet because of its small size as compared with conventional celecoxib oral preparations and can be expected to have an equivalent therapeutic effect owing to no change in dissolution rate even after storage for a long period of time, It is possible to provide a tablets having a fast drug efficacy since the drug concentration is quickly reached.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph showing the comparison of the apparent sizes of the Celebrex capsules and the tablets of the present invention (Example 6). FIG.
2 is a graph comparing the dissolution rates of celecoxib in the Celebrex capsules and tablets of the present invention (Example 6).

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. It should be understood, however, that the embodiments and examples are provided for illustrative purposes only, and are not intended to limit the scope of the present invention.

Example  And Comparative Example

≪ Comparative Examples 1 to 3 >

The liquid mixture prepared by mixing celecoxib, lactose hydrate, povidone and croscarmellose sodium according to the prescription set forth in Table 1 below and sodium laurylsulfate in water was sprayed evenly to the mixed powder to prepare wet granules. The prepared granules were thoroughly dried in an oven at 60 캜, passed through a 30-mesh sieve, and further mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate by extragranular mixing to prepare tablets containing celecoxib .

[Table 1]

(Comparative Example 1: Example 4 of Korean Patent No. 0501034)

≪ Examples 1 to 5 and Comparative Examples 4 to 6 >

In order to improve the rapid drug release and tableting properties of the celecoxib tablets, tablets were prepared by tableting according to the same preparation method as Comparative Examples 1 to 3 according to the prescription described in Tables 2 and 3 below.

[Table 2]

[Table 3]

≪ Example 6 and Comparative Example 7 >

The napped tablets prepared in Example 1 and Comparative Example 3 were film-coated using hydroxypropylcellulose as a film coating agent, titanium oxide as a light shielding agent, and polyethylene glycol 6000 with a plasticizer. Respectively, as Example 6 and Comparative Example 7, respectively.

Experimental Example

<Experimental Example 1> Confirmation of physical properties and qualities of granules

Examples 1-5 and Comparative Example 1 was confirmed by the bulk density, flowability, and the other fixed and disintegration time of the granulate prepared in 1-6, conventional same-dose capsule for the granulate in the capsule (Celebrex ^® capsule, Pfizer) Bulk density, flowability and saturation were measured. The bulk density was measured three times and then the values were averaged. The fluidity was measured using the following Carr's compressibility (%).

The results are shown in Tables 4 and 5 below.

[Table 4]

[Table 5]

As can be seen from Tables 4 and 5, the granules of Examples 1 to 5, unlike the granules of Comparative Examples 1 to 6, were able to secure the fluidity of the granules and to overcome the tableting difficulties. On the other hand, the granules of the Celebrex capsules had insufficient flowability for tableting, and the bindings during tableting (a phenomenon in which tablets were hardly discharged from the die due to friction between the tablets and the die wall surface, The powder surface adhered to the tablet surface and the surface of the tablet was not clean, and in some cases, the tablet was damaged).

Experimental Example 2 Comparison of the volume of tablets of Example 1 and Comparative Example 1

The granules of Example 1 and Comparative Example 1 were tableted with the same rectangular punch at a pressure of 11 KN, and the volume of the tablet was measured. The results are shown in Table 6 below.

[Table 6]

From the above results, it was confirmed that the tablets of Example 1 were remarkably small in volume and convenience of taking was improved.

<Experimental Example 3> Size comparison with commercially available capsules

Example 6 and the tablets available on the market Celebrex ^® 200mg capsules (Pfizer) and size were observed. The results are shown in Table 7 and Fig.

[Table 7]

As a result, it can be seen that Example 6 according to the present invention is remarkably small in size as compared with a commercial capsule, and thus, is easy to take.

<Experimental Example 4> Measurement of dissolution rate

Example 6, Comparative Example 7, and Conventional Capsules of Celvelex &lt; ( ^R ) &gt; The elution test was carried out using the dissolution test method and the second method (paddle method) in the general test method of KP, and 1000 mL of pH 12 phosphate buffer solution containing 1% sodium laurylsulfate was used as an eluent. 1 mL samples were taken at 5, 10, 15, 30, 45 and 60 min at 65 rpm and maintained at 37 ° C and analyzed by high performance liquid chromatogram. The results are shown in Table 8 below.

[Table 8]

From the above results, Example 6 is carried out can be confirmed, and represents a dissolution rate equal to the Celebrex ^® capsule, even though tablets. In the case of the Celebrex capsules, the dissolution rate of the drug was released according to the dissolution rate of the gelatin of the capsule, and the dissolution rate was much larger than that of Example 6. In the case of Comparative Example 7, it was confirmed that after the disintegration of the tablets, the disintegrated mixture was piled up at the bottom of the elution vessel, which prevented the release of the drug, and the deviation of the dissolution rate was large.

<Experimental Example 5> Biological equivalence test

2X2 was conducted for bioequivalence test on the conducted with healthy adult volunteers 40 people in alternating test according to the Latin square gyeokbeop Example 6 Purification and Celebrex ^® capsule 200mg (Pfizer).

As a result, it was found that the tablets of Example 6 according to the present invention were biologically equivalent to those of commercial tablets, Tmax of 3.23 ± 1.13 for the commercial capsules, and Tmax of 2.12 ± 1.34 for the tablets of Example 6, It is expected to be possible. The results are shown in Fig.

&Lt; Experimental Example 6 > Evaluation of stability under severe conditions

Example 6 Purification of the conventional capsule agent Celebrex ^® capsules (Pfizer) were evaluated by the stability over time under the harsh conditions in the dissolution rate measured. 40 占 폚 and RH 75%, and the dissolution rate was evaluated after one month. The results are shown in Table 9 below.

[Table 9]

From the above results, it was confirmed that the release rate of the Celebrex capsules was delayed due to the curing of the capsules under severe conditions, whereas the tablets of Example 6 were more stable than the commercial capsules due to the constant rate of release even under severe conditions.

Claims (5)

50 to 70% by weight of a pharmacologically effective amount of celecoxib or a pharmaceutically acceptable salt thereof; And
(i) low-substituted hydroxypropylcellulose,
(ii) a single particle containing microcrystalline cellulose and colloidal silicon dioxide,
(iii) a single particle containing lactose hydrate and microcrystalline cellulose,
(iv) a single particle containing lactose hydrate and powdered cellulose, and
(v) a mixture thereof. &lt; RTI ID = 0.0 &gt; 5. &lt; / RTI &gt; The tablet according to claim 1, further comprising 8 to 30% by weight of a water-soluble excipient selected from the group consisting of lactose hydrate, sorbitol, mannitol, xylitol, maltodextrin and mixtures thereof. The tablet according to claim 1, wherein the cellulosic excipient is an extragranular excipient. The tablet according to claim 2, wherein the water-soluble excipient is an intragranular excipient. (a) preparing a granulate from a mixture comprising a therapeutically effective amount of celecoxib or a pharmaceutically acceptable salt thereof and a water-soluble excipient; And (b) tableting the mixture comprising the granule and the cellulose-based excipient, wherein the amount of celecoxib or pharmaceutically acceptable salt thereof is from 50 to 70% by weight based on the total tablet weight, the water-soluble excipient is Wherein the cellulose-based excipient comprises (i) low-substituted hydroxypropylcellulose, (ii) microcrystalline cellulose, and a single particle containing colloidal silicon dioxide, wherein the cellulose-based excipient comprises from 5 to 20% (iii) a single particle containing lactose hydrate and microcrystalline cellulose, (iv) a single particle containing lactose hydrate and powdered cellulose, and (v) a mixture thereof, wherein the water-soluble excipient is selected from the group consisting of lactose hydrate, sorbitol, Mannitol, xylitol, maltodextrin, and mixtures thereof. The method for producing a celecoxib tablet .

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