JP2019530755A - Tablets containing celecoxib - Google Patents

Abstract

The present invention relates to a tablet containing celecoxib, which is smaller in size than existing celecoxib oral preparations, is easy to take, has no change in dissolution rate even after long-term storage, and has an equivalent therapeutic effect. It can be expected and is manufactured in a tablet form, has high productivity, reaches the maximum blood drug concentration early, and has a rapid onset of drug efficacy.

Description

  The present invention relates to a tablet containing celecoxib, specifically, smaller in size than existing celecoxib oral preparations, excellent in convenience of administration, and has no change in dissolution rate even when stored for a long period of time. The present invention relates to a tablet that can be expected to have an excellent therapeutic effect, is manufactured in a tablet form, has high productivity, reaches a maximum blood drug concentration quickly, and has a rapid onset of drug efficacy, and a method for producing the same.

  Celecoxib is the general name for the chemical name 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, It has the structure of Formula 1.

  Celebrex (registered trademark) (Pfizer), which contains celecoxib, which is an inhibitor of selective cyclooxygenase-2 (COX-2), as an active ingredient and is sold in the form of capsules, is currently used to treat arthritis without gastrointestinal disorders. It has the highest share in the drug market.

  Celecoxib may be administered in dosage forms containing large amounts (100-400 mg). However, due to the physical and chemical properties peculiar to celecoxib, there is a problem that it is difficult to produce tablets that are small enough to be easily taken. For example, celecoxib is a material that has electrostatic properties, low compressibility and cohesion, and low density. Due to such characteristics, it is difficult to produce a tablet having suitable characteristics. Also, in order to reduce the tablet mass, limited amounts of excipients to facilitate rapid drug release had to be used. For this reason, the low solubility of celecoxib is also a problem.

  Celecoxib has heretofore been developed as a capsule due to such physical and chemical properties. However, such capsules are not only bulky but also expensive to manufacture. In addition, the disintegration and elution rate depends on the degree of dissolution of the gelatin that constitutes the capsule due to its characteristics. During storage, the disintegration and elution rate is further delayed by the influence of the external environment such as moisture and temperature. Or the pattern changes.

  On the other hand, Korean Registered Patent No. 0501034 (Patent Document 1) discloses an orally administrable pharmaceutical composition containing celecoxib as an active ingredient. However, when a tablet is manufactured according to the Korean Registered Patent No. 0501034, there is a problem that the volume of the completed tablet is too large and the convenience of taking is inferior.

  Therefore, the inventors of the present invention have conducted research in order to improve the problems of the prior art, and as a result, they are smaller in size than the conventional composition, excellent in convenience of taking, and stored for a long time. The present invention relates to a tablet that can be expected to have a uniform therapeutic effect without any change in dissolution rate, is manufactured in a tablet form, has high productivity, reaches the maximum blood drug concentration quickly, and has a rapid onset of drug efficacy. Was completed.

Republic of Korea Registered Patent No. 0501034

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

  In order to solve the above-mentioned problems, the present invention (1) uses a minimum amount of excipient, reduces the administration volume, improves the convenience of taking, and (2) improves the stability and speeds up. Provided is a tablet having drug release characteristics, (3) easy to manufacture, increasing economy and efficiency, and (4) having suitable tablet characteristics, and a method for producing the same. Hereinafter, the present invention will be described in detail.

Tablets with high content of celecoxib

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

  In the present invention, the celecoxib or a pharmaceutically acceptable salt thereof may be celecoxib free base or a pharmaceutically acceptable salt thereof. Preferably, celecoxib free base is used. Celecoxib or a pharmaceutically acceptable salt thereof can be directly synthesized by a known production method or purchased in the market.

  In the present invention, celecoxib or a pharmaceutically acceptable salt thereof is included in a pharmacologically effective amount, and the amount varies depending on the condition, weight, etc. of the patient to be treated. Specifically, celecoxib or a pharmaceutically acceptable salt thereof is 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 is contained at 50 to 70% by weight, preferably 60 to 70% by weight, based on the total weight of the tablet. The active ingredient celecoxib or a pharmaceutically acceptable salt thereof is contained in a high content in the tablet, and various excipients may be contained in minimum amounts. Therefore, the tablet of the present invention is manufactured in a smaller size than the existing celecoxib oral preparation (capsule), thereby greatly increasing the convenience of taking the patient.

  The “cellulosic excipient” contained in the tablet of the present invention can overcome tableting obstacles during tableting and can accelerate the disintegration rate of the tablet. Suitable cellulose-based excipients include powdered cellulose, low-substituted hydroxypropylcellulose, microcrystalline cellulose / colloidal silicon dioxide (eg, Prosolv), lactose hydrate / microcrystalline cellulose (eg, microshell), and lactose water It may be selected from Japanese products, cellulose (eg, lactose), and mixtures thereof.

  The “powdered cellulose” contains amorphous cellulose, and for example, those comprising 45% by weight of crystalline form and 55% by weight of amorphous may be used. The average particle size of the powdered cellulose is preferably 30 to 180 μm, and more preferably 40 to 80 μm.

  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 hydroxypropoxy group content of about 5 to 16% by weight, preferably 9 to 13% by weight. The average particle size of the low-substituted hydroxypropylcellulose is preferably 35 to 75 μm, and more preferably 50 to 60 μm.

  The above-mentioned “microcrystalline cellulose / colloidal silicon dioxide” means siliconized microcrystalline cellulose in which colloidal silicon dioxide particles are thinly distributed on the surface of the microcrystalline cellulose to form monoparticles. Preferably, 98% by weight of microcrystalline cellulose and 2% by weight of colloidal silicon dioxide may be used. The average particle diameter of the microcrystalline cellulose / colloidal silicon dioxide is preferably 40 to 130 μm, and more preferably 90 to 130 μm.

  The above-mentioned “lactose hydrate / microcrystalline cellulose” is obtained by spray-drying lactose hydrate and microcrystalline cellulose to form single particles containing 75% by weight of lactose hydrate and 25% by weight of microcrystalline cellulose. Means an excipient.

  The “lactose hydrate / cellulose” is an excipient formed by spray-drying lactose hydrate and powdered cellulose to form single particles containing 75% by weight of lactose hydrate and 25% by weight of powdered cellulose. Means.

  In the present invention, the cellulosic excipient may be contained at 5 to 20% by weight, preferably 6 to 12% by weight, based on the total weight of the tablet. Outside the above numerical range, tableting troubles may occur, or a problem may occur in the dissolution rate of celecoxib.

  The cellulosic excipient may also be used as an extragranular excipient mixed with granules containing celecoxib or a pharmaceutically acceptable salt thereof.

  The tablet of the present invention may further contain a water-soluble excipient. The “water-soluble excipient” used in the present invention means a diluent that is soluble in water. Water-soluble excipients are one or more compounds that can increase tablet density to improve the electrostatic and cohesive properties so as to obtain the desired tablet mass. Suitable water soluble excipients may be selected from lactose hydrate, sorbitol, mannitol, xylitol, maltodextrin, and mixtures thereof.

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

  The tablet of the present invention may further contain a surfactant, a disintegrant, a binder, and a lubricant that are commonly used in the art.

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

  The “disintegrant” used in the tablet of the present invention has an effect of expanding and disintegrating the tablet in the gastrointestinal tract when contacted with moisture. Suitable disintegrants may be selected from crospovidone, carboxymethylcellulose calcium, sodium carboxymethylcellulose, croscarmellose sodium, starch, sodium starch glycolate, low substituted hydroxypropylcellulose, and mixtures thereof. . However, it is not limited to this. In the present invention, the disintegrant may be contained at 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 the granules and further increase the granulation into flowable granule particles. Suitable binders may be selected from povidone, hypromellose, hydroxypropylcellulose, gelatinized starch, and mixtures thereof. However, it is not limited to this. In the present invention, the binder may be contained at 1 to 6% by weight based on the total weight of the tablet.

  The “lubricant” used in the composition of the present invention has effects such as improvement in fluidity from a tableting die, prevention of adhesion to punches and dies, and reduction in resistance when discharging tablets from the tableting machine. is there. Suitable lubricants may be selected from talc, sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, and mixtures thereof. However, it is not limited to this. In the present invention, the lubricant may be contained at 1 to 5% by weight based on the total weight of the tablet.

  The tablet of the present invention comprises celecoxib or a pharmaceutically acceptable salt thereof in a high content of 50 to 70% by weight, and various excipients are contained in a low content to produce a small size tablet. As a result, the convenience of taking the patient can be greatly increased. In addition, the tablet of the present invention minimizes tableting obstacles and exhibits an equal dissolution pattern compared to existing celecoxib capsules (Celebrex).

  The tablet of the present invention contains celecoxib as an active ingredient and is used for suppressing selective cyclooxygenase-2 (COX-2). Specifically, it is used for the prevention or treatment of arthritis, for anti-inflammation, and for analgesia. May be.

Method for producing tablets containing a high content of celecoxib

  The production method of the present invention can produce celecoxib tablets by a wet granulation method. Specifically, the production method of the present invention comprises (a) producing granules from a mixture comprising a therapeutically effective amount of celecoxib or a pharmaceutically acceptable salt thereof and a water-soluble excipient, and (b) Tableting a mixture comprising granules and cellulosic excipients.

  The step (a) is a step of producing a wet granule, and may be performed by further adding a surfactant, a binder, and a disintegrant. At this time, based on the total weight of the tablet, about 50 to about 70% by weight of celecoxib or a pharmaceutically acceptable salt thereof, about 8 to 30% by weight of a water-soluble excipient, about 1 to about 1% of a surfactant. 5% by weight, about 1-6% by weight of the binder and about 1-6% by weight of the disintegrant are mixed to obtain a powdery mixture. Further, after remixing the mixture, it can be granulated with water or an aqueous surfactant solution to form granules. The granules are dried and pulverized and used in subsequent steps.

  In the step (b), a disintegrating agent and a lubricant may be further added as a step of manufacturing a tablet after further adding a cellulose-based excipient to the granules. At this time, about 5 to 20% by weight of the cellulosic excipient, about 1 to 6% by weight of the disintegrant, and about 1 to 5% by weight of the lubricant may be used based on the total weight of the tablet.

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

  The tablet of the present invention may be film-coated, and the film composition may be contained at 1 to 5% by weight based on the total weight of the tablet.

  The present invention is smaller in size than existing celecoxib oral preparations, is easy to take, has no change in dissolution rate even after long-term storage, and can be expected to have a uniform therapeutic effect. Thus, it is possible to provide a tablet with high productivity, fast reaching the maximum blood drug concentration, and rapid onset of drug efficacy.

It is the photograph which compared the external appearance size of the Celebrex capsule and the tablet (Example 6) of this invention. It is the graph which compared the celecoxib elution rate of the Celebrex capsule and the tablet of the present invention (Example 6).

  Hereinafter, the present invention will be specifically described with reference to examples and experimental examples. However, these examples and experimental examples are provided for illustrative purposes in order to help understanding of the present invention, and the scope of the present invention is not limited thereby.

Examples and Comparative Examples

<Comparative Examples 1 to 3>
According to the formulation shown in Table 1 below, celecoxib, lactose hydrate, povidone, croscarmellose sodium are mixed, and a kneaded solution prepared by dissolving sodium lauryl sulfate in water is uniformly sprayed onto the mixed powder to obtain wet granules. Manufactured. After the produced granules are sufficiently dried in an oven at 60 ° C., they are passed through a 30-mesh sieve and further mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate by extragranular mixing to obtain celecoxib. The contained tablets were produced by tableting.

(Comparative Example 1: Example 4 in Patent Document 1)

<Examples 1 to 5 and Comparative Examples 4 to 6>
In order to improve the rapid drug release and tabletability of celecoxib tablets, the tablets were produced by the same production method as in Comparative Examples 1 to 3 according to the formulations shown in Tables 2 and 3 below.

<Example 6 and Comparative Example 7>
The bare tablets produced in Example 1 and Comparative Example 3 were film coated using hydroxypropyl cellulose as a film coating agent, titanium oxide as a light shielding agent, and polyethylene glycol 6000 as a plasticizer. Example 6 and Comparative Example 7 were used respectively.

Experimental example

<Experimental Example 1> Confirmation of Physical Properties and Tableting Properties of Granules The volume density, fluidity, tableting property, and disintegration time of the granules produced in Examples 1 to 5 and Comparative Examples 1 to 6 were confirmed, and the same as before. Volume density, flowability, and tabletability were measured on granules in capsules of volume capsules (Celebrex® capsules, Pfizer). The volume density was measured three times and then averaged, and the fluidity was measured using the following Carr's compressibility (%).

  The results are shown in Tables 5 and 6 below.

  As can be seen from the above Tables 5 and 6, unlike the granules of Comparative Examples 1 to 6, the granules of Examples 1 to 5 can ensure the fluidity of the granules and overcome the tableting obstacle. On the other hand, the granules of Celebrex capsules are not sufficiently fluid for tableting, and when tableting, binding (the tablet is difficult to be discharged from the die due to friction between the tablet and the wall of the die; Tableting troubles such as a phenomenon in which the side of the tablet is broken and sticking (a phenomenon in which powder adheres to the surface of the punch, the surface of the tablet is not clean, and partly damages in some cases) occurred.

  <Experimental example 2> Comparison of volume feeling of tablets of Example 1 and Comparative Example 1

  When the granules of Example 1 and Comparative Example 1 were tableted with the same rectangular punch at a tableting pressure of 11 KN, the tablet volume was measured. The results are shown in Table 7 below.

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

  <Experimental example 3> Size comparison with commercially available capsules

  The size of the tablet of Example 6 and a commercially available Celebrex (registered trademark) capsule 200 mg (Pfizer) were observed. The results are shown in Table 8 and FIG.

  As a result, it can be seen that Example 6 according to the present invention is remarkably smaller in size than a commercially available capsule and is excellent in convenience of taking.

  <Experimental Example 4> Measurement of dissolution rate

  Six elution tests were conducted on each of Example 6, Comparative Example 7, and Celebrex (registered trademark) capsules of conventional capsules. The dissolution test was conducted by using the dissolution test method, the second method (paddle method), among the general test methods of the Korean Pharmacopoeia. The dissolution solution was phosphorous at pH 12 containing 1% sodium lauryl sulfate. 1 mL of sample was taken at 5, 10, 15, 30, 45, and 60 minutes at a speed of 65 rpm while using 1000 mL of an acid buffer and maintaining the eluate at 37 ° C., and analyzed by a high performance liquid chromatogram. . The results are shown in Table 9 below.

  From the above results, it was confirmed that Example 6 showed an elution rate equal to that of Celebrex (registered trademark) capsules, regardless of the tablets. In the case of Celebrex capsules, the drug was released by the dissolution rate of gelatin forming the capsules, and it was confirmed that the dissolution rate deviation was much larger than that in Example 6. Further, in the case of Comparative Example 7, it was confirmed that after the tablet disintegrated, the disintegrated mixture was accumulated on the bottom surface of the elution machine, disturbing the release of the drug, and a large deviation in dissolution rate.

  <Experimental example 5> Bioequivalence test

  A bioequivalence test was conducted on the tablet of Example 6 and 200 mg of Celebrex (registered trademark) capsule (Pfizer) using 40 healthy adult supporters by the cross test method of 2 × 2 Latin squares.

  As a result, it was found that the tablet of Example 6 according to the present invention was biologically equivalent to a commercially available capsule, the commercially available capsule was Tmax 3.23 ± 1.13, and the tablet of Example 6 was Since Tmax is 2.12 ± 1.34, it is expected that a faster rapid onset of expression is possible. The results are shown in FIG.

  <Experimental example 6> Evaluation of stability over time under severe conditions

  The tablets of Example 6 and Celebrex (registered trademark) capsules (Pfizer), which are conventional capsules, were evaluated for stability over time by measuring dissolution rate under severe conditions. Open storage was performed under the conditions of 40 ° C. and RH 75%, and the dissolution rate was evaluated after one month. The results are shown in Table 10 below.

  From the above results, Celebrex capsules are delayed in dissolution due to the hardening of the capsules under severe conditions, whereas the tablet of Example 6 has a constant dissolution rate under severe conditions. It was confirmed that it eluted more stably than the capsule.

  This specification omits the detailed description of the content that can be recognized and analogized by those who have ordinary knowledge in the technical field of the present invention, and other than the specific examples described in this specification. In addition, various modifications can be made without departing from the technical idea and essential configuration of the present invention. Accordingly, the present invention may be implemented in a manner different from that specifically described and illustrated herein, and will be understood by those of ordinary skill in the art of the present invention. It can be done.

  The tablet of the present invention contains celecoxib as an active ingredient and is used for suppressing selective cyclooxygenase-2 (COX-2).

  The tablet of the present invention is smaller in size than existing celecoxib oral preparations, excellent in convenience of administration, no change in dissolution rate even after long-term storage, and can be expected to have an equivalent therapeutic effect, Manufactured in a tablet form, it is possible to provide a tablet with high productivity, fast reaching the maximum blood drug concentration, and rapid onset of drug efficacy.

Claims (5)

  A pharmacologically effective amount of celecoxib or a pharmaceutically acceptable salt thereof of 50 to 70% by weight, powdered cellulose, low-substituted hydroxypropylcellulose, microcrystalline cellulose / colloidal silicon dioxide, lactose hydrate / microcrystalline cellulose And 5-20% by weight of a cellulosic excipient selected from the group consisting of lactose hydrate / cellulose and mixtures thereof.   The tablet according to claim 1, further comprising 8-30% 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) producing granules from a mixture comprising a therapeutically effective amount of celecoxib or a pharmaceutically acceptable salt thereof and a water-soluble excipient;
(B) compressing the mixture comprising the granules and the cellulosic excipient;
And based on the total weight of the tablet, celecoxib or a pharmaceutically acceptable salt thereof is 50 to 70% by weight, a water-soluble excipient is 8 to 30% by weight, and a cellulosic excipient is 5 to 20% by weight. The cellulose-based excipient is powdered cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose / colloidal silicon dioxide, lactose hydrate / microcrystalline cellulose, lactose hydrate / cellulose, and its Celecoxib tablets selected from the group consisting of a mixture, wherein the water-soluble excipient is selected from the group consisting of lactose hydrate, sorbitol, mannitol, xylitol, maltodextrin, and mixtures thereof Manufacturing method.