A capsule composition of celecoxib

Abstract

The application relates to a celecoxib capsule composition and belongs to the technical field of pharmaceutical preparations. The celecoxib capsule composition is prepared from the following components in percentage by weight: celecoxib 74.1%, lactose monohydrate 16.4%-17.4%, arginine 1.0%-2.0%, sodium dodecyl sulfate 3.0%, povidone (K30) 2.5%, cross-linked sodium carboxymethyl cellulose 1.0%, and magnesium stearate 1.0%. The problem that the dissolution curve of the celecoxib capsule is significantly slowed down during storage is solved by adding appropriate arginine in the prescription.

Description

Technical Field

[0001] This invention relates to a celecoxib capsule composition, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Celecoxib, chemically known as 4-[5-(4-tolyl)-3-(trifluoromethyl)-1H-1-pyrazol-1-yl]benzenesulfonamide, belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs) and is used for analgesia, anti-inflammation, and antipyresis. It is a selective COX-2 inhibitor and is mainly used for OA and RA. It can selectively inhibit COX-2 without COX-1 inhibition, thus significantly reducing gastrointestinal side effects compared to traditional NSAIDs.

[0003] Celecoxib capsules were developed by GDSearle LLC in the United States and marketed under the brand name CELEBREX. ® It was approved by the FDA on December 23, 1999, with marketed specifications of 0.1g, 0.2g, and 0.4g; and approved for marketing in my country on August 4, 2000, with marketed specifications of 0.1g and 0.2g, under the brand name Celebrex. ® The original formulations listed in China are listed as reference formulations by the State Food and Drug Administration, and the development and research of generic drugs must achieve consistency with them in vivo and in vitro.

[0004] Celecoxib belongs to the BCS II class, characterized by low solubility and high permeability. The solubility of the raw material and the dissolution performance of the formulation have become key focuses in formulation development. To achieve good dissolution of celecoxib capsules, current methods mainly involve preparing solid dispersions and adding accelerators to improve its solubility. For example, Chinese patent CN11064722B provides a method for preparing a solid dispersion of the raw material, characterized by mixing the raw material and some excipients, and then pulverizing it using ultra-micro airflow or mechanical means to reduce problems such as astringency, adhesion to the wall, and slow dissolution of the celecoxib material. Another example is Chinese patent CN104721169B, which provides a method for improving the dissolution rate of the formulation by adding organic acids and calcium carbonate to the formula. Comparative studies revealed that the above patents were all derived from the formulations of the original patents CN1288378A and US9750756B2 through formulation exploration and optimization. However, during the development of celecoxib capsule formulations, it was found that the dissolution curve of the formulation slowed down significantly during the stability study. The above patents focused on dissolution but did not address the problem of the slowed dissolution curve during the stability study. Therefore, further research is necessary. Summary of the Invention

[0005] Objective of the invention: To provide a celecoxib composition that is processable and of stable quality, thereby solving the problem of significant changes in the dissolution profile during the stability period.

[0006] Experiments have shown that during the formulation development process, researchers accidentally discovered that adding a certain amount of arginine to the formulation can keep the dissolution curve of the product stable during the stability period.

[0007] The technical solution of this invention is:

[0008] A celecoxib capsule composition, comprising the following components by weight percentage: celecoxib 74.1%, lactose monohydrate 16.4%~17.4%, arginine 1.0%~2.0%, sodium lauryl sulfate 3.0%, povidone (K30) 2.5%, croscarmellose sodium cellulose 1.0%, and magnesium stearate 1.0%.

[0009] Preferably, the celecoxib capsule composition of the present invention comprises, by weight percentage, the following components: celecoxib 74.1%, lactose monohydrate 16.9%, arginine 1.5%, sodium lauryl sulfate 3.0%, povidone (K30) 2.5%, croscarmellose sodium 1.0%, and magnesium stearate 1.0%.

[0010] In the technical solution of this invention, in order to make celecoxib capsules have better solubility, the particle size distribution of the raw materials needs to be controlled within a D90 range of 13.0 to 18.0 μm.

[0011] The method for preparing celecoxib capsules according to the present invention includes the following steps:

[0012] Step 1: Preparation of sodium dodecyl sulfate and arginine aqueous solution: Take the prescribed amount of sodium dodecyl sulfate and arginine, slowly add them to deionized water, and stir continuously until the sodium dodecyl sulfate and arginine are completely dissolved and ready for use.

[0013] Step 2 Granulation: Take the prescribed amount of celecoxib, lactose monohydrate, povidone, and croscarmellose sodium and premix them in a wet granulator for 5 minutes. Under stirring conditions, spray granulation is performed using the solution obtained in Step 1 at a spraying speed of 1.5 kg / min.

[0014] Step 3: Drying and Granulation: Transfer the granules obtained in Step 2 to a fluidized bed, controlling the inlet air temperature at 50~60℃ and the air volume at 2000-3000 m³ / h. 3 The drying process is carried out at a rate of / h, and the dried particles are then granulated using a granulator with a 1.0mm aperture screen.

[0015] Step 4: Mixing: Mix magnesium stearate with the particles obtained in Step 3 until homogeneous to obtain mixed particles.

[0016] Step 5 Capsule filling: Fill the No. 2 capsule shell with the total mixed granules. Beneficial effects

[0017] The celecoxib capsule composition of the present invention solves the problem of significantly slower dissolution curve of celecoxib capsules during storage by adding an appropriate amount of arginine to the formula. Implementation

[0018] The present invention will be further illustrated by the following examples, but the present invention is not limited thereto.

[0019] Example 1: Preparation of Celecoxib Capsules

[0020] (1) Prescription composition

[0021]

[0022] (2) Preparation

[0023] Step 1: Preparation of sodium dodecyl sulfate and arginine aqueous solution: Take the prescribed amount of sodium dodecyl sulfate and arginine, slowly add them to deionized water, and stir continuously until the sodium dodecyl sulfate and arginine are completely dissolved and ready for use.

[0024] Step 2 Granulation: Take the prescribed amount of celecoxib, lactose monohydrate, povidone, and croscarmellose sodium and premix them in a wet granulator for 5 minutes. Under stirring conditions, spray granulation is performed using the solution obtained in Step 1 at a spraying speed of 1.5 kg / min.

[0025] Step 3: Drying and Granulation: Transfer the granules obtained in Step 2 to a fluidized bed, controlling the inlet air temperature at 50~60℃ and the air volume at 2000-3000 m³ / h. 3 The drying process is carried out at a rate of / h, and the dried particles are then granulated using a granulator with a 1.0mm aperture screen.

[0026] Step 4: Mixing: Mix magnesium stearate with the particles obtained in Step 3 until homogeneous to obtain mixed particles.

[0027] Step 5 Capsule filling: Fill the No. 2 capsule shell with the total mixed granules.

[0028] Example 2: Preparation of Celecoxib Capsules

[0029] (1) Prescription composition

[0030]

[0031] (2) Preparation was carried out according to the preparation method in Example 1.

[0032] Example 3: Preparation of Celecoxib Capsules

[0033] (1) Prescription composition

[0034]

[0035] 2) Preparation was carried out according to the preparation method in Example 1.

[0036] Comparative Example 1: Preparation of Celecoxib Capsules: Original Patent (CN1288378A) Formulation

[0037] (1) Prescription composition

[0038]

[0039] (2) Preparation was carried out according to the preparation method in Example 1.

[0040] Preparation of Celecoxib Capsules (Comparative Example 2): The formulation of Comparative Example 1 was followed, with the use of a small amount of arginine.

[0041] (1) Prescription composition

[0042]

[0043] (2) Preparation was carried out according to the preparation method in Example 1.

[0044] Preparation of Celecoxib Capsules (Comparative Example 3): Citric acid was used in accordance with the prescription of Comparative Example 1.

[0045] (1) Prescription composition

[0046]

[0047] (2) Preparation was carried out according to the preparation method in Example 1.

[0048] Preparation of celecoxib capsules in Comparative Example 4: Arginine was added in a different manner, referring to the formulation of Example 1.

[0049] (1) Prescription composition

[0050]

[0051] (2) Preparation Step 1 Preparation of sodium dodecyl sulfate aqueous solution: Take the prescribed amount of sodium dodecyl sulfate, slowly add it to deionized water, and stir continuously until the sodium dodecyl sulfate is completely dissolved and ready for use.

[0052] Step 2 Granulation: Take the prescribed amount of celecoxib, lactose monohydrate, arginine, povidone, and croscarmellose sodium and premix them in a wet granulator for 5 minutes. Under stirring conditions, spray granulation is performed using the solution obtained in Step 1 at a spraying speed of 1.5 kg / min.

[0053] Step 3: Drying and Granulation: Transfer the granules obtained in Step 2 to a fluidized bed, controlling the inlet air temperature at 50~60℃ and the air volume at 2000-3000 m³ / h. 3The drying process is carried out at a rate of / h, and the dried particles are then granulated using a granulator with a 1.0mm aperture screen.

[0054] Step 4: Mixing: Mix magnesium stearate with the particles obtained in Step 3 until homogeneous to obtain mixed particles.

[0055] Step 5 Capsule filling: Fill the No. 2 capsule shell with the total mixed granules.

[0056] Dissolution curves of the reference formulation, the above-mentioned examples, and the control examples were determined according to the dissolution test method of the imported registration standard for celecoxib capsules (JX20130156).

[0057] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-triethylamine phosphate buffer (0.5% triethylamine aqueous solution, pH adjusted to 7.0±0.1 with phosphoric acid) (55:45) was used as the mobile phase; the detection wavelength was 256 nm; and the injection volume was 5 μl.

[0058] pH 12.0-1.0% SDS dissolution medium: Weigh 15.2g of sodium phosphate, dissolve and dilute to 1000ml with water, shake well, adjust the pH to 12.0 with phosphoric acid or sodium hydroxide test solution, add 10.0g of SDS, and stir to dissolve.

[0059] Dissolution test method: paddle method, rotation speed of 50 rpm, samples were taken at 10 minutes, 15 minutes and 45 minutes respectively, filtered through a 0.45 μm microporous membrane, and the filtrate was injected into the high performance liquid chromatograph. The dissolution amount at each time point was determined by external standard method.

[0060] Table 1 Summary of Dissolution Curve Measurement Data

[0061]

[0062] As shown in the table above, the addition of arginine or citric acid has no significant effect on the dissolution curve at a ratio close to that of the reference formulation. The dissolution curves of the samples prepared by the proposed process are similar to those of the reference formulation. The above samples were then subjected to stability studies at 30℃±2℃ and 70%RH±5%RH. The data are shown in the table below.

[0063] Table 2 Summary of Dissolution Curve Data from Stability Tests

[0064]

[0065]

[0066] As shown in the table above, within the preferred formulation range, the dissolution curves of Examples 1, 2, and 3 were relatively stable during the stability study. In Control Example 1, which lacked arginine, the dissolution curve slowed significantly during the stability study. In Control Example 2, the arginine content was below the lower limit of the formulation, and the dissolution curve also showed a slowing trend during the stability study. In Control Example 3, the use of citric acid also resulted in a significantly slowing dissolution curve during the stability study. In Control Example 4, different methods of adding arginine had different effects on the stability of the dissolution curve.

[0067] In summary, the preparation of celecoxib capsules using the formulation and preparation method disclosed herein solves the problem of slowing dissolution curves during the stability period, and the dissolution curves are similar to those of the reference formulation.

Claims

1. A celecoxib capsule composition, comprising, by weight percentage: celecoxib 74.1%, lactose monohydrate 16.4%~17.4%; arginine 1.0%~2.0%; sodium lauryl sulfate 3.0%; povidone K30 2.5%; croscarmellose sodium 1.0%; magnesium stearate 1.0%, and prepared by the following method: Step 1: Preparation of sodium dodecyl sulfate and arginine aqueous solution: Take the prescribed amount of sodium dodecyl sulfate and arginine, slowly add them to deionized water, and stir continuously until the sodium dodecyl sulfate and arginine are completely dissolved and ready for use. Step 2 Granulation: Take the prescribed amount of celecoxib, lactose monohydrate, povidone K30, and croscarmellose sodium and place them in a wet granulator for 5 minutes to premix. Under stirring conditions, the mixed material is sprayed with the solution obtained in Step 1 at a spraying speed of 1.5 kg / min. Step 3: Drying and Granulation: Transfer the granules obtained in Step 2 to a fluidized bed, controlling the inlet air temperature at 50~60℃ and the air volume at 2000-3000 m³ / h. 3 The drying process is carried out at a rate of / h, and the dried particles are then granulated using a granulator with a 1.0mm aperture screen. Step 4: Mixing: Mix magnesium stearate with the particles obtained in Step 3 until homogeneous to obtain mixed particles; Step 5 Capsule filling: Fill the No. 2 capsule shell with the total mixed granules.

2. The celecoxib capsule composition as described in claim 1, characterized in that, The components, by weight percentage, are as follows: celecoxib 74.1%, lactose monohydrate 16.9%, arginine 1.5%, sodium lauryl sulfate 3.0%, povidone K30 2.5%, croscarmellose sodium 1.0%, and magnesium stearate 1.0%.

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