KR102257685B1 - Tablet formulation for prevention or treatment of inflammation pain comprising COX-2(cyclooxygenase-2) inhibitor as active ingredient - Google Patents

Abstract

The present invention relates to an anti-inflammatory analgesic prophylactic or purified pharmaceutical composition comprising a selective COX-2 inhibitor as an active ingredient and a method for preparing the same, wherein the present inventors have anti-inflammatory analgesic using etoricoxib, a selective COX-2 inhibitor, as an active ingredient. When the tablet composition for prevention or treatment was prepared with the composition of the present invention, it was confirmed that it showed improved workability and effective dissolution rate. It could be widely used.

Description

Tablet formulation for prevention or treatment of inflammation pain comprising COX-2 (cyclooxygenase-2) inhibitor as active ingredient}

The present invention relates to a tablet composition for preventing or treating anti-inflammatory pain, comprising a selective COX-2 inhibitor as an active ingredient, and a method for preparing the same.

Inflammation is caused by various causes such as infection by microorganisms, wounds, surgery, burns, frostbite, electrical stimulation, or chemicals, and causes pain along with symptoms such as skin swelling and fever. The major chemicals involved in the inflammatory response are known as histamine, kinins, prostaglandin, and leukotriene. Histamine works to bring more blood and lymph fluid to the damaged area, and kinin relieves muscle contraction and expands capillaries, facilitating blood transport and causing pain. Leukotriene is involved in the adhesion and activity of leukocytes to the inner wall of blood vessels. When leukocytes enter the cell, prostaglandin is synthesized, causing pain and fever.

On the other hand, osteoarthritis is a disease in which local degenerative changes appear as joint cartilage wears out and is called degenerative joint disease. The incidence of osteoarthritis is high with aging after the 40s, and about 2.3 million patients are reported in Korea, and it is known that the prevalence of osteoarthritis is higher and more severe in women than in men. However, it is not an absolute cause, and it is known that osteoarthritis progresses when the balance between the production and decomposition of articular cartilage is broken, and the decomposition rate is faster than the rate of cartilage substrate generation. It is increasing.

Drugs that treat inflammation such as arthritis include steroidal drugs such as prednisolone, hydrocortisone, or dexamethasone, and non-steroidal, anti-inflammatory drugs (NSAIDs) or anti-leukotriene ( Leukotriene receptor antagonist, 5-lipoxygenase antagonist) can be classified into non-steroidal drugs. These drugs are drugs that regulate inflammation by synthesizing leukotriene and prostaglandin, which are chemicals involved in inflammation. In particular, NSAIDs are drugs most often used for osteoarthritis with moderate pain or inflammation due to their high analgesic effect and patient compliance. This inhibits the action of cyclooxygenase (COX), thereby inhibiting the synthesis of prostaglandin, thereby exhibiting anti-inflammatory and analgesic action. Cyclooxygenase (COX) has two isoforms, COX-1 and COX-2, and COX-1 is a housekeeping enzyme related to gastrointestinal mucosa, platelet function, and renal blood flow regulation. And COX-2 is an inducible enzyme expressed in relation to trauma and cell growth. NSAIDs are commercially available, classified into non-selective NSAIDs and COX-2 selective NSAIDs, depending on the selectivity of these enzymes. In particular, COX-2 selective anti-inflammatory analgesics have the advantage of reducing complications related to the gastrointestinal tract, so they have an advantage in the anti-inflammatory analgesic market after launch, but they have the risk of developing thrombotic diseases such as acute myocardial infarction, unstable angina, sudden death, and stroke. As COX-2 inhibitors, excluding celecoxib, have been retired from the market, celecoxib has been the main choice in the COX-2 selective anti-inflammatory analgesic market.

In addition, Etoricoxib is a therapeutic drug developed as a new COX-2 inhibitor, which can inhibit COX-2 106 times stronger than COX-1, and has a bioavailability of 100% compared to other COX-2 inhibitors. It is effective and has a fast effect and a long half-life. In particular, there is no allergic reaction due to the sulfonamide structure of celecoxib, and liver or kidney toxicity is significantly reduced compared to celecoxib, so it can be prescribed not only to the elderly, but also to patients with mild or moderate liver or renal dysfunction. Since it is not necessary and has few gastrointestinal disorders, it can be taken once a day regardless of food, so it has the advantage of increasing medication compliance to patients.

However, there is a need for a study on an efficient preparation method and the proportion of the composition for preparing an oral tablet formulation with improved dissolution rate containing etoricoxib as an active ingredient.

Republic of Korea Patent Publication 10-2012-0123691

The present inventors confirmed the present invention by confirming that the tablet composition for preventing or treating anti-inflammatory analgesia containing etoricoxib, which is a selective COX-2 inhibitor, as an active ingredient, exhibits improved workability and effective dissolution rate compared to the composition of the present invention. Completed.

Accordingly, an object of the present invention is to provide a tablet composition for preventing or treating anti-inflammatory pain, comprising a cyclooxygenase-2 (COX-2) inhibitor as an active ingredient.

However, the technical task to be achieved by the present invention is not limited to the above-mentioned tasks, and other tasks that are not mentioned can be clearly understood by those of ordinary skill in the technical field to which the present invention belongs from the following description. There will be.

In order to achieve the object of the present invention as described above, the present invention provides a tablet composition for preventing or treating anti-inflammatory pain, comprising a cyclooxygenase-2 (COX-2) inhibitor as an active ingredient.

In one embodiment of the present invention, the COX-2 inhibitor may be Etoricoxib.

In another embodiment of the present invention, the tablet composition may be prepared by a wet granulation method.

In another embodiment of the present invention, the tablet composition may contain one or more selected from the group consisting of an active ingredient, an excipient, a disintegrant, a pH adjuster, and a lubricant.

In another embodiment of the present invention, the active ingredient is etoricoxib, the excipient is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the pH adjuster is anhydrous calcium hydrogen phosphate, and the lubricant is magnesium stearate. Can be

In another embodiment of the present invention, the tablet composition is active ingredient 26 to 30% by weight, excipient 30 to 50% by weight, disintegrant 3 to 8% by weight, pH adjuster 10 to 30% by weight, and lubricant 0.5 to 6 It may contain weight percent.

In another embodiment of the present invention, the tablet composition may have a disintegration time of 5 minutes or less, a hardness of 9 to 12 kp, a friability of 0.1 to 0.3%, or a dissolution rate of 70% to 90%.

In another embodiment of the present invention, the tablet composition may be coated with a coating base containing a coating agent.

In another embodiment of the present invention, the coating agent may be hydroxypropylmethylcellulose or polyvinyl alcohol.

The present inventors confirmed that the tablet composition for preventing or treating anti-inflammatory analgesia containing etoricoxib, a selective COX-2 inhibitor, as an active ingredient, showed improved workability and an effective dissolution rate when prepared with the composition of the present invention. It can be widely used in the development of anti-inflammatory analgesic treatments with improved friability, hardness, and dissolution rate, and can be manufactured efficiently and efficiently.

1 is a diagram showing the chemical structure of Etoricoxib.
Figure 2 is a diagram showing the dissolution profiles of tablets containing etoricoxib and commercial products in vitro.

The present inventors the present invention by confirming that the tablet composition for preventing or treating anti-inflammatory analgesia containing etoricoxib, which is a selective COX-2 inhibitor, as an active ingredient, exhibits improved workability and effective dissolution rate than when the composition of the present invention is finally prepared. Was completed.

Hereinafter, the present invention will be described in detail.

In one embodiment of the present invention, in order to determine the manufacturing method in order to prepare a tablet containing etoricoxib, as a result of evaluating the fluidity and compressibility of etoricoxib, the wet granulation method was adopted (see Example 1).

In another embodiment of the present invention, a tablet containing etoricoxib was prepared by varying the weight ratio of each component according to the manufacturing method according to Example 1 (see Example 2).

In another embodiment of the present invention, it was confirmed that compound 5 is a comprehensively excellent tablet composition by evaluating friability, hardness, disintegration, and dissolution, respectively, for the tablet composition prepared according to Example 2 and the reference drug ( See Examples 3-6).

Accordingly, the present invention provides a tablet composition for preventing or treating anti-inflammatory pain, comprising a cyclooxygenase-2 (COX-2) inhibitor as an active ingredient.

The COX-2 inhibitor may be Etoricoxib, but is not limited thereto, and the tablet composition may be prepared by a wet granulation method, but is not limited thereto.

The term'wet granulation method' used in the present invention is a method of forming a moist mass by mixing a granulating liquid that aids granulation with the mixed powder components, and forming a larger lump of granules from the moist masses. When the desired granule growth is achieved, the granulation end point is used and the process proceeds to drying the granules. As drying occurs, the components dissolved in the granulation liquid form solid bridges and hold the particles. Ingredients that play this role are called binders. Then, the dry granules can be pulverized and finally adjusted to a desired particle size. Although the wet granulation method has the advantage of improving the process, it has the disadvantage that the formulation components are exposed to the binder and exposed to high temperatures in the process of drying the wet granules. Alternatively, wet granulation production can be carried out in equipment capable of providing high shear forces or fluid bed granulation techniques can be used.

Accordingly, the tablet composition prepared in the present invention may contain an appropriate active ingredient, a carrier, an excipient, a disintegrant, a pH adjusting agent, a lubricant, and a diluent that are commonly used. In addition, it can be formulated and used in the form of oral dosage forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, and sterile injectable solutions according to a conventional method.

Active ingredients, carriers, excipients, disintegrants, pH adjusters, lubricants, and diluents that may be included in the tablet composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, Alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, croscarmellose sodium, Anhydrous calcium hydrogen phosphate, magnesium stearate and mineral oil. In the case of formulating the composition, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., which are usually used, and preferably, the active ingredient is etoricoxib, and the excipient is microcrystalline cellulose. , The disintegrant may be croscarmellose sodium, the pH adjuster may be anhydrous calcium hydrogen phosphate, and the lubricant may be magnesium stearate, but is not limited thereto.

In this case, the active ingredient may be 26 to 30% by weight, the excipient may be 30 to 50% by weight, the disintegrant may be 3 to 8% by weight, the pH adjuster may be 10 to 30% by weight, and the lubricant may be 0.5 to 6% by weight. It is not limited thereto, and the tablet composition may have a disintegration time of less than 5 minutes, a hardness of 9 to 12 kp, a friability of 0.1 to 0.3%, or a dissolution rate of 70% to 90%, but is not limited thereto.

Further, in the present invention, the tablet for preparing the pharmaceutical composition may be coated with a coating base containing a coating agent, and the coating agent may preferably be hydroxypropylmethylcellulose or polyvinyl alcohol, but is not limited thereto.

The term "prevention" used in the present invention means any action that inhibits or delays the onset of anti-inflammatory pain by preemptively administering the pharmaceutical composition according to the present invention before the onset of anti-inflammatory pain.

The term "treatment" used in the present invention refers to any action in which symptoms of anti-inflammatory pain are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention after the onset of anti-inflammatory pain.

The tablet composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, and drug activity of the patient. , Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.

In order to enhance the therapeutic effect, the tablet composition according to the present invention may be administered simultaneously (simultaneous), separately (separate), or sequentially (simultaneous), separately (separate), or sequentially (sequential) with the drug to be used, preferably single or multiple administration. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, body weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, and the drug to be used in combination.

The tablet composition of the present invention can be administered to a subject by various routes. All modes of administration can be expected, for example, oral administration, intranasal administration, transbronchial administration, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection, or by intraperitoneal injection, preferably Oral administration, but not limited thereto. The daily dosage is preferably administered once to several times a day, but is not limited thereto.

The tablet composition of the present invention is determined according to the type of drug as the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex, weight, and severity of the disease.

Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1. Evaluation of flowability and compressibility of Etoricoxib

The fluidity and compressibility of etoricoxib were evaluated to determine the manufacturing method in order to manufacture tablets containing etoricoxib. Conventional oral formulations are prepared by one of a direct tableting method, a wet granulation method, and a dry granulation method. The manufacturing method is determined according to the fluidity and compressibility of the raw material, and if the fluidity and compressibility of the raw material is good, the manufacturing process is manufactured by a simplified direct tableting method. On the other hand, when the fluidity and compressibility of the raw material is not good, tablets are manufactured through a granulation process to improve this, and when the raw material has poor stability against moisture, the tablet is manufactured by applying a dry granulation method. The fluidity and compressibility of etoricoxib was evaluated by measuring the density, true density, and angle of repose described in the Korean Pharmacopoeia, and the results of etoricoxib fluidity and compressibility evaluation in Table 1 based on the fluidity and compressibility evaluation criteria listed in Table 2. Is shown.

Evaluation item Evaluation results Angle of repose (°) 47.42 Density (g/mL) 0.66 True density (g/mL) 0.94 Carr's Index(%) 29.3 Hausner Ratio 1.41

As a result of the evaluation, it was judged that granulation was feasible due to poor fluidity and compressibility to apply the direct tableting method, and the deterioration of etoricoxib moisture stability was not reported, so that the tablets were made by applying the wet granulation method with excellent workability and excellent yield. It was decided to manufacture.

Example 2. Preparation of tablets containing Etoricoxib

In order to prepare a tablet containing etoricoxib, it was prepared according to each of the compounds 1 to 5 in Table 3 below. First, etoricoxib, microcrystalline cellulose, a part of croscarmellose sodium, and anhydrous calcium hydrogen phosphate were sufficiently mixed using a mixer. After kneading using water as a binder solution in a high speed mixer, it was dried at about 60°C in a fluidized bed dryer. The dried product was sized with a 25 mesh standard mesh, mixed with the remaining amount of croscarmellose sodium and magnesium stearate, and then tableted to fit the weight of the uncoated tablet described below.

division Ingredient name Weight ratio (%) Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Active ingredient Etoricoxib 28.30 28.85 27.52 29.41 30.00 Excipient Microcrystalline cellulose 51.89 49.04 41.28 34.31 34.50 Disintegrant Croscarmellose Sodium 3.30 5.29 4.59 5.88 7.00 pH regulator Calcium hydrogen phosphate anhydrous 11.32 13.46 25.69 29.41 28.00 Lubricant Magnesium stearate 5.19 3.37 0.92 0.98 0.50 Sum 100.00 100.00 100.00 100.00 100.00

After preparing according to each of the compounds 1 to 5, about 3% by weight of the uncoated tablet was film-coated with a suitable coating agent to prepare a film-coated tablet containing etoricoxib.

Example 3. Evaluation of the friability of the prepared tablets

For the pharmaceutical evaluation of Compounds 1 to 5 according to the present invention, the friability was measured and shown in Table 4. The degree of friability was measured by taking 20 tablets of a sample and rotating 100 according to the general test method of the Korean Pharmacopoeia. As a control drug, commercially available etoricoxib tablets (alkoxya tablet 30 mg, MSD) were purchased and used.

Evaluation item Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Reference drug Friction degree (%) 0.3 0.2 0.3 0.2 0.1 N/A

As a result of the evaluation, when all of the compounds 1 to 5 were coated within the range of 0.5%, it was determined that quality defects due to wear of the tablets would not occur.

Example 4. Evaluation of hardness of prepared tablets

The hardness was measured and shown in Table 5 for the pharmaceutical evaluation of the compounds 1 to 5 according to the present invention and the control drug (commercially available etoricoxib tablets (30 mg, MSD) were purchased and used).

Evaluation item Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Reference drug Hardness(kp) 12 11 12 11 9.5 12

As a result of the evaluation, all of the compounds 1 to 5 were tableted within the range of 5 to 15 kp. In each example, when the hardness is 10 kp or more, capping tends to occur, and the hardness range was set to 8 to 10 kp in order to prevent quality defects during tableting.

Example 5. Evaluation of disintegration of prepared tablets

Disintegration was measured and shown in Table 6 for the pharmaceutical evaluation of the compounds 1 to 5 according to the present invention and the control drug (commercially available etoricoxib tablets (30 mg, MSD) were purchased and used).

Evaluation item Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Reference drug Disintegration Within 5 minutes Within 5 minutes Within 5 minutes Within 5 minutes Within 5 minutes Within 5 minutes

As a result of the evaluation, it was confirmed that the tablets were disintegrated within 5 minutes of both compounds 1 to 5 and the control drug.

Example 6. Evaluation of dissolution of prepared tablets

The tablets prepared by the compounds 1 to 5 according to the present invention and the tablets of the reference drug were evaluated for dissolution rate over time using a dissolution tester. Etoricoxib is an active substance that is classified into BCS (Biopharmaceutical Classification System) 2, which has low solubility in water, and considering the selection of a dissolution test solution for quality control in the future, it is notified in the Korean Pharmacopoeia Drug Equivalence Test Regulation. Solution 2 was selected as the eluate. The eluate was sampled at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes at the time of determination of the dissolution rate and evaluated through HPLC instrument analysis. The dissolution profiles of compounds 1 to 5 are shown in FIG. 2.

As a result of the evaluation, the dissolution rate of compound 5 was the best, and it was confirmed that the dissolution rate was improved in the case of compounds 3 and 4 compared to compounds 1 and 2. It was judged to be the most desirable.

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that it is possible to easily transform into 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 illustrative and non-limiting in all respects.

Claims (10)

Etoricoxib 30% by weight, microcrystalline cellulose 34.5% by weight, croscarmellose sodium 7% by weight, anhydrous calcium hydrogen phosphate 28% by weight, and magnesium stearate 0.5% by weight as active ingredients for preventing or treating anti-inflammatory pain As a tablet composition,
The tablet composition has a hardness of 8 to 10 kp,
A tablet composition for preventing or treating anti-inflammatory pain, characterized in that the dissolution rate measured by selecting a pH 1.2 solution notified in the Korean Pharmacopoeia Drug Equivalence Test Regulations as the dissolution solution is 70 to 90% at the time point of 10 minutes.
delete The method of claim 1,
The tablet composition is characterized in that produced by a wet granulation method, anti-inflammatory and analgesic prevention or treatment tablet composition.
delete delete delete The method of claim 1,
The tablet composition is characterized in that the disintegration time is within 5 minutes or the friability is 0.1 to 0.3%, anti-inflammatory and analgesic prevention or treatment tablet composition.
The method of claim 1,
The tablet composition is characterized in that coated with a coating base containing a coating agent, anti-inflammatory and analgesic prevention or treatment tablet composition.
The method of claim 8,
The coating agent is a tablet composition for preventing or treating anti-inflammatory pain, characterized in that hydroxypropylmethylcellulose or polyvinyl alcohol.

(a) mixing etoricoxib, microcrystalline cellulose, croscarmellose sodium, and anhydrous calcium hydrogen phosphate and kneading with water;
(b) drying in a fluidized bed dryer after the coalescence; And
(c) a method for preparing a tablet composition using a wet granulation method, comprising the step of mixing and then tableting croscarmellose sodium and magnesium stearate after drying,
The tablet composition has anti-inflammatory analgesic prophylactic or therapeutic activity,
The tablet composition comprises 30% by weight of etoricoxib, 34.5% by weight of microcrystalline cellulose, 7% by weight of croscarmellose sodium, 28% by weight of anhydrous calcium hydrogen phosphate, and 0.5% by weight of magnesium stearate,
The tablet composition has a hardness of 8 to 10 kp,
A manufacturing method, characterized in that the dissolution rate measured by selecting a pH 1.2 solution notified in the Korean Pharmacopoeia Drug Equivalence Test Regulations as the dissolution solution is 70 to 90% at 10 minutes.

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