KR20200121591A - Pharmaceutical Composition Comprising Aceclofenac and Method of Preparing Thereof - Google Patents

Abstract

The present invention relates to a sustained-release bilayer tablet of aceclofenac and a method for manufacturing the same. The sustained-release bilayer tablet of aceclofenac according to the present invention is characterized by achieving a rapid pharmacological effect and maintaining an effect even with administration once a day. In addition, the sustained-release bilayer tablet of aceclofenac according to the present invention does not cause obstacles even in continuous mass production, and has excellent stability even in long-term storage.

Description

Pharmaceutical Composition Comprising Aceclofenac and Method of Preparing Thereof {Pharmaceutical Composition Comprising Aceclofenac and Method of Preparing Thereof}

The present invention relates to a sustained-release pharmaceutical composition comprising aceclofenac and a method for preparing the same.

Aceclofenac (2-[(2,6-dichlorphenyl)amino]-phenylacetoxyacetic acid) is a known compound having the following chemical structure, as well as chronic joint diseases such as rheumatoid arthritis, osteoarthritis or ankylosing spondylitis, as well as toothache, surgery It is a phenylacetic acid-based anti-inflammatory analgesic that exhibits excellent efficacy in postpartum or postpartum pain.

[Chemical Formula]

Compared to anti-inflammatory analgesics such as naproxen and diclofenac, this drug is easier to penetrate into inflamed tissues such as joints, and has an excellent effect of blocking the production of prostaglandin. On the other hand, the normal blocking action of prostaglandin in the gastric mucosa is weak, so it is suitable for long-term use because it alleviates gastrointestinal disorders.In particular, it inhibits the production of interleukin-1, which destroys cartilage in the joints, and thus glycosamino It promotes the production of glycans (Glycosaminoglycan), so it has features such as preventing exacerbation of rheumatoid arthritis or osteoarthritis.

Aceclofenac is well soluble in organic solvents and relatively insoluble in water. When aceclofenac is administered orally, it is rapidly absorbed in the gastrointestinal tract and is distributed in high concentrations in the kidneys, bladder, liver, and thyroid gland, and in low concentrations in the eyes, brain, and adipose tissue. When administered orally, the onset time of action is within 30 minutes, the time to reach the maximum blood concentration is about 1.5 to 2.5 hours, and the duration is about 12 hours. When aceclofenac is administered orally, 46 to 75% of the administered drug is present as aceclofenac at the time of reaching the highest blood concentration (Tmax), and after Tmax, a wide range of metabolism occurs. Among the nine metabolites, 4-hydroxyaceclofenac, 4-hydroxy Diclofenac and diclofenac are the main metabolites, and the remaining 6 species have individual differences, but are usually present in 1 to 2%.

Aceclofenac is a prodrug type drug that is absorbed into the body and then metabolized into 4-hydroxyaceclofenac, 5-hydroxyaceclofenac, 4-hydroxydiclofenac, 5-hydroxydiclofenac and other metabolites, and the main activity among them. Efficacy is shown by the metabolites diclofenac and 4-hydroxydiclofenac.

Afterwards, about 70% of aceclofenac and metabolites in the body are excreted through urine and about 20% through feces, and the main route of excretion is the excretion of 4-hydroxydiclofenac and 4-hydroxyaceclofenac at a high rate through urine. It is known that the speed (half-life) is about 4 hours.

The clinical characteristics of aceclofenac are: 1) It blocks the production of Interleukin-1, which destroys joint cartilage, and promotes the production of glycosaminoclycan, a component of joint cartilage, so it is suitable for rheumatoid arthritis or osteoarthritis. ) The effect on the normal prostaglandin production in the gastric mucosa is small, so gastrointestinal disorders are minimized. 3) Since the drug penetrates into the inflamed area such as joints at a high concentration, the effect of blocking prostaglandin production at the lesion site is strong.

Aceclofenac is conventionally developed and marketed in the form of tablets and solubilized soft capsules, and 100mg is administered once per tablet and per capsule twice a day. However, due to the characteristics of patients with musculoskeletal pain, there is still no development of a dosage form that can be taken once a day, despite the need for long-term use.Therefore, patients who take aceclofenac for a long time have discomfort in medication guidance and compliance. Was brought about.

In this regard, Korean Patent Registration No. 1076648 (Patent Document 1), Korean Patent Registration No. 1050076 (Patent Document 2), and Korean Patent Registration No. 1234254 (Patent Document 3) achieve rapid pharmacological activity while sustaining the drug for 24 hours. This possible aceclofenac sustained-release double-layer tablet is described.

The formulations of Patent Documents 1 to 3 are two-layer tablet formulations consisting of an immediate-release layer in which the active ingredient is rapidly released and a sustained-release layer in which the active ingredient is slowly released, and while the effective blood concentration is quickly reached at the initial dose, the drug effect is maintained for 24 hours. It features. In addition, it exhibits excellent pharmacokinetic effects equivalent to conventional aceclofenac tablets administered twice a day.

However, in the case of the formulations of Patent Documents 1 to 3, when mass production of more than 500,000 tablets for commercialization is performed, an unexpected problem occurs in that tableting disorders and weight deviations occur due to sticking. In addition, a problem was found that the properties of some formulations collapsed upon long-term distribution.

Korean Patent Registration No. 1076648 Korean Patent Registration No. 1050076 Korean Patent Registration No. 1234254

The present invention is a novel aceclofenac sustained release that improves the problems of the above-described conventional formulations, which does not cause obstacles even when the formulations are continuously mass-produced, has excellent stability even during long-term storage, and exhibits sufficient pharmacological effects even once a day is administered. It aims to provide a double-layer tablet.

In order to achieve the above object, aceclofenac sustained-release two-layer tablet of the present invention includes an immediate-release layer comprising aceclofenac, an excipient, and a lubricant; And a sustained-release layer comprising aceclofenac, an excipient, a solubilizing agent, a sustained-release base, and a lubricant; and, the weight ratio of aceclofenac contained in the immediate-release layer and the sustained-release layer may be 1:1 to 1.5:1, and more preferably For example, it may be 1.1:1 to 1.3:1.

In this case, the lubricant may be used by selecting from known lubricants, but it is preferable to use sodium stearyl fumarate or a mixture of sodium stearyl fumarate and silicon dioxide colloidal because it does not inhibit the dissolution of the active ingredient.

On the other hand, the content of the lubricant is preferably 2 to 6% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.If the lubricant is included in excess of 6% by weight based on the total weight of the tablet, the dissolution rate may decrease, and the lubricant When the amount is less than 2% by weight, the flowability of the formulation may be poor during tableting.

The solubilizing agent is poloxamer, TPGS, labrasol, labrafil, laprafac, polysorbate, castor oil, transcutol, sodium lauryl sulfate, polyethylene glycol, macrogol 15-hydroxy-stearate (macrogol 15-hydroxy stearate), solution plus ^R (soluplus ^R), Theodore ^R Angelou (gelucire ^R) of two or more kinds selected from the group consisting of a mixture may be used.

Since aceclofenac is a poorly soluble drug, bioavailability can be increased when the above-described solubilizing agent or a known substance equivalent thereto is included in a specific amount in the formulation. However, if the content of the solubilizing agent is too high, there may be problems with tableting due to sticking during mass production.

Accordingly, the solubilizing agent is preferably contained in an amount of 0.5 to 1.5% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet. When the solubilizing agent is contained in a small amount of less than 0.5% by weight, the dissolution of aceclofenac may not be sufficiently performed, and when it exceeds 1.5% by weight, tableting disorder due to sticking may occur.

As the sustained-release base, a sustained-release material known to the formulation side may be selectively used, but among them, 1 from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, polyvinyl alcohol, carbomer, xanthan gum, and collidone SR. It is preferred to use species or mixtures of two or more. In particular, when using a mixture of hydroxypropylmethylcellulose and carbomer having a viscosity of 75,000 to 140,000 mPa·s in a ratio of 10: 1 to 20: 1 is used, it is possible to maintain a constant elution rate of the active ingredient.

In this case, the sustained-release base is preferably included in 15 to 30% by weight based on the total weight of the sustained-release part, and if it is contained less than 15% by weight, the sustained-release effect may be reduced, and side effects may occur due to excessively high blood concentration. On the other hand, when it exceeds 30% by weight, the drug dissolution rate is low, and the pharmacological effect may be reduced.

The excipient may be one or a mixture of two or more selected from the group consisting of microcrystalline cellulose, lactose, mannitol, powder cellulose, colloidal silicon dioxide, and magnesium aluminosilicate, and the content of the excipient is the content of drugs, excipients or additives. And/or it may be appropriately adjusted in consideration of the tablet size.

Meanwhile, the aceclofenac sustained-release two-layer tablet is one or two or more selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, and crospovidone for rapid disintegration and rapid initial dissolution of the immediate-release layer. It may further comprise a disintegrant.

At this time, the disintegrant is preferably included in 1 to 3% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.If it is contained in less than 1% by weight, it is difficult to expect the effect of the addition of the disintegrant and contains more than 3% by weight. Even so, it is not preferable because the effect is not great compared to the weight increase of the tablet.

In addition, the aceclofenac sustained-release two-layer tablet further comprises one or two or more binders selected from hydroxypropyl cellulose, povidone, acetate-polyethylene glycol graft copolymer, and polyethylene-co-vinyl acetate. .

The content of the binder is adjusted in consideration of the total weight of the formulation. Specifically, it is preferable to contain 3 to 5% by weight of the total weight of the aceclofenac sustained-release two-layer tablet.If it is less than 3% by weight, the stability of the formulation may be deteriorated, and if it exceeds 5% by weight, the drug dissolution is delayed. Can give

It is preferable that the immediate release layer and the sustained release layer are prepared by a wet granulation method, but when prepared by a dry granulation method or a direct press method, it has been found that some of the formulations generate gas inside and the tablet properties collapse. .

Aceclofenac sustained-release bilayer tablet according to the present invention is characterized in that rapid pharmacological activity is expressed and immediate analgesic and anti-inflammatory effects are exhibited, and the effect is maintained by maintaining a constant drug concentration in the body only by administration once a day. In addition, the problem of tableting problems that occurred during mass production of the prior art does not appear, and even during long-term storage, the properties are not altered and stability is excellent.

1 is a diagram showing a comparison of the average dissolution profile of the test drug and the reference drug under the condition of the pH 1.2 eluate.
Figure 2 shows the comparison of the average dissolution profile of the test drug and the reference drug in the pH 4.5 eluate condition.
Figure 3 shows the comparison of the average dissolution profiles of the test drug and the reference drug under the pH 6.8 eluate condition.
Figure 4 shows the comparison of blood concentrations of the test drug and the reference drug after oral administration in fasting conditions.
FIG. 5 shows the comparison of the blood concentrations of the test drug and the reference drug after oral administration in postprandial conditions.
6 is a photograph of the properties of the formulation after storage for 2 weeks at 40°C and 75%RH acceleration conditions for the test drug.
7 is a photograph of the properties of some of the disintegrated formulations after storage for 2 weeks at 40°C and 75%RH acceleration conditions for the reference drug.

Terms used in the present specification and claims are not limited to their usual or dictionary meanings and should not be interpreted, and that the inventor can appropriately define the concept of terms in order to describe his own invention in the best way. Based on the principle, it should be interpreted as a meaning and concept consistent with the technical idea of the invention. Therefore, the configuration described in the present specification and each embodiment is only one of the most preferred embodiments of the present invention and does not represent all the technical spirit of the present invention, and various equivalents and equivalents that can replace them at the time of the present application It should be understood that there may be variations.

The ``total weight of aceclofenac sustained-release two-layer tablet'' used throughout the specification and claims refers to the total weight of the extended-release two-layer tablet uncoated tablet tableted into an immediate-release layer and a sustained-release layer, and does not include the weight of the film coating layer.

The terms "about" and "substantially" used throughout this specification are used as meanings at or close to the numerical values when manufacturing and material tolerances specific to the stated meanings are presented, and are accurate to aid understanding of the present application. Or absolute figures are used to prevent unfair use of the stated disclosure by unconscionable infringers.

In the entire specification of the present application, the term "mixture(s) thereof" included in the expression of the Makushi format refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of the Makushi format, It means to include at least one selected from the group consisting of the above components.

In the entire specification of the present application, the description of "A and/or B" means "A or B or both".

Hereinafter, the present invention will be described in more detail.

Aceclofenac sustained-release bilayer tablet according to the present invention is characterized in that it exhibits equivalent pharmacological effects while improving the problems of the conventional sustained-release aceclofenac once a day.

In the above-described Patent Documents 1 to 3, aceclofenac sustained-release formulations improved to achieve sufficient pharmacological effects only by administering a conventional aceclofenac formulation twice a day are described.

However, an unexpected problem was discovered in the process of launching the product according to the patent by the present applicant.

First, when tablets of several hundred thousand tablets or more are continuously tableted at a time for product production and release, sticking occurred. This phenomenon worsened as the number of tablets to be manufactured increased, and after producing about 600,000 tablets, it became impossible to manufacture any more tablets. For this reason, production was inevitably suspended, equipment was washed, and the manufacturing process was first started. I had to start over.

Secondly, if the product is stored for several months or longer in the distribution process after release, the properties of some formulations are deteriorated, causing defects.

Accordingly, in order to improve the above-described problems, the applicant of the present invention discovered that the cause of the sticking phenomenon was due to the oil component of the solubilizing agent while repeating research while redesigning the formulation from the beginning. Accordingly, an attempt was made to significantly reduce the content of the solubilizing agent, but since aceclofenac is a poorly soluble drug, a problem of lowering the solubility occurred when the content of the solubilizing agent was reduced in the developed formulation, and thus, bioavailability compared to conventional sustained-release formulations. The result was lowered.

Accordingly, after removing the solubilizing agent from the conventional sustained-release formulation, the ratio of the drug content in the immediate-release layer was increased compared to that of the sustained-release layer.However, when the solubilizing agent was completely excluded, the bioavailability of aceclofenac, a poorly soluble drug, did not appear sufficiently high. .

Accordingly, the applicant of the present invention was able to specify the content of the solubilizing agent that does not cause sticking disorder even when the formulation is tableted more than 1 million tablets through repeated studies. Based on this, the present invention was completed by re-establishing the formulation.

The present invention does not contain a solubilizing agent in the immediate release layer, unlike the conventional inventions described in Patent Documents 1 to 3, and the sustained release layer also contains a solubilizing agent in a lower content than the conventional invention. In addition, as the content of the solubilizing agent decreases compared to the conventional invention, the low solubility was supplemented by including a high ratio of aceclofenac in the immediate release layer compared to the sustained release layer.

However, this alone did not result in sufficient drug dissolution or inferior sustained-release effect, and the present applicant tried to change the excipient to minimize dissolution disorder. During repeated studies, it was found that when the lubricant was changed and a mixture of sodium stearyl fumarate or sodium stearyl fumarate and colloidal silicon dioxide was contained in a specific amount, a desirable dissolution profile appeared.

In addition, by redesigning the type and content of the sustained-release base and the binder disintegrant, the composition of the sustained-release bilayer tablet of aceclofenac of the present invention could be specified. In a preferred embodiment of the present invention, it was found that the dissolution properties over time were almost identical to that of the once-a-day aceclofenac sustained-release formulation released by the present applicant, and the bioavailability was also equivalent.

On the other hand, unlike conventional aceclofenac sustained-release formulations, even if more than one million tablets were prepared, the sticking phenomenon did not occur, so that the production could be stably and the occurrence of weight deviation was improved.

In addition, granules of an immediate-release layer and a sustained-release layer were prepared by a wet granulation method by changing the conventional direct-pressing method. As a result, the phenomenon of disintegration due to gas generation in the formulation disappeared, and unlike the conventional invention, it was found that the stability was excellent even during long-term storage.

Hereinafter, aceclofenac sustained-release two-layer tablet and a method for preparing the same according to the present invention will be described in detail with reference to Examples and Comparative Examples. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited by the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

<Method of manufacturing aceclofenac sustained-release double-layer tablet>

Aceclofenac sustained-release two-layer tablet according to the present invention is prepared by preparing an immediate-release layer and a sustained-release layer by a wet granulation method, and then tableting into a two-layer single tablet. It is prepared in accordance with the preparation method of the refining section of the Korean Pharmacopoeia, but it can be prepared through the following steps as a preferred manufacturing method.

Preparation of immediate-release granules

The binder is dissolved in a solvent to prepare a binder solution. Aceclofenac, excipients, and disintegrants are uniformly premixed, added to the binding solution, combined, granulated, and dried. Thereafter, a disintegrant and a lubricant are added, followed by mixing to prepare immediate-release granules.

Preparation of slow-release granules

The binder is dissolved in a solvent to prepare a binder solution. The main ingredient, excipient, solubilizing agent, and sustained-release base are uniformly premixed, added to the binding solution, combined and granulated, and dried. Afterwards, it is mixed with a lubricant to prepare a sustained-release layer granules.

Two-layer tablet manufacturing

After tableting using the above-prepared immediate-release layer granules and sustained-release layer granules two-layer tablet tablet press to prepare uncoated tablets, film coating is performed using a coating agent.

<Preparation of aceclofenac sustained-release double-layer tablet>

Aceclofenac sustained-release double-layer tablets according to each of the Examples and Comparative Examples were prepared in the composition of Table 1 below according to the above manufacturing method.

Configuration ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Immediate release Aceclofenac 110.00 110.00 120.00 105.00 85.00 Excipient 114.50 111.50 101.50 116.50 136.50 Binder 14.50 14.50 14.50 14.50 14.50 Disintegrant 9.70 9.70 9.70 9.70 9.70 Lubricant 7.30 10.30 10.30 10.30 10.30 Western Aceclofenac 90.00 90.00 80.00 95.00 115.00 Excipient 45.00 45.00 55.00 40.00 20.00 Solubilizer 4.50 4.50 4.50 4.50 4.50 Slow release mechanism 43.00 43.00 43.00 43.00 43.00 Binder 5.00 5.00 5.00 5.00 5.00 Lubricant 8.00 8.00 8.00 8.00 8.00 Film coating base 12.00 12.71 12.00 12.00 12.00 Gross weight 463.50 464.21 463.50 463.50 463.50

Elution suitability test

For the sustained-release bilayer tablet of aceclofenac according to the composition of Table 1, first, a dissolution suitability test was performed to confirm whether sufficient dissolution was achieved. The criterion was to be suitable when 80% or more of the active ingredient was eluted for 12 hours in a 900 mL pH 6.8 eluate environment that rotates 50 times per minute according to the second method of dissolution test of the Korean Pharmacopoeia (paddle method). The results of the elution suitability test are shown in Table 2 below.

refine Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Elution compatibility fitness fitness fitness fitness incongruity

As shown in Table 2, Examples 1 to 4 were found to be suitable because at least 80% of aceclofenac was eluted within 12 hours.

However, in the case of Comparative Example 1, it was found that the elution was decreased. This is believed to be because the solubility of the active ingredient in the immediate release layer was decreased by reducing the content of poloxamer, which is a solubilizing agent, compared to the conventional method in order to improve the tableting disorder problem.

From the above results, it was found that the aceclofenac content of the immediate-release layer and the sustained-release layer is preferably in a weight ratio of at least 1:1 to 1.5:1. In addition, as a result of additional experimentation by the present applicant, when included in a weight ratio of 1.1:1 to 1.3:1, the dissolution pattern equivalent to that of the conventional reference drug appeared, which was preferable.

<Preparation of a counter treaty>

Aceclofenac sustained-release control drug (Comparative Example 2) was prepared by the conventional method described in Patent Document 3. The specific composition is as described in Table 3 below.

Configuration ingredient Comparative Example 2 Immediate release Aceclofenac 85.00 Excipient 86.45 Binder 11.50 Disintegrant 7.70 Solubilizer 6.00 Lubricant 5.80 Western Aceclofenac 115.00 Excipient 57.50 Solubilizer 6.00 Slow release mechanism 53.80 Binder 6.70 Lubricant 10.00 Gross weight 451.45

<Test Example 1> In vitro dissolution test

Using Example 2 as a test drug and Comparative Example 2 as a reference drug, 12 tablets each were prepared in different eluate environments at pH 1.2, 4.5, and 6.8, and the dissolution rates were compared and tested.

Dissolution test conditions

The test conditions used in the dissolution test are as follows.

Specimen: Test drug (Example 2) 36 tablets, Control drug (Comparative Example 2) 36 tablets

Eluent: pH 1.2, pH 4.5, pH 6.8 in the dissolution test method of the Korean Pharmacopoeia

Eluent volume: 900 ml, Test temperature: 37±0.5℃

Test method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 rotations per minute

Sampling: Take 10 mL of the eluate at each sampling time, filter it with a 0.45㎛ filter, and make the sample solution. After taking the eluate, correct the same amount of the new eluate.

Analysis equipment: HPLC

Dissolution comparison test result

Each of 12 tablets of the test drug and the reference drug was tested under pH 1.2, 4.5, and 6.8 eluate conditions, and the average values of the dissolution rates of the test drug and the reference drug were compared graphically in FIGS. 1 to 3 and shown.

Results and Discussion

As a result of the dissolution test of the test drug (Example 2) and the reference drug (Comparative Example 2), it was difficult to determine the equivalence due to insufficient dissolution due to the dissolution characteristics of aceclofenac in the low pH environment of the pH 1.2 and pH 4.5 eluate. .

However, as a result of measuring the dissolution rate in a pH 6.8 eluate environment, the dissolution rate of aceclofenac of the test drug and the reference drug is 85% or more within 1440 minutes, and the average dissolution rate of aceclofenac of the reference drug is 30%, 60%, and 80%. It was found that the error between the average dissolution rate of the test drug and the average dissolution rate of the reference drug was less than 10%, and the dissolution profiles of the test drug and the reference drug were judged to be equivalent.

<Test Example 2> In-vivo test

Fasting conditions

25 healthy men were divided into 2 groups so that the test drug and the reference drug could be compared and administered, and the bioavailability was compared under fasting conditions. Dosing was done with 240 mL of water at approximately 6:00 AM after a fast of 10 hours or more. Subjects were not allowed to eat any food for at least 4 hours after dosing. Subjects were allowed to drink water as desired, with the exception of 1 hour before and 2 hours after drug administration. After administration of the test drug and the control drug for each group, blood concentration was measured at regular time intervals.

Postprandial conditions

The test drug and the reference drug were divided into two groups so that the test drug and the reference drug could be administered to 27 healthy men, and the bioavailability was compared under postprandial conditions. The doses of the test and reference drugs were followed by a high fat/high calorie breakfast containing a glass of milk, with 240 mL of water at approximately 6:00 AM. Subjects started the presented diet 30 minutes prior to drug administration. Subjects finished their meals for less than 30 minutes and the drug was administered approximately 30 minutes after the start of the meal. Subjects were not allowed to eat any food for at least 4 hours after dosing. Subjects were allowed to drink water as desired, with the exception of 1 hour before and 2 hours after drug administration. After administration of the test drug and the control drug for each group, blood concentration was measured at regular time intervals.

Results and Discussion

The fasting and postprandial in vivo test results are shown in FIGS. 4 and 5. According to the results of FIGS. 4 and 5, the bioavailability of the test drug and the reference drug was determined to be equal in both fasting conditions and postprandial conditions.

<Test Example 3> Preparation and storage stability test

In Test Examples 1 and 2, it was found to be pharmacokinetic equivalent to the aceclofenac sustained-release double-layer tablet according to the present invention, so that the problem of sticking disorder during mass production and the problem of stability reduction during long-term storage that occurred in the conventional reference drug was improved. Comparative tests were performed.

Granule flowability evaluation

In order to check the tabletability of the test drug and the reference drug in advance, a flowability evaluation was performed.

First, immediate-release and sustained-release granules were prepared according to each composition for the test drug and the reference drug, and then the immediate-release and sustained-release granules were simply mixed. Thereafter, the flowability evaluation was performed on the mixed granules of the test drug and the reference drug. The fluidity assessment was made through an angle of repose measurement commonly used in the art.

Each granule was measured for an angle of repose using an angle of repose meter (GTB, ERWEKA GmbH), and the results are shown in Table 4 below.

division Angle of repose (°) Test drug 32° Reference drug 43°

As shown in Table 4, the granules of the test drug had an angle of repose of 32°, and when manufactured using methods and equipment commonly used in the art, excellent tabletting properties were expected without obstacles. On the other hand, in the case of the reference drug, the angle of repose was as high as 43°, indicating that there is a possibility of an obstacle during the manufacturing process due to the oil component.

Comparison of tableting failures in mass production

When manufacturing more than 600,000 tablets of the reference drug, a sticking problem occurred, resulting in a tableting disorder, and a failure occurred while manufacturing the test drug (Example 2) and the reference drug (Comparative Example 2) by 1.5 million tablets according to each manufacturing method. It was observed whether or not, and the results are shown in Table 5 below.

division 500,000 tablets manufactured 1 million tablets manufactured 1.5 million tablets manufactured Test drug Good Good Good Reference drug Good Failure (sticking) Not manufactured

As shown in Table 5, in the case of the reference drug, the sticking problem appeared prominently from the time of manufacture of 500,000 to 1 million tablets, and continuous tabletting was impossible due to the raw materials sticking to the equipment. On the other hand, in the case of the test drug, the sticking problem did not occur, and the tabletting property was excellent until the manufacture of 1.5 million tablets.

Measurement of physical properties of manufactured tablets

At the time when about 500,000 tablets that did not cause tableting disorders in both the test drug and the reference drug were compressed, 100 tablet samples were taken each, and then the friability, hardness, and weight deviation of the tablets were measured. The measurement results are shown in Table 6 below.

division Masondo Hardness Weight deviation Test drug Less than 1% 13.5 kps 5.6% Reference drug 1.3% 7.8 kps 8.5%

As shown in Table 6, the test drug was found to have excellent physical properties compared to the control drug with a friability of 1% or less, a hardness of 13.5 kps, and a weight deviation of 5.6%.

Long-term storage stability comparison

For the test drug (Example 2) and the control drug (Comparative Example 2), the properties of the formulation were observed after storage for 2 weeks at 40° C. and 75% RH acceleration conditions. In the case of the test drug, the tablet properties were stably maintained as shown in FIG. 6, but in the case of the reference drug, tablet breakage occurred due to gas generation in some individuals as shown in FIG. 7.

Claims (14)

An immediate release layer containing aceclofenac, an excipient and a lubricant; And
Aceclofenac, an excipient, a solubilizing agent, a sustained-release layer comprising a sustained-release base and a lubricant; Including,
The weight ratio of the aceclofenac contained in the immediate-release layer and the sustained-release layer is 1: 1 to 1.5: 1 aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The lubricant is aceclofenac sustained-release double-layer tablet that is a mixture of one or two selected from the group consisting of sodium stearyl fumarate and colloidal silicon dioxide.
The method of claim 1,
The lubricant is aceclofenac sustained-release two-layer tablet containing 2 to 6% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The solubilizing agent is poloxamer, TPGS, labrasol, labrafil, laprafac, polysorbate, castor oil, transcutol, sodium lauryl sulfate, polyethylene glycol, macrogol 15-hydroxy-stearate (macrogol 15-hydroxy stearate), solution plus ^R (soluplus ^R), Angelou Shea ^R (gelucire ^R) 1 either individually or in combination of two or sustained release bi-layer tablets of aceclofenac is at least selected from the group consisting of.
The method of claim 1,
The solubilizing agent is aceclofenac sustained-release two-layer tablet containing from 0.5 to 1.5% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The sustained-release base is one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, polyvinyl alcohol, carbomer, xanthan gum, and collidone SR.
The method of claim 1,
The sustained-release base is a mixture of hydroxypropylmethylcellulose and carbomer having a viscosity of 75,000 to 140,000 mPa·s in a ratio of 10:1 to 20:1. Aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The sustained-release base is aceclofenac sustained-release two-layer tablet containing 15 to 30% by weight based on the total weight of the sustained-release part.
The method of claim 1,
The excipient is one or a mixture of two or more selected from the group consisting of microcrystalline cellulose, lactose, mannitol, powdered cellulose, colloidal silicon dioxide, and magnesium aluminosilicate.
The method of claim 1,
The aceclofenac sustained-release two-layer tablet further comprises one or two or more disintegrants selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, and crospovidone. refine.
The method of claim 10,
The disintegrant is aceclofenac sustained-release two-layer tablet containing 1 to 3% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The aceclofenac sustained-release two-layer tablet further comprises one or two or more binders selected from the group consisting of hydroxypropyl cellulose, povidone, acetate-polyethylene glycol graft copolymer, and polyethylene-co-vinyl acetate. refine.
The method of claim 12,
The binder is aceclofenac sustained-release two-layer tablet containing 3 to 5% by weight based on the total weight of the aceclofenac sustained-release two-layer tablet.
The method of claim 1,
The immediate-release layer and the sustained-release layer are aceclofenac sustained-release two-layer tablets prepared by a wet granulation method.

Images