EP2393486A1

EP2393486A1 - Aceclofenac-containing controlled-release oral drug preparations and their manufacturing process

Info

Publication number: EP2393486A1
Application number: EP09839738A
Authority: EP
Inventors: Beom-Jin Lee; Youn-Woong Choi; Byung-Gu Min; Seung-Ho An
Original assignee: Korea United Pharm Inc
Current assignee: Korea United Pharm Inc
Priority date: 2009-02-04
Filing date: 2009-04-29
Publication date: 2011-12-14
Also published as: RU2011132480A; RU2493843C2; CN102307575B; KR20100089532A; EP2393486A4; KR101050076B1; WO2010090371A1; CN102307575A

Abstract

Disclosed herein are single-layer and double-layer tablets, which release aceclofenac in a controlledmanner so as to achieve ideal drug release close to a straight line. Also, the tablets promote drug absorption in the stomach by controlling pH, contain aceclofenac with improved stability and haveboth immediate-release properties and sustained-release properties. Specifically, provided is an aceclofenac sustained-release tablet which is composed of an immediate-release layer containing aceclofenac, a water-soluble additive, a pH-controlling agent, a disintegrant, a filler and a lubricant and of a sustained-release layer containing aceclofenac, a release-controlling polymer, an oil-soluble surfactant, a filler and a lubricant, wherein the pH-controlling agent is sodium hydrogen carbonate, and the release-controlling polymer is a mixture of hydroxypropylmethylcellulose and carbomer.

Description

ACECLOFENAC-CONTAINING CONTROLLED-RELEASE ORAL DRUG PREPARATIONS AND THEIR MANUFACTURING PROCESS

The present invention relates to a method for preparing aceclofenac-containing single-layer and double-layer tablets having sustained-release properties and immediate-release properties, and more particularly to a method of preparing sustained-release and immediate-release tablets by preparing granules using a polymer compound and an oil-soluble surfactant in a sustained-release portion and forming an immediate-release layer using aceclofenac powder, a disintegrant and a pH controlling agent in an immediate-release portion. The single-layer and double-layer tablets according to the present invention release aceclofenac in a controlledmanner so as to achieve ideal drug release close to a straight line, and these tablets promote drug absorption in the stomach by controlling pH, contain aceclofenac with improved stability and have both immediate-release properties and sustained-release properties.

Aceclofenac (2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid), which is a known compound represented by the following structural formula, is a phenylacetic acid-based anti-inflammatory analgesic drug showing an excellent efficacy against chronic joint diseases, including rheumatoid arthritis, osteoarthrosis and ankylosing spondylitis, as well as dentalgia, post-operation pain or post-delivery pain. This drug shows an excellent therapeutic effect in that it easily penetrates into inflammatory tissues occurring in a joint and the like, and thus exhibits an excellent action of inhibiting prostaglandin production, as compared to other anti-inflammatory analgesic drugs, including naproxen and dichlorofenac. On the other hand, this drug shows weak inhibition of normal prostaglandin production in gastric mucosa, and thus has a reduced effect on gastroenteric troubles, so that it is suitable for long-term application. Particularly, this drug is characteristic in that it inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, thus preventing rheumatoid arthritis, osteoarthrosis and the like from being worse.

Aceclofenac (2-[(2,6-dichlorphenyl)amino]-phenylacetoxyacetic acid) is characteristic in that it is easily soluble in an organic solvent and relatively poorly soluble in water. Aceclofenac, when administered orally, is absorbed rapidly in the gastrointestinal tract and distributed in kidneys, bladder, liver, thyroid gland and the like at high concentrations but distributed in eye, brain, fat tissue and the like at low concentrations. Upon oral administration, aceclofenac shows an onset time shorter than 30 minutes, a time to maximum blood concentration (T_max) of about 1.5-2.5 hours, and a duration time of about 12 hours. Upon oral administration, 46-75% of the administered drug is present as aceclofenac at the time to maximum blood concentration (T_max) and widely metabolized after T_max. In this case, a main metabolite is 4-hydroxyaceclofenac, which also shows activity, and it is known that 4-hydroxydichlorofenac and indole derivatives are also observed as other metabolites. It is known that, upon oral administration, about 66.8% of the administered aceclofenac is eliminated in urine and about 18% is eliminated in feces, and aceclofenac has an elimination half-life of about 4 hours.

Aceclofenac has the following clinical characteristics. (1) Aceclofenac inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, so that it is suitable for the prevention of rheumatoid arthritis and osteoarthrosis. (2) Aceclofenac has a reduced effect on normal prostaglandin production in a gastric mucosa such that gastrointestinal trouble is minimized. (3) Aceclofenac penetrates into an inflammatory site such as a joint at high concentration, so that it has apowerful effect of inhibiting prostaglandin production in foci.

In order to improve the dissolution and bioavailability of poorly soluble drugs, various formulation means for improving the solubilization or dissolution rate of poorly soluble drugs have been developed. For example, various means, including a micronization method, a micelle method, a solid dispersion method, a spray drying method, an inclusion complex method, and a solubilization method employing water-soluble polymers or surfactants, are used, but the increase in solubility of drugs is not constant depending on the method used, and the commercialuse of such means is greatly limited in terms of preparation method, commercial viability and efficiency.

Also, when a poorly soluble drug is formulated into a tablet which is a pharmaceutical formulation, the tablet requires several processes in which the tablet must be first disintegrated upon oral administration, and a drug mixed with excipients is absorbed only after it was dissolved in digestive fluid or body fluid. Furthermore, if a drug such as aceclofenac, which is poorly soluble in water, is formulated into a tablet, the tablet generally has slow drug dissolution rate leading to low in vivoabsorption rate and low bioavailability. For this reason, the onset time of the tablet will be necessarily delayed as compared to the case where pre-dissolved drugs, such as liquid formulations or soft capsules, are administered.

However, when a drug is formulated into a soft capsule or a liquid phase, the stability of the drug is reduced, but when the drug is formulated into a tablet, there is an advantage in that the stability of the drug can be increased.

Aceclofenace is currently being developed and marketed in the form of tablets and solubilized soft capsules. However, aceclofenac is not yet developed as a once-daily dosage formulation, even though it must be administered for a long period of time due to the characteristics of musculoskeletal pain patients. Thus, medication teaching and compliance for patients who take aceclofenac formulations for a long period of time can become inconvenient. Accordingly, the present invention improves the problems of twice-daily dosage formulations of aceclofenac and is advantages in terms of medication and treatment effects for musculoskeletal pain patients.

Also, the present inventors have conducted studies on various compositions capable of improving dissolution properties and stability against pH changes for aceclofenac tablets and, as a result, have found that the use of poorly soluble drug aceclofenac, an oil-soluble surfactant and a release-controlling polymer shows excellent aceclofenac dissolution rate and product stability, thereby completing the present invention.

It is an object of the present invention to provide a controlled-release formulation of aceclofenac in a once-daily dosage form. The formulation according to the present invention is used at an once-daily dosage of 200 mg active ingredient, releases the active ingredient at a concentration effective for pain alleviationat an initial stage, and then releases the drug in a sustained manner over a long period of time, such that the drug effect can be sustained for 24 hours. Also, the formulation maintains the active drug concentration at a constant level to increase the therapeutic effect of the drug and simplifies drug therapy for musculoskeletalpain patients, thus increasing medication compliance for the patients.

The present invention provides single-layer and double-layer sustained-release tablets of aceclofenac, which solve the property of aceclofenac having low dissolution rate when formulated into a tablet, have excellent dissolution rate and stability against pH and have both immediate-release properties and sustained-release properties.

According to a suitable embodiment of the present invention, there is provided an aceclofenac sustained-release tablet which is composed of an immediate-release layer containing aceclofenac, a water-soluble additive, a pH-controlling agent, a disintegrant, a filler and a lubricant and of a sustained-release layer containing aceclofenac, a release-controlling polymer, an oil-soluble surfactant, a filler and a lubricant, wherein the pH-controlling agent is sodium hydrogen carbonate, and the release-controlling polymer is a mixture of hydroxypropylmethylcellulose and carbomer.

According to another suitable embodiment of the present invention, the mixing weight ratio of hydroxypropylmethylcellulose and carbomer is preferably 10:1 to 20:1.

According to still another suitable embodiment of the present invention, sodium hydrogen carbonate is preferably contained in an amount of 0.25-1 wt% based on the total weight of the aceclofenac sustained-release tablet.

According to still another embodiment of the present invention, the water-soluble additive is preferably poloxamer.

According to still another suitable embodiment of the present invention, the water-soluble additive is preferably contained in an amount of 0.75-3 wt% based on the total weight of the aceclofenac sustained-release tablet.

Aceclofenac is a poorly soluble drug, and thus has a disadvantage in that it is difficult to mix with a release-controlling polymer without an additive. To solve this disadvantage, in the present invention, the oil-soluble surfactant is used to facilitate the mixing of aceclofenac with the release-controlling polymer (a mixture of hydroxypropylmethylcellulose and carbomer) and to control the dissolution rate of a given portion of the tablet.

The controlled-release aceclofenac formulation of the present invention is prepared through a method comprising the steps of: preparing sustained-release granules of aceclofenac using a suitable sustained-release base or adding an oil-soluble surfactant to impart controlled-release properties to aceclofenac; and preparing immediate-release granules of aceclofenac alone or a mixture of aceclofenac, a pH-controlling agent and a disintegrant, mixing the granules with other excipients, andformulating the mixture into a single-layer tablet or a double-layer tablet.

The aceclofenac sustained-release tablet according to the present inventionis characterized in that it has a double structure of an immediate-release layer and a sustained-release layer, and thus it has immediate release properties at the initial stage of oral administration and has sustained-release properties after the immediate release of the active drug.

The immediate-release layer of the aceclofenac sustained-release tablet according to the present invention contains aceclofenac, a water-soluble additive, a pH-controlling agent, a disintegrant, a filler and a lubricant.

The immediate release layer of aceclofenac can show the effects of not only increasing initial dissolution rate to increase initial pain-relieving effects, but also converting pHto the weak alkaline range to increase the stability of the drug.

The aceclofenac drug is unstable in the acidic pH range, while it is not easily absorbed in the stomach. To overcome such phenomena, in the present invention, sodium hydrogen carbonate is used as a pH-controlling agent in the immediate release layer.

The weight ratio of sodium hydrogen carbonate as a pH-controlling agent in the immediate-release portion for preparing the aceclofenac sustained-release tablet which can be administered in a once-daily dosage form is 0.25-1 wt%, and preferably 0.5-1 wt%, based on the total weight of the aceclopenac sustained-release tablet. If the weight ratio of sodium hydrogen carbonate is less than 0.25 wt%, the effect of stabilizing the drug in the acidic pH range will be reduced, and if it exceeds 1 wt%, the initial release rate of the drug will be reduced.

The water-soluble additive which is included in the immediate-release layer of the aceclofenac sustained-release tablet according to the present invention may be one or a mixture of two or more selected from the group consisting of NaH₂PO_4, KH₂PO_4, polyvinyl pyrrolidone, polyethylene glycol, gelatin, gums, carbohydrates, cellulose and its derivatives, polyethylene oxide and its derivatives, polyvinyl alcohol, poloxamer, polymethylacrylate and inorganic materials. Preferably, poloxamer may be used, but the scope of the present is not limited thereto.

The water-soluble additive functions to additionallyincrease water absorbance in the preparation of oral formulations to increase the initial release rate of the drug and enhances drug absorption in the stomach.

The weight ratio of the water-soluble additive is 0.75-3 wt%, and preferably 1-2.5 wt%, based on the total weight of the aceclofenac sustained-release tablet. If the weight ratio of the water-soluble additive is less than 0.75 wt%, the initial release rate of the drug will be reduced, and if it exceeds 3 wt%, the release rate of the drug will be excessively increased.

The disintegrant that is included inthe immediate-release layer of thethe aceclofenac sustained-release tablet is used to absorb water so as to promote the initial disintegration of aceclofenac and the dissolution of aceclofenac. Examples of disintegrants which can be present invention in the formulation of the present invention include croscamellose sodium, sodium starch glycolate, pregelatinized starch (starch 1500 or Primojel), microcrystalline cellulose, crospovidone, cross-linked povidone and commercially available polyvinylpyrrolidone (PVP, Povidone), low-substituted hydroxypropylcellulose, alginic acid, carboxymethylcellulose, calcium salts and sodium salts, fumed silica (colloidal silica), guar gum, magnesium aluminum silicate, methylcellulose, powdery cellulose, starch and sodium alginate.

Preferably, the disintegrant may be one or a mixture of two or more selected from the group consisting of croscamellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone and commercially available polyvinylpyrrolidone. More preferably, the disintegrant may be crospovidone, sodium starch glycolate or microcrystalline cellulose. Particularly, the use of a mixture of two or more disintegrants is most effective.

The immediate release layer of the aceclofenac sustained-release tablet according to the present invention contains a filler. The filler that is used in the present invention may be one or a mixture of two or more selected from the group consisting of microcrystalline cellulose, light anhydrous silicic acid, pregelatinized starch, and lactose.

The immediate release layer of the aceclofenac sustained-release tablet according to the present invention contains a lubricant.

The lubricant is used to improve the formability of oral formulations, and examples thereof include, but are not limited to, magnesium stearate, silicon oxide (SiO₂), colloidal silica (fumed silicacommercially available under the trade name Aerosil) and talc.

The lubricant may be contained in an amount of 0.25-2.5 wt% based on the total weight of the aceclofenac sustained-release tablet. If the lubricant is used in an amount of less than 0.25wt%, there can be a problem associated with flowability in tableting, and if it is used in an amount of more than 2.5 wt%, there can be a problem associated with the decrease in hardness in tableting. Preferably, the lubricant that is used in the present invention may be magnesium stearate or colloidal silica.

The sustained-release layer of the aceclofenac sustained-release layer comprises aceclofenac, a release-controlling polymer, an oil-soluble surfactant, a filler and a lubricant.

The sustained-release layer provides an aceclofenac sustained-release formulation in a once-daily dosage form. The formulation according to the present invention is used at an once-daily dosage of 200 mg active ingredient and releases the drug in a sustained manner for a long period of time, such that the drug effect can be sustained for 24 hours. Also, the formulation maintains the active drug concentration at a constant level to increase the therapeutic effect of the drug and simplifies drug therapy for musculoskeletal pain patients, thus increasing medication compliance for the patients.

Aceclofenac is a poorly soluble drug, and thus has a disadvantage in that it is difficult to mix with a release-controlling polymer without an additive. To solve this disadvantage, in the present invention, the oil-soluble surfactant is used tofacilitate the mixing of aceclofenac with the release-controlling polymer (a mixture of hydroxypropylmethyl cellulose and carbomer) and to control the dissolution rate of a given portion of the tablet.

As the release-controlling polymer, any polymer may be used as long as it is a pharmaceutically acceptable polymer. It may be one or a mixture of two or more selected from the group consisting of cellulose derivatives, including hydroxypropymethylcellulose, methylcellulose, ethylcellulose, hydropropylmethylcellulose and sodium carboxymethylcellulose, propylene oxide and its derivatives, polyvinylpyrrolidone (molecular weight: 90 commercially available under the trade name Povidone K-90), polyethylene glycol, polyvinyl alcohol, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate, a polymer of polymethacrylate (commercially available under the trade name Eudragit), polyacrylic acid, polymethacrylate derivatives (typically carbomer), glycerol monostearate and poloxamer. Preferably, the release-controlling polymer may be one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.

When a general release-controlling polymer is used, the dissolution rate of the drug will not be constant and, in addition, most of the active ingredient will be released at the initial stage of administration. For this reason, the general release-controlling polymer will not provide a sustained-release tablet.

To solve this problem, in the present invention, hydroxypropylmethylcellulose was used as a release-controlling polymer, and carbomer was used as a release-controlling auxiliary polymer.

In the case of hydroxypropylmethylcellulose, products having various viscosities are known, and the dissolution rate of the aceclofenac sustained-release tablet can be controlled by controlling the viscosity of hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose which is included in the aceclofenac sustained-release tablet according to the present invention may be high-viscosity hydroxypropylmethylcellulose and has a viscosity of 60,000-140,000 cps, and preferably 80,000-120,000 cps. If the viscosity is less than 60,000 cps, a large amount of hydroxypropylmethylcellulose will be required to increase the size of the tablet, and if the viscosity exceeds 140,000 cps, uniform mixing with the drug will be difficult.

Sustained-release tablets containing a pharmacologically active ingredient show swelling upon dissolution. In this case, if the release-controlling polymer matrix is not strong, a portion of the matrix can be eroded to disintegrate the tablet, and this can lead to rapid drug release, thus causing a headache or suffusion in patients. To solve this problem, in the present invention, a mixture of hydroxypropylmethylcellulose and carbomer was used as the release-controlling polymer. When carbomer is used as the drug release-controlling polymer together with hydroxypropylmethylcellulose, it has the effect of making the matrix in the sustained-release tablet strong, maintains the tablet shape upon swelling and maintains the matrix of the tablet to prevent the tablet from eroding, thus maintaining constant dissolution rate.

The weight ratioof hydroxypropylmethylcellulose and carbomer for preparing the aceclofenace sustained-release tablet which can be administered in a once-daily dosage form is preferably 10:1 to 20:1. If the weight ratio is less than 10:1, the formation of the matrix in the tablet will be difficult, thus reducing the effect of delaying drug release, and if it exceeds 20:1, drug dissolution rate in alkaline pH conditions will be reduced, and uniform mixing between the release controlling polymers will be difficult.

The oil-soluble surfactant which is contained in the sustained-release layer of the aceclofenac sustained-release tablet according to the present invention may be one or a mixture of two or more selected from the group consisting of sodium lauryl sulfate and its derivatives, poloxamer and its derivatives, middle-chain triglyceride (MCT), labrasol, transcutol, labrafil, labrafac, poloxamer, various polysorbates [e.g., polyoxyethylene sorbitan monolaurate (hereinafter referred to as 'Tween 20'), polyoxyethylene sorbitan monopalmitate (hereinafter referred to as 'Tween 40'), polyoxyethylene sorbitan monostearate (hereinafter referred to as 'Tween 60') and polyoxyethylene sorbitan monooleate (hereinafter referred to as 'Tween 80')], sorbitan esters) [e.g., sorbitan monolaurate (hereinafter referred to as 'Span 20'), sorbitan monopalmitate (hereinafter referred to as 'Span 40'), sorbitan monostearate (hereinafter referred to as 'Span 60'), sorbitan monooleate (hereinafter referred to as 'Span 80'), sorbitan trilaurate (hereinafter referred to as 'Span 25'), sorbitan trioleate (hereinafter referred to as 'Span 85'), and sorbitan tristearate (hereinafter referred to as 'Span 65')], cremophor, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, and fumed silica (colloidal silica). The oil-soluble surfactant is preferably colloidal silica in consideration of harmonization with other components and is contained in an amount of 1-3 wt% based on the total weight of the aceclofenac sustained-release tablet.

If the oil-soluble surfactant is used in an amount deviating from the range of 1-3 wt% based on the total weight of the tablet, stickingand laminating phenomena can occur during tableting, and a problem can arise in tablet formation.

The sustained-release layer of the aceclofenac sustained-release tablet contains a filler and a lubricant, which are the same as the filler and lubricant contained in the immediate-release layer.

The controlled-release oral formulation according to the present invention may be in the form of tablets, compressed pellets, granules or capsules containing the granules. The oral tablets can be formulated using a commercially available tableting machine, and the compressed pellets can also be formulated using a conventional press machine. The granules can be formulated using a conventional granulator, and the capsules containing the granules can also be formulated by filling the granules in commercial empty capsules. Such formulations are known such that they can be easily implemented by one skilled in the art.

A method for preparing the oral formulation according to the present invention comprises the steps of: (1) mixing aceclofenac as a pharmacologically active ingredient, which is to sustained-released, with a polymer base as a binder; (2) adding a liquid solvent to the mixture of step (1) to prepare wet sustained-release granules; (3) milling the sustained-release granules and (4) mixing aceclofenac as a pharmacologically active ingredient, which is to be immediately released, with a water-soluble additive and a disintegrant. The granules of steps (3) and (4) can be formed into tablets or compressed pellets or filled in conventional empty capsules to prepare capsule formulations. As the liquid solvent in step (2), a liquid solvent selected from the group consisting of water, ethanol, isopropyl alcohol, glycerin, propylene glycol, polyethylene glycol, polyethylene glycol, and mixtures of two or more thereof, may preferably used, but the scope of the present inventionis not limited thereto. The use of the liquid solvent can facilitate formation into granules. If the solvent is water alone or a mixed solvent of water and ethanol, it is used in an amount of 5-40 wt%, and preferably 10-20 wt%, based on the total weight of the mixture obtained in step (1). If the amount of liquid solvent used is less than 5 wt%, the binder solution will not be sufficiently distributed in granules, thus causing a problem associated with hardness in tableting, and if it exceeds 40 wt%, the binder solution will be excessively used, leading to the problems of increasing the drying time of granules and delaying the dissolution of aceclofenac.

Also, the granules of step (3) and (4) can be compressed directly into tablets using a general tableting machine. Particularly, according to the present invention, a single mixturemay be formed into tablets by simple tableting and may be simply and easily formulated using a double-layer tablet machine together with conventional mixing, milling and tableting machines. Accordingly, additional equipment costs are not required, and formulations can be simply prepared with high productivity.

When the immediate-release layer and the sustained-release layer are separately tableted with the granules using a double-layer tablet machine, the effects of the present invention can be more securely obtained, but the scope of the present invention is not limited thereto.

Hereinafter, the present invention will be described in further detail with reference to examples and comparative examples. However, the scope of the present invention is not limited to these examples.

Examples 1 to 4

In an immediate-release layer, aceclofenac, lactose, microcrystalline cellulose, sodium hydrogen carbonate, poloxamer, crospovidone and magnesium stearate were mixed with each other according to the components and contents shown in Table 1 below, thus preparing immediate-release granules.

In a sustained-release layer, aceclofenac, lactose and microcrystalline cellulose were uniformly mixed with each other to increase the flowability of the drug. The mixture was uniformly mixed with hydroxypropylmethylcellulose (HPMC, 100,000 cps)and carbomer as polymer bases in a powder mixer, and then sprayed with ethanol, thus preparing wet granules. The amount of each of the components is shown in Table 1 below. Generally, 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymer base may be dissolved in water or a mixed solvent of water and alcohol and used to granulate powder.

The prepared granules were sufficiently dried in an oven at a temperature of 60 ℃, and then uniformly milled. For formationof formulations by post mixing, magnesium stearate as a lubricant was added to the milled material. The resulting material was compressed into double-layer tablets having immediate-release properties and sustained-release properties using a rotary tableting machine.

Table 1

Comparative Examples 1 to 4

In Comparative Examples 1 to 4, tablets comprising only a sustained-release layer without an immediate-release layer were prepared. In the sustained-release layer, aceclofenac, lactose and microcrystalline cellulose were uniformly mixed with each other to increase the flowability of the drug. Then, hydroxypropylmethylcellulose (HPMC 100,000 cps)and Povidone as polymer bases were uniformly mixed with the mixture in a powder mixer, and the resulting mixture was sprayed with ethanol, thus preparing wet granules. The amount of each of the components is shown in Table 2 below.

Generally, 10 ml of ethanol was used to prepare 100 tablets.If necessary, a small amount of the polymer base may be dissolved in water or a mixed solvent of water and alcohol and used to granulate powder.

The prepared granules were sufficiently dried in an oven at a temperature of 60 ℃, and then uniformly milled. For formation of formulations by post mixing, magnesium stearate as a lubricantwas added to the milled material. The resulting material was compressed into tablets containing only a sustained-release layer using a rotary tableting machine.

Table 2

Comparative Example 5

In Comparative Example 5, tablets comprising only a sustained-release layer without an immediate-release layer were prepared. In the sustained-release layer,aceclofenac, lactose and microcrystalline cellulose were uniformly mixed with each other to increase the flowability of the drug. Then, hydroxypropylmethylcellulose (HPMC 100,000 cps) as a polymer base was uniformly mixed with the mixture in a powder mixer, and the resulting mixture was sprayed with ethanol, thus preparing wet granules.The amount of each of the components is shown in Table 3 below.

Generally, 10 ml of ethanol was used to prepare 100 tablets. If necessary, a small amount of the polymerbase may be dissolved in water or a mixed solvent of water and alcohol and used to granulate powder.

Table 3

Comparative Example 6

In Comparative Example 6, tablets comprising only a sustained-release layer without an immediate-release layer were prepared. In the sustained-release layer, aceclofenac, lactose and microcrystalline cellulose were uniformly mixed with each other to increase the flowability of the drug. Then, carbomer as a polymer base was uniformly mixed with the mixture in a powder mixer, and the resulting mixture was sprayed with ethanol, thus preparing wet granules.The amount of each of the components is shown in Table 4 below.

Table 4

Dissolution test 1

The aceclofenac sustained-release tablets prepared in Examples and Comparative Examples were subjected to a dissolution test according to the dissolution test method described in the Korean Pharmacopoeia. As a dissolution medium, phosphate buffer (pH 6.8 artificial gastric juice), and the dissolution test was carried out using a paddle method in 900 ml of the dissolution medium at a paddle rotating speed of 50 rpm at a temperature of 37 0.5 ℃. At 15, 30, 60, 90, 120, 240, 360, 480, 600 and 720min, 5 ml of the sample was taken and the same amount of the dissolution medium was added. In analysis, the sample obtained in the dissolution test was filtered through a 0.45㎛ membrane filter and quantified for aceclofenac using HPLC. The analysis of the sample was carried out in the following conditions. Wavelength: 254 nm mobile phase: 0.16% sodium dihydrogen phosphate controlled to pH 2.5 with 0.1% phosphoric acid: methanol = 34:66 and column: octadecylsilylated column. The results of the dissolution test are shown in Tables 5 and 6 below.

Table 5

Table 6

Dissolution test 2

The aceclofenac sustained-release tablets prepared in Examples 1 to 4 were subjected to a dissolution test. Also, a commercially available tablet was used as Comparative Example 7 and subjected to a dissolution test. As dissolution media, an aqueous solution of artificial gastric juice (pH 1.2) and an aqueous solution of artificial intestinal juice (pH 6.8), described in the dissolution test method of the Korean Pharmacopoeia, were used. The dissolution test was carried out using a paddle method in 900 ml of the dissolution medium at a paddle rotating speed of 50 rpm at a temperature of 37 0.5 ℃.The sample collection time was based on the residence time of each tablet in the stomach after administration, and the sample which has been subjected to the dissolution test at pH 1.2for 2 hours was subsequently subjected to the dissolution test at pH 6.8. 5 ml of the sample was collected and the same amount of the dissolution medium was added. The sample obtained in the dissolution test was filtered through a 0.45㎛membrane filter and quantified for aceclofenac using HPLC. The analysis of the sample was carried out in the following conditions. Wavelength: 254 nm mobile phase: 0.16% sodium dihydrogen phosphate controlled to pH 2.5 with 0.1% phosphoric acid: methanol = 34:66 and column: octadecylsilylated column. The test results are shown in Table 7 below.

Table 7

Claims

An aceclofenac sustained-release tablet which is composed of an immediate-release layer containing aceclofenac, a water-soluble additive, a pH-controlling agent, a disintegrant, a filler and a lubricant and of a sustained-release layer containing aceclofenac, a release-controlling polymer, an oil-soluble surfactant, a filler and a lubricant, wherein the pH-controlling agent is sodium hydrogen carbonate, and the release-controlling polymer is a mixture of hydroxypropylmethylcellulose and carbomer.
The aceclofenac sustained-release tablet of Claim 1, wherein the mixing weight ratio of hydroxypropylmethylcellulose and carbomer is preferably is 10:1 to 20:1.
The aceclofenac sustained-release tablet of Claim 1, wherein sodium hydrogen carbonate is contained in an amount of 0.25-1 wt% based on the total weight of the aceclofenac sustained-release tablet.
The aceclofenac sustained-release tablet of Claim 1, wherein the water-soluble additive is poloxamer.
The aceclofenac sustained-release tablet of Claim 1, whereinthe water-soluble additive is contained in an amount of 0.75-3 wt% based on the total weight of the aceclofenac sustained-release tablet.