WO2010024576A2

WO2010024576A2 - Sustained release tablet containing talniflumate with enhanced body absorption

Info

Publication number: WO2010024576A2
Application number: PCT/KR2009/004734
Authority: WO
Inventors: 이정은; 신병철; 조선행; 성하수; 안신병; 권무길; 김종택
Original assignee: 한국화학연구원; 근화제약 주식회사
Priority date: 2008-08-27
Filing date: 2009-08-25
Publication date: 2010-03-04
Also published as: KR20100025427A; KR101018894B1; WO2010024576A3

Abstract

The present invention relates to a sustained release tablet containing talniflumate. More specifically, the present invention relates to a talniflumate sustained release tablet formed as a drug coated tablet comprising a cored tablet and a double layered tablet or a drug coating layer. A solubilizing aid is used to increase the solubility of talniflumate which is an insoluble drug in the tablet. The tablet contains hydrophilic polymers to stablize the sustained release in the user's body. The sustained release tablet containing talniflumate according to the present invention has a relatively easy manufacturing process and is able to control release rate. Also, the tablet has excellent release efficiency for gradually releasing drug components in the body at a constant rate, compared with conventional immediate release talniflumate 370, 720 mg formulations which are available. Therefore, the tablet has an advantage that the inconvenience of administering three times a day is relieved by administering once or twice a day.

Description

Sustained-release tablets containing talniflumate with enhanced body absorption

The present invention relates to a talni flumate-containing sustained-release tablet with enhanced absorption in the body, and more specifically, using a nucleating tablet, a double-crystal tablet or a hydrophilic polymer containing a hydrophilic polymer so as to stably sustained release using an adjuvant that can enhance absorption in the body and The present invention relates to a sustained-release tablet for talniflumate in the form of a drug-coated tablet having a drug coating layer.

Talniflumate is used for pain relief after surgery or extraction and for the treatment of inflammation and pain in inflammatory diseases such as rheumatoid arthritis and osteoarthritis. The dose is 370 mg three times daily for adults, and 740 mg three times daily for severe disease. The method of administration is typically a poorly soluble drug which is taken orally and is almost insoluble in water. In order to improve this and increase the bioavailability, a lot of research is being conducted. Representative examples include the use of cosolvents, the addition of counterions to poorly soluble materials to form salts of acids or bases, and the combination of polymer compounds or ligands to form soluble complexes.

Republic of Korea Patent Publication No. 10-2001-0075695 and 10-2002-0062302 consists of applying a water-insoluble coating film to the spherical sugar granules, coding the tolterodine drug layer thereon, and then avoiding the release control film made of water-insoluble polymer. A method for producing tolterodine sustained release beads is introduced.

On the other hand, Korean Patent Laid-Open Publication No. 10-2001-009439 discloses a technique for tableting a sephae antibiotic with hydroxypropylmethylcellulose and vinylpyrrolidone vinyl acetate copolymer to sustain release. Recently, Shin-Etsu, Dow Chemical and others have introduced the preparation of sustained-release matrix tablets using cellulose polymers.

In addition, Korean Patent No. 0379299 discloses a method of preparing a solid dispersion using a mixer or a spray dryer after dissolving the felodipine and the enteric polymer in a mixed solvent of a polar solvent and a non-polar solvent, the Republic of Korea Patent Publication No. 0060730 No. discloses that sustained-release preparations can be prepared by dissolving the sustained-release acrylic polymer in an organic solvent and then wetting and mixing it with a mixed powder of poorly soluble drugs and excipients to obtain granular material and containing polyethylene glycol as an wicking accelerator. Doing.

However, simply by increasing the solubility and dissolution rate, it is rapidly absorbed due to the nature of poorly soluble drugs, may shorten the duration of action and in some cases may cause side effects. Therefore, while solubilizing poorly soluble drugs, the drug release rate is appropriately controlled to facilitate patient comfort and reduce side effects while obtaining excellent therapeutic effects.

Accordingly, the present inventors have conducted research and efforts to supplement the shortcomings of the conventional talni flu mate single-core form of immediate release formulations, improve the solubility of the drug by using an adjuvant that can enhance the absorption in the body to improve the absorption in the west The present invention has been accomplished by improving the rate of drug release by using nucleated tablets and multi-layered tablet methods of sex formulations and sustained release mechanisms using drug-coated tablets.

The present invention is characterized by a talni flu mate sustained-release tablet containing talni flu mate as an active ingredient, a dissolution aid for promoting absorption and a hydrophilic polymer for sustained release.

Tablets of talni flu mate according to the present invention can increase the dissolution of talni flu mate in the case of immediate release, so that the bioavailability is high, when the sustained-release tablet is made, the manufacturing process is relatively easy, the release rate can be controlled, The same effect can be obtained at a smaller dose than commercially available immediate release talniflumate 370 and 720 mg formulations, while the sustained release exhibits excellent dissolution properties that allow the drug to be released slowly at a constant rate in the body. There is an advantage that the discomfort to administer can be reduced to twice daily administration at low doses.

Figure 1 shows the tablet form of the nucleated tablet, multi-layered tablet and drug-coated tablet according to the present invention.

2 is a graph showing the dissolution rate over time in the dissolution test according to the experimental example of the Examples 1 to 5 tablets.

3 is a graph showing the dissolution rate over time in the dissolution test according to the experimental example of the Examples 6 to 10 tablets.

Figure 4 is a graph showing the dissolution rate over time in the dissolution test according to the experimental example of the Examples 11 to 14 tablets.

It is characterized by the talni flu mate sustained-release tablet containing a talni flu mate as an active ingredient, a dissolution aid for promoting absorption and a hydrophilic polymer for sustained release.

Talni flu mate is a representative poorly soluble drug, it is necessary to use a dissolution aid to promote absorption to increase the body absorption. The dissolution aid that can enhance the dissolution and absorption in the body of the tablet is preferably mixed with anionic or nonionic surfactants, especially bile salts for the purpose of promoting absorption in the gastrointestinal tract. The anionic surfactants include sodium lauryl sulfate, or bile salt derivatives such as taurodioxycholine acid, choline acid, deoxycholine acid, kenodeoxycholine acid, urosodeoxycholine acid, and dehydrocholine acid. The nonionic surfactants include twins and spans including polyethylene oxide, specifically, twin 20, twin 40, twin 60, twin 80, span 20, span 40, span 60 and span 80. Dissolution aid is characterized in that one or a mixture of two or more selected from the anionic or nonionic surfactant, it is preferably included in 1 to 50% by weight relative to the total weight of the tablet.

Hydrophilic polymers that can be used in the sustained-release tablet according to the present invention include talniflumate, cellulose, polyalkylene oxide, alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyalkylglycol, polydextrin, pectin, povidone, carbo It is characterized in that one or two or more selected from mercury and eudragit, more specifically hydroxypropylmethylcellulose, polyethylene oxide, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, poly Dextrin, pectin, methyl cellulose, cellulose acetate, hydroxymethyl cellulose, ethyl cellulose, povidone, carbomer, and one or more mixtures of Eudragit, characterized in that 1 to 50% by weight of the total tablet It is preferably included in%.

In addition, the talni flu mate sustained-release tablet is composed of a sustained portion and a rapid release portion, wherein the sustained portion forms a core layer, and the outer layer surrounding the core layer is a nucleus tablet or a double crystal in which the sustained portion and the immediate release portion each layer. Can be refined.

At this time, the immediate release base includes lactose, white sugar, glucose, sucrose, sugars such as mannitol or sorbitol, starch such as potato, wheat and corn, minerals such as calcium carbonate, calcium sulfate, sodium bicarbonate or sodium chloride, and licorice. It is preferable to use a compound selected from plant powders such as powders and solvent powders.

The sustained-release tablet of the present invention can control the release characteristics of the active ingredient according to the selection and content of the hydrophilic polymer, the binder, and the disintegrant contained in the sustained-release tablet. For example, increasing the viscosity of a hydrophilic polymer decreases the release rate of the drug.

As a preferable embodiment of the sustained-release tablet of the present invention,

1) preparing granules by mixing talni flumate and a hydrophilic polymer, and then tableting the granules to prepare a sustained release tablet;

2) The rapid-release tablet is added to the granules, followed by mixing and tableting into nucleated tablets or double tablets.

3) The sustained-release tablet of 1) may be coated with a coating solution containing talni flu mate to prepare a sustained-release tablet having a coating layer.

When preparing the granules of 1) known in the pharmaceutical field using a conventional adjuvant used in the manufacture of granules in the pharmaceutical field, such as excipients, binders, lubricants, coloring agents in addition to hydrophilic polymers as the active ingredient talni flu mate and matrix agent It can manufacture according to the conventional manufacturing method of the granule.

The talni flu mate sustained-release tablet according to the present invention may further include one or more adjuvants of excipients, binders, lubricants, and colorants.

The excipient is one or two or more selected from lactose, microcrystalline cellulose, low substituted hydroxypropyl cellulose, corn starch, potato starch, wheat starch, white sugar, di-mannitol, precipitated calcium carbonate, dextrin, and pre-gelatinized starch. It is a mixture, preferably 10 to 30% by weight based on the total weight of the tablet.

The binder is one or a mixture of two or more selected from polyvinylpyrrolidone, hydroxypropyl cellulose, dextrin, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, paste, gum arabic, It is preferably included in an amount of 2 to 20% by weight based on the total weight of the tablet.

The disintegrant is one or a mixture of two or more selected from sodium starch glycolate, crospovidone, sodium chromosmellose, low-substituted hydroxypropyl cellulose, starch, carboxymethyl cellulose, and 0.1 to about the total weight of the tablet composition. It is preferably included in 10% by weight.

The lubricant is one or a mixture of two or more selected from magnesium stearate, talc, mousse silicic acid, and preferably contained in an amount of 0.1 to 10% by weight based on the total weight of the tablet.

In the present invention, the talni flu mate drug requiring sustained release may be prepared as a coating liquid by suspending together with the film coating agent and coated on the surface of the sustained release tablet. The talni flu mate of the coating layer has a first release effect, and the talni flu mate of the core tablet included with the hydrophilic polymer has a second release effect.

At this time, the amount of the coating liquid is preferably kept to a minimum in order to limit the size of the formulation and to effectively manufacture, and may be included in 1 to 10% by weight, preferably 2 to 8% by weight based on the total weight of the sustained-release formulation. It may be coated by a pan coating method, a fluidized bed coating method, an extrusion coating method and the like.

The polymer used in the coating solution is one or a mixture of two or more selected from polyvinyl alcohol, polypropylene glycol, acrylic acid copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and cellulose acetate.

In addition, if necessary, a colorant may be included in the tablet of the present invention, and titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lake, for example blue No. 1 aluminum lake, red No. 40 aluminum One or a mixture of two or more selected from the lakes may be used.

Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to the Examples.

실시예 1 ~ 5 : 탈니플루메이트를 함유한 서방성 유핵정의 제조 Examples 1 to 5: Preparation of sustained-release nucleated tablet containing talni flu mate

The granules were prepared by mixing talni flumate and sodium alginate, carbomer, hydroxypropylmethylcellulose or eudragit according to the component ratios of Table 1, followed by the addition of excipients, binders, disintegrants and glidants. The granules prepared were compressed to prepare sustained release tablets.

Table 1

1) poly methacrylate methyl methacrylate copolymer

실시예 6 ~ 10 : 탈니플루메이트를 함유한 서방성 이중정의 제조Examples 6 to 10: Preparation of sustained-release double tablets containing talni flu mate

The granules prepared in the weight ratio of Examples 1 to 5 were mixed with the rapid-release tablet compositions mixed in the ratios of Table 2 and tableted into double tablets.

TABLE 2

실시예 11 ~ 14 : 코팅제의 탈니플루메이트를 함유한 정제 제조Examples 11-14: Preparation of tablets containing talniflumate of coating

The tablets prepared in Example 1 were coated with respective drug-containing coating layers as shown in Table 3 below to prepare drug coated tablets.

TABLE 3

실험예 1 : 용출시험Experimental Example 1 Dissolution Test

A dissolution test was performed on the sustained release tablets prepared in Examples 1 to 14.

Each of the sustained-release tablets prepared in Examples 1 to 14 was subjected to a dissolution test according to the paddle method under the following conditions, and the dissolution rate of talniflumate, an active ingredient from these sustained-release preparations, was measured over time. It was.

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

Eluate: pH 6.8 phosphate buffer solution (prepared by adjusting pH6.8 with 0.05 M potassium dihydrogen phosphate, 0.05 M sodium dihydrogen phosphate solution, and phosphoric acid) + 1% polysorbate 80

Eluent Temperature: 37 ℃ ± 0.5 ℃

Eluent amount: 900 mL

Stirring Speed: 50 rpm

Sampling: Each time the sample was taken, the eluate was taken and filtered through a 0.2 μm filter to obtain a sample solution. After the eluate was taken, the new eluate was corrected in the same amount.

The dissolution rate of the active ingredient was analyzed from the sample solution obtained every hour in the dissolution test. Dissolution rate analysis was performed at an absorbance of 285 nm using an ultraviolet-visible spectrophotometer.

Test Results The results of testing the dissolution rate over time are shown in FIG. 2 (Examples 1 to 5), FIG. 3 (Examples 6 to 10), and FIG. 4 (Examples 11 to 14).

Looking at the dissolution rate according to the time of FIGS. 2 to 4, all sustained-release tablets exhibit the property of continually releasing active ingredient for 12 to 24 hours, so that the sustained-release tablet of the present invention is suitable for twice daily administration desired. I could confirm that. It can be seen that even with the same sustained-release tablet, it is possible to prepare talniflumate sustained-release tablets whose dissolution rate can be controlled according to the process step.

From the test results, it can be seen that the sustained-release tablet of the present invention can be easily adjusted according to the selection and the content of the type of hydrophilic polymer to be contained.

Claims

A talni flu mate sustained-release tablet comprising a talni flu mate as an active ingredient, a dissolution aid for promoting absorption and a hydrophilic polymer for sustained release.
The method of claim 1, wherein the dissolution aid is sodium lauryl sulfate, taurodioxycholine acid, choline acid, deoxycholine acid, kenodeoxycholine acid, urosodeoxycholine acid, dehydrocholine acid, twins or Talni flu mate sustained-release tablet characterized in that it is one or a mixture of two or more selected from the spans.
According to claim 1, wherein the hydrophilic polymer is selected from cellulose, polyalkylene oxide, alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyalkylglycol, polydextrin, pectin, povidone, carbomer and eudragit Talni flu mate sustained-release tablet characterized by the 1 type, or 2 or more types of mixtures.
The method of claim 1, wherein the hydrophilic polymer is hydroxypropylmethylcellulose, polyethylene oxide, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polydextrin, pectin, methyl cellulose, cellulose acetate, hydroxymethyl cellulose Talni flu mate sustained-release tablet, characterized in that one or two or more mixtures selected from ethyl cellulose, povidone and carbomer.
The sustained-release tablet according to claim 1, wherein the talniflumate sustained-release tablet is purified into a nucleated tablet or a double tablet consisting of a sustained portion and a rapid release portion.
The talni flu mate sustained-release tablet according to any one of claims 1 to 5, wherein the surface of the talni flu mate sustained release tablet is coated with a drug coating solution containing the talni flu mate, and further comprises a drug coating layer.
The sustained-release tablet according to any one of claims 1 to 5, wherein the talniflumate sustained-release tablet further comprises one or more adjuvants of an excipient, a binder, a lubricant, and a colorant.
8. The excipient is selected from lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, potato starch, wheat starch, white sugar, di-mannitol, precipitated calcium carbonate, dextrin, pre-gelatinized starch. Talni flu mate sustained-release tablet characterized by the 1 type, or 2 or more types of mixtures.
According to claim 7, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, dextrin, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, paste, gum arabic or Talni flu mate sustained-release tablet characterized in that it is a mixture of two or more.
8. The method of claim 7, wherein the disintegrant is one or a mixture of two or more selected from sodium starch glycolate, crospovidone, sodium oscarmellose, low-substituted hydroxypropyl cellulose, starch, and carboxymethyl cellulose. Talni flu mate sustained-release tablet to be made.
The sustained-release tablet according to claim 7, wherein the lubricant is one or a mixture of two or more selected from magnesium stearate, talc, and mousse silicic acid.
According to claim 6, wherein the drug coating liquid is polyvinyl alcohol, polypropylene glycol, acrylic acid copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate selected from one or two or more Talni flu mate sustained-release tablet comprising a.