KR20120006300A - Composition of extended release tablet containing tacrolimus - Google Patents

Abstract

PURPOSE: A composition containing tacrolimus for sustained release oral administration is provided to release tacrolimus effect for 14 hours. CONSTITUTION: A composition for sustained release oral administration contains tacrolimus as an active ingredient, a mixture of hydroxypropyl beta-cyclodextrin and dioctylsulfosuccinate as an excipient, a mixture of hydroxypropylmethyl cellulose and ethyl cellulose as a sustained release excipient.

Description

Composition for extended-release oral administration containing tacrolimus {Composition of extended release tablet containing tacrolimus}

The present invention relates to a tacrolimus-containing sustained release oral composition which can be administered once a day by continuously releasing the active ingredient.

Tacrolimus is a macrolide antibiotic with immunosuppressive effects. Although structurally different from Cyclosporin A, an immunosuppressive agent currently widely used, its mechanism of action is known to be similar. Tacrolimus is used as a first-line or palliative therapy for tissue rejection reactions during kidney or liver transplantation, and when used as a primary therapy to prevent acute tissue rejection or to reduce the use of corticosteroids. It is evaluated to have higher efficacy than Porin A.

Generally a variety of techniques are known for preparing formulations in which the active compound is controlled release. For example, an increase in the density of the preparation (EP-A 265 061) or the use of a highly spaced preparation (EP-A 235 718) to extend the residence time in the stomach. However, these techniques have disadvantages, specifically, expensive and complex manufacturing methods, or there are differences between individuals and within individuals.

EP-A 265 061 2.EP-A 235 718

Accordingly, it is an object of the present invention to provide a sustained release formulation of tacrolimus that enables administration once a day in an inexpensive and easy manufacturing method.

Through the following specific aspects of the present invention it was possible to achieve the above object:

(A) (1) tacrolimus as an active ingredient;

    (2) a mixture of hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as an excipient for solid dispersion formation; And

(3) Tacrolimus-containing sustained release oral composition comprising a mixture of hydroxypropylmethylcellulose and ethylcellulose as a sustained-release excipient;

(B) In the above (a), the hydroxypropyl beta cyclodextrin is included in 1 to 10 parts by weight based on 1 part by weight of tacrolimus, the dioctylsulfosuccinate is contained in 0.5 to 1.0 parts by weight based on 1 part by weight of tacrolimus. Composition to be; or

(C) In the above (a), the mixture of hydroxypropylmethylcellulose and ethyl cellulose is contained in an amount of 5 to 10 parts by weight based on 1 part by weight of the total weight of the excipient for forming tacrolimus and a solid dispersion, wherein The weight ratio of oxypropylmethyl cellulose and ethyl cellulose is 1: 1.6 to 2.

The present invention provides a tacrolimus-containing sustained-release orally administered composition in which the active ingredient is continuously released for at least 14 hours or more, so that once-daily administration is possible. It is greatly expected.

1 is a view of the effects of the ratio of hydroxypropylmethylcellulose and ethyl cellulose, Comparative Example 3 (●), Comparative Example 4 (○), Example 1 (▼), Example 2 (△) and Comparative Examples The tacrolimus elution curve from the composition of 5 (■) is shown.
Fig. 2 shows tacrolimus elution curves from the compositions of Comparative Example 1 (●) and Comparative Example 2 (○).

In accordance with the above object, in the present invention, tacrolimus as an active ingredient, hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as excipients for making solid dispersions, and hydroxypropylmethylcellulose and ethyl as excipients for making sustained-release preparations It provides a tacrolimus-containing oral sustained release formulation composition comprising cellulose.

 Hereinafter, the present invention will be described in detail.

(Iv) active ingredients

Tacrolimus is a well-known immunosuppressant for organ transplantation. However, because the drug is very fat-soluble, it is insoluble in water, and the presence of bile determines its absorption in the gastrointestinal tract. The average bioavailability in humans after oral administration is about 29%, usually in the range of 0.5-67%. The drug is distributed throughout the body, especially at high concentrations in the liver, spleen, heart and kidneys.

(Ii) excipients for solid dispersions

Hydroxypropylbetacyclodextrin is a kind of betacyclodextrin and is used similarly to the general β-cyclodextrin. However, it has the advantage of low nephrotoxicity, which makes it an useful excipient when preparing oral or parenteral formulations. The hydroxypropyl betacyclodextrin is preferably added 1 to 10 times by weight of tacrolimus in the tacrolimus oral solid preparation composition of the present invention, and more preferably 7 to 9 times.

Dioctylsulfosuccinate is also called docuate sodium. It acts as an anionic surfactant in formulating formulations and is primarily used to aid wetting and dissolution when making capsule formulations and direct compression tablets. It is also used as a laxative to make oral preparations. The dioctylsulfosuccinate preferably adds 0.5 to 1.0 times the tacrolimus weight in the tacrolimus oral solid preparation composition of the present invention, and more preferably adds 0.7 to 0.9 times.

(Iii) excipients for making sustained release preparations;

Hydroxypropylmethylcellulose is the most widely used cellulose-based polymer, and its properties vary depending on the average molecular weight, the proportion of methyl groups and propyl groups. In addition, according to the use of each formulation is also different, generally used in the preparation of tablets or granules in oral preparations are most commonly used as a binder or film forming agent.

Ethylcellulose is mainly used for hydrophobic coating of oral preparations such as tablets and granules. Such coatings are intended to modify the release of the drug and also to improve taste or improve the stability of the formulation. For example, the granules coated with ethyl cellulose can be prevented from being oxidized in the air.

Hydroxypropylmethylcellulose and ethylcellulose are preferably added so that the mixed weight thereof is 5 to 10 times the total weight of the excipient for forming tacrolimus and solid dispersion, and more preferably 8 to 10 times. On the other hand, the ratio of hydroxypropylmethylcellulose and ethyl cellulose is preferably 1: 1.6 to 2.

The compositions of the present invention may further comprise excipients and additives necessary for the preparation of conventional formulations.

Comparative example  1-5 and Example  1 to 2

According to the composition of Table 1 below, hydroxypropyl betacyclodextrin and dioctylsulfosuccinate together with tacrolimus were dissolved in a mixed solution of ethanol and methylene chloride, and then hydroxypropylmethylcellulose and ethylcellulose were added to the powder obtained by spray drying. It was formulated using a terminal tablet machine.

Each ingredient content (mg / formulation) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Example 1 Example 2 Comparative Example 5 Tacrolimus 2.04 2.04 2.04 2.04 2.04 2.04 2.04 Hydroxypropylbeta-cyclodextrin 16.33 16.33 16.33 16.33 16.33 16.33 16.33 Dioctylsulfosuccinate 1.63 1.63 1.63 1.63 1.63 1.63 1.63 Hydroxypropylmethylcellulose 178 - 89 71.2 66 59.33 44.5 Ethylcellulose - 178 89 106.8 112 118.66 133.5 Talc 2 2 2 2 2 2 2

Spray drying conditions are as follows.

Spray dryer: BUCHI mini spray dryer B-191

Pump speed: pump speed-5ml / min

Air flow rate: 600 NI / h

Inlet air temperature: 80 ℃

Outlet air temperature: 55-60 ° C.

75 ml of 0.25 g of tacrolimus is used as a mixture in a volume ratio of solvent-methylene chloride: ethanol = 1: 2.

Experimental Example  1: dissolution test

The dissolution test was performed on the formulations prepared in Comparative Examples 1 to 5 and Examples 1 to 2 according to the Dissolution Test No. 2 method (paddle method) of the Korean Pharmacopoeia General Test Method, and were used for 30 minutes, 1 hour, 2 hours, and 4 hours. The amount of tacrolimus eluted for hours, 6 hours, 12 hours and 24 hours was measured according to the following assay. As the eluate, 500 ml of a solution in which hydroxypropyl cellulose (HPC) was dissolved to 0.005% in distilled water and adjusted to pH 4.5 with phosphoic acid was used. The temperature of the eluate was 37 ± 0.5 ° C. and the rotation speed was maintained at 100 rpm. The results are shown in FIGS. 1 and 2.

Method: liquid Chromatography

Column: ODS-2 (5um, 4.6mm x 250mm)

Mobile phase: H ₂ O: AcCN = 25: 75

Flow rate: 1.0 ml / min

Detector: L-2130, HITACHI

Wavelength: 210 nm

Injection volume: 50μl

Claims (3)

(1) tacrolimus as an active ingredient;
(2) a mixture of hydroxypropylbetacyclodextrin and dioctylsulfosuccinate as an excipient for solid dispersion formation; And
(3) Tacrolimus-containing sustained-release oral administration composition comprising a mixture of hydroxypropylmethylcellulose and ethylcellulose as a sustained-release excipient.
The composition of claim 1, wherein the hydroxypropyl betacyclodextrin is included in 1 to 10 parts by weight based on 1 part by weight of tacrolimus, and the dioctylsulfosuccinate is included in 0.5 to 1.0 parts by weight based on 1 part by weight of tacrolimus. .
The method of claim 1, wherein the mixture of hydroxypropylmethylcellulose and ethylcellulose is contained in an amount of 5 to 10 parts by weight based on 1 part by weight of an excipient for forming tacrolimus and a solid dispersion, wherein hydroxypropylmethylcellulose And the weight ratio of ethylcellulose is 1: 1.6 to 2.

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