KR20060093931A - Pellet-typed formulation comprising tamsulosin with controlled release - Google Patents

Abstract

The present invention constitutes a seed layer, an outer layer of the seed layer, a first coating layer containing 65 to 75% of the total amount of tamsulosin, an outer layer of the first coating layer, and a second for drug release control of tamsulosin. Provided is a controlled release pellet formulation containing tamsulosin comprising a coating layer and a third coating layer constituting the outer layer of the second coating layer and containing 25 to 35% of the total content of tamsulosin.

The controlled release pellet preparation according to the present invention can accurately perform the release control required when designing a tamsulosin preparation, and a novel controlled release probe capable of producing such a controlled release tamsulosin preparation by a simple method. Provide a new formulation.

Tamsulosin, release control

Description

Pellet-typed Formulation Comprising Tamsulosin with Controlled Release}

1 is a result diagram showing the upper and lower limits of the release control of the conventional tamsulosin preparations

2 is a cross-sectional view of a tamsulosin preparation according to the present invention.

Figure 3 is a result drawing showing the release control characteristics of the tamsulosin formulation according to the present invention

The present invention relates to a controlled release tamsulosin preparation, and more particularly, it is possible to accurately perform the release control required when designing a tamsulosin preparation, and to manufacture such a controlled release tamsulosin preparation by a simple method. And a novel controlled release tamsulosin formulation.

Tamsulosin was first described in Japanese Patent Application Laid-open No. 56-110665 with its pharmaceutically acceptable salts. Its chemical name is (R) (-)-5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide and is represented by the following formula.

<Formula>

Urination disorder due to enlarged prostate is a common disease in men.The enlarged prostate causes the closure of the bladder outlet, and as the α ₁ receptor increases in the enlarged prostate, excess muscle contraction causes the bladder muscle to drain urine. This thickens. Due to the strong bladder contraction movement, the pressure of the bladder is increased and the mucous membrane between the thick muscle fibers is compressed so that urine cannot be discharged well during urination. Is accompanied by symptoms of [see; UROLOGY 51 (Suppl 4A): 1-7, 1998].

Tamsulosin or a salt thereof is known to have an adrenergic α _1A receptor blocking action, in particular its hydrochloride (hydrochloride tamsulosin) has an α ₁ receptor blocking action of the urethra and prostate, and reduces the prostate pressure of the urethral pressure curve It is widely used as an excellent agent for improving urination disorder following prostatic hyperplasia [see; UROLOGY 58 (Suppl 6A): 42-48, 2001].

In addition, Korean Laid-Open Patent Publication 02-0016944 treats tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient as a treatment for lower urinary tract disease. Lower urinary tract disorder is a symptom of urination disorder due to functional obstruction of the lower urinary tract of men and women. It includes a symptom. The causative diseases include: urination difficulties, bladder cervical sclerosis, bladder neck obstruction, urethral syndrome, urinary sphincter dysfunction, unstable bladder, chronic prostatitis, chronic cystitis, prostate pain, Hinman's syndrome, Fowler syndrome, psychogenic urination disorder, drug urination disorder , Urination disorder due to aging is considered.

Typical oral doses of tamsulosin hydrochloride for the treatment of urination disorders range from 0.2 to 0.4 mg / day. UROLOGY 58 (Suppl 6A): 42-48, 2001] and the preferred dosage form is a sustained release sustained release formulation. Yamano already day day ^® capsule Uchida constraint (as a new hydrochloric tamsul 0.2㎎) and Boehringer Ingelheim FLOMAX ^TM capsule (as new as hydrochloric tamsul 0.4㎎) it is commercially available in the sustained-release formulation of the medication once a day.

Korean Patent Laid-Open Publication No. 86-0006984, Japanese Patent Laid-Open No. 62-9, and Japanese Patent Laid-Open No. 62-9 deal with the preparation of sustained-release preparations of tamsulosin hydrochloride, which use crystalline cellulose as a unit-forming substance and use it as a release inhibitor. Is an acrylic acid polymer used in the form of an aqueous suspension, an aqueous emulsifier, a water-containing organic solvent solution, or a water-insoluble high molecular material such as a copolymer or a cellulose derivative, for example Eudragit L30D-55 (meta Obtained by assembling with a centrifugal flow granulator using Krylic acid copolymer LD), Eudragit E30D (ethyl acrylate methyl methacrylate copolymer emulsion), Aquacoat ECD-30 (ethylcellulose aqueous suspension), etc. The granules were filled into capsules to prepare a capsule.

Tamsulosin is contained in a small amount and it is required to be precisely controlled between the upper limit and the lower limit as shown in FIG. However, according to any of the methods described above, the precisely controlled formulation between the upper limit and the lower limit with time as in FIG.

The present invention is proposed to solve the problems of the prior art as described above,

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel controlled release tamsulosin preparation which can accurately perform the release control required in designing a tamsulosin preparation and can prepare such a controlled release tamsulosin preparation by a simple method. have.

The present invention to achieve the above object

A seed layer, a first coating layer constituting the outer layer of the seed layer and containing 65 to 75% of the total amount of tamsulosin, a second coating layer for controlling the drug release of tamsulosin, constituting the outer layer of the first coating layer, and It provides a controlled release formulation containing tamsulosin consisting of a third coating layer constituting the outer layer of the second coating layer and containing 25 to 35% of the total amount of tamsulosin.

According to the present invention the first coating layer preferably contains 70% of the total amount of tamsulosin, and the third coating layer provides a controlled release formulation characterized in that it contains 30% of the total content of tamsulosin.

According to the present invention, tamsulosin used as the drug provides a controlled release preparation, which is preferably in the form of tamsulosin hydrochloride.

According to the present invention, the second coating layer provides a controlled release formulation, characterized in that it is formed of a release control film containing no tamsulosin.

According to the present invention, the third coating layer provides a controlled release formulation, characterized in that it contains a polymer having solubility dependent on pH.

Hereinafter, the content of the present invention in more detail as follows.

The release characteristic of tamsulosin should be located between the upper and lower limits shown over time as shown in FIG. 1. According to the conventional formulation, while the release properties as described above are not fully exhibited, the present invention can provide a formulation that satisfies these conditions.

The controlled release tamsulosin preparation according to the present invention comprises a seed 1, a first outer layer 2 coated on the seed, a second outer layer 3 coated on the first outer layer, as shown in FIG. And a third outer layer 4 coated on the second outer layer.

The material that can be used as the seed (1) in the above does not require a special limitation, for example, may be used consisting of starch, sugar and a mixture of starch and sugar.

The controlled release tamsulosin preparation according to the present invention preferably contains tamsulosin hydrochloride, and the first outer layer 2 in contact with the seed layer 1 is preferably in the weight ratio of total tamsulosin content together with a water-soluble polymer. Preferably, a coating layer in which 65% to 75% of tamsulosin is dissolved in a solvent is formed.

The water-soluble polymer used therein may preferably include polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropylmethylcellulose, polyethylene glycol and the like.

The controlled release tamsulosin formulation according to the present invention is coated with a controlled release polymer solution as the second outer layer 3 in contact with the first outer layer 2. The type of release controlling polymer does not require any particular limitation, but it is a cellulose derivative (ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate as a polymer capable of forming a water-insoluble film. , Cellulose acetate phthalate, cellulose triacetate, etc., and acrylic acid polymers and copolymers thereof (polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, poly Isodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, poly methyl acrylate, poly isopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate The tree, and so on) may be used. Commercially available polymers that satisfy these conditions include Eudragit RL, Eudragit RS, and the like.

The second outer layer 3 preferably contains no tamsulosin, preferably tamsulosin hydrochloride. When tamsulosin hydrochloride is included, there is a concern that it is difficult to control the emission characteristic to be positioned between the upper limit and the lower limit as shown in FIG. 1.

The controlled release tamsulosin preparation according to the present invention is a layer which is in contact with the second outer layer (3) and is released from artificial gastric juice and has a pH-dependent solubility, preferably 25 to 35% by weight ratio of total tamsulosin content. The third outer layer 4 containing tamsulosin corresponding thereto is formed.

The type of the polymer having a pH-dependent solubility used in the third outer layer also does not require any particular limitation, but is a polymer that is generally dissolved at a neutral to basic pH and is a cellulose derivative, hydroxymethylcellulose phthalate, an acrylic acid polymer and its air. Coalescing and the like can be used. Commercially available polymers that satisfy these conditions include Eudragit L, Eudragit S, Eudragit L100-55, Eudragit L30-55, and the like.

Tamsulosin preparations according to the present invention exhibits complete release characteristics because the dissolution characteristics over time are located inside the upper and lower limits of FIG. 1.

The preparation of tamsulosin preparations according to the present invention can be carried out using a fluidized bed coater, which will be described in more detail through the following examples.

When the release rate of the primary coating layer of the controlled release tamsulosin preparation prepared according to the present invention is slow, a method of controlling the amount of the cellulose derivative used in the primary coating and a silicon dioxide used as a lubricant to enhance the flow of the pellets It is also possible to increase the penetration of the discharged liquid by increasing the content of.

Hereinafter, the contents of the present invention will be described in more detail with reference to Examples, but the following Examples are for understanding the contents of the present invention and the scope of the present invention is not limited thereto.

<Example 1>

The first outer layer coated on the seed was coated with a fluid containing a tamsulosin corresponding to 70% by weight of the total tamsulosin content under the following conditions using a fluidized bed coater.

TABLE 1 Rx. Primary coating solution

Tamsulosin hydrochloride 0.38 g HPMC 21 g Syloid 244FP (SiO ₂ ) 3 g ethanol 200 g Distilled water 200 g total 424.38 g

The HPMC used in the coating liquid of the first outer layer had a concentration of 4.95%.

<Table 2> Spray condition of primary coating solution

inflow 55 ℃ product 48 ℃ outflow 48 ℃ Pumping speed 6-7 ml / min Atomizing aprox 1.5 bar Blower 0.4 to 0.5 bar

The second outer layer to be coated on the first outer layer was a coating solution containing no tamsulosin at all, and was coated under the following conditions using a fluidized bed coater.

TABLE 3 Rx. Secondary coating solution

Eudragit RL 100 4.9 g (10%) Eudragit RS 100 44.1 g (90%) Dibutyl sebacate 4.9 g (10% polymer) Syloid 244FP 4.9 g (10% polymer) ethanol 245 g 2-propanol 245 g total 548.8 g

The concentration of the release controlling polymer used in the coating liquid of the second outer layer was 8.93%.

<Table 4> Spray condition of secondary coating solution

inflow 28 ~ 29 ℃ product 27 ~ 28 ℃ outflow 27 ~ 28 ℃ Pumping speed 6-7 ml / min Atomizing aprox 1.5 bar Blower 0.4 to 0.5 bar

In this case, if the injection speed is high, particles may stick together, and if it is too slow, the fluid may not have a smooth flow in the fluidized bed due to the static electricity of the polymer.

The third outer layer coated on the second outer layer was coated with a fluid containing a tamsulosin corresponding to 70% by weight of the total tamsulosin content under the following conditions using a fluidized bed coater.

TABLE 5 Rx. 3rd coating solution

Tamsulosin hydrochloride 0.16 g Eudragit S 100 38 g Triacetin 3.8 g Syloid 244FP 7.6 g ethanol 330 g Distilled water 70 g Poloxamer 188 0.38 g (1% of polymer) total 449.94 g

The concentration of the polymer constituting the coating layer having a pH dependent solubility used in the coating liquid of the third outer layer was 8.45%.

<Table 6> Spray condition of 3rd coating

inflow 28 ~ 29 ℃ product 27 ~ 28 ℃ outflow 27 ~ 28 ℃ Pumping speed 6-7 ml / min Atomizing aprox 1.5 bar Blower 0.4 to 0.5 bar

The release rate of the controlled release tamsulosin preparation prepared through the above process according to the present invention was able to control the desired release rate.

The experimental results of FIG. 3 were obtained in accordance with the Emission Test Clause 2 of the General Test Methods of the 8th Amendment. At this time, the number of rotation of the discharge paddle was 100rpm, and the test solution was prepared by accurately adding 1 ml of polysorbate 80 solution (3 → 200) prepared in 500 ml of the first solution of the disintegration test method. Testing continued at 37 ± 0.5 ° C., with 500 ml of pH 7.2 phosphate buffer. According to the above results, it can be seen that the controlled release formulation obtained according to the present invention is located between the upper limit and the lower limit.

As described above, according to the present invention, it is possible to accurately perform the release control required when designing the tamsulosin preparation, and it is possible to prepare such a release-controlled tamsulosin preparation by a simple method.

Claims (6)

A seed layer, a first coating layer constituting the outer layer of the seed layer and containing 65 to 75% of the total amount of tamsulosin, an outer layer of the first coating layer, and a second coating layer for controlling drug release of tamsulosin, and Controlled release formulation containing tamsulosin, consisting of a third coating layer constituting the outer layer of the second coating layer and containing 25 to 35% of the total amount of tamsulosin The controlled release formulation of claim 1, wherein the first coating layer contains 70% of the total content of tamsulosin and the third coating layer contains 30% of the total content of tamsulosin. The controlled release formulation of claim 1, wherein the tamsulosin is in the form of tamsulosin hydrochloride. 2. A controlled release formulation according to claim 1, wherein the second coating layer is a release controlling coating containing no tamsulosin. 5. A controlled release formulation according to claim 4, wherein the second coating layer contains a polymer capable of forming a water insoluble coating. The controlled release formulation of claim 1, wherein the third coating layer contains a polymer having a pH-dependent solubility.

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