JP2004269506A - Sustained release type compounded unit preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sustained release type compounded unit preparation, while keeping the strength sufficiently in digestive tract, also setting the degree of release of an active ingredient into the body in a suitable state, and surely capable of exhibiting the effect by the active ingredient in the unit preparation. <P>SOLUTION: This sustained release type compounded unit preparation is provided by blending a unit-forming substance with 5-ä2-[2-(O-ethoxyphenoxy)ethylamino]propyl}-2-methoxybenzenesulfonamide hydrochloride, further adding a dissolution-regulating agent and granulating. The unit-forming substance consists mainly of lactose and crystalline cellulose and further the blending ratio of the lactose to crystalline cellulose is made within (50:59)-(45:55) range in weight ratio. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention relates to a sustained release compound unit preparation for oral medicine, and more particularly to a unit preparation for improving urinary insufficiency due to benign prostatic hyperplasia.

  5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride (hereinafter referred to as tamsulosin hydrochloride) is used as an agent for improving urinary insufficiency due to benign prostatic hyperplasia. The main unit is a unit preparation containing an active ingredient, and this unit preparation is generally widely marketed as an oral sustained release composite unit preparation. The sustained release composite unit preparation is formed into a granule obtained by adding an elution controlling agent to a mixture of a physiologically active substance as an active ingredient and a unit molding substance as an inactive ingredient, and granulating the mixture. Was hardly disintegrated in the digestive tract, but the physiologically active substance in the unit preparation was gradually released into the digestive tract.

  However, crystalline cellulose, which is widely used as a unit molding substance in this type of sustained-release composite unit preparation, can secure the strength of the unit preparation, but due to its properties, when the amount of crystalline cellulose in the whole increases, the production of crystalline cellulose increases. Fluctuations in the amount of water at the time of granulation are greatly increased, thereby affecting the surface area or the granule density, and consequently causing a large fluctuation in the sustained release. From this fact, in the case of a unit preparation containing 50% or more by weight of crystalline cellulose in the unit molding substance, there is a concern that the elution may be unexpectedly delayed in the digestive tract, and the active ingredient in the body after taking the unit preparation. Release is not carried out smoothly, and conversely, even if the blending ratio of crystalline cellulose is extremely small, the sustained release of the preparation is significantly impaired, and consequently the effect of the active ingredient of the unit preparation is sufficiently reduced. There was an inconvenience that could not be demonstrated.

  The present invention provides a sustained-release composite unit preparation which can maintain its strength in the gastrointestinal tract and release the active ingredient into the body in an appropriate state to ensure that the efficacy of the active ingredient in the unit preparation can be exerted. To provide.

  The invention according to claim 1 of the present invention is a method of forming a unit into 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride which is a physiologically active substance. A sustained release composite unit preparation obtained by compounding a substance, further adding an elution control agent and granulating, wherein the unit molded substance contains lactose and crystalline cellulose as main components, and further contains lactose and crystalline cellulose. It is characterized in that the mixing ratio is in the range of 50:50 to 45:55 in weight ratio.

  Here, as the elution controlling agent, specifically, talc, which is the mainstream as this kind of coating agent, is used, but calcium stearate or magnesium stearate can also be used. In addition, lactose was selected in addition to crystalline cellulose as a raw material of the unit molding substance, because lactose is excellent in improving the hygroscopicity of a physiologically active substance, which is important at the time of tablet molding, and has a mutual property with the physiologically active substance. It has little effect and is widely used in various pharmaceuticals and health foods, and its safety has been confirmed.

  When formed in this way, the compounding ratio of the two components lactose and crystalline cellulose, which account for the major proportion of the constituents of the unit molding substance in the unit preparation, is adjusted so that lactose: crystalline cellulose is in the range of 50:50 to 45:55. By doing so, it is possible to control the physical fluctuation of the molded product of the unit preparation after granulation. As a result, the unit preparation is not easily destroyed in the gastrointestinal tract, and tamsulosin hydrochloride as an active ingredient is gradually released into the body over a long period of time.

  The invention according to claim 2 of the present invention regulates the sustained release of the 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride. The control substance is a mixture obtained by mixing an enteric coating agent of an acrylic acid polymer or a coating agent of a cellulose derivative into an aqueous suspension, an aqueous emulsifier, or a water-containing organic solvent. The unit dosage form can be rendered insoluble in the acidic solution.

  Further, the invention according to claim 3 of the present invention is characterized in that the 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride has a weight per unit preparation. The ratio is less than 5%, and the invention according to claim 4 of the present invention is characterized in that each unit preparation is a spherical granule having a size of 0.2 mm to 1.0 mm in diameter. And the sustained release of tamsulosin hydrochloride into the body is ensured in a well-balanced manner.

  The sustained-release composite unit preparation containing tamsulosin hydrochloride obtained as an active ingredient according to the present invention, for example, retains its shape without disintegration for 2 weeks or more even when immersed in water, and furthermore, with respect to an acidic solution. Is also insoluble, it is presumed that this unit preparation is not easily destroyed even in the digestive tract. From this, it is possible to provide a unit preparation that is highly persistent and continues to exert the effect of the active ingredient for a long time.

The actual manufacturing process of the sustained release composite unit preparation of the present invention will be described in detail below.
First, tamsulosin hydrochloride used as a physiologically active substance as an active ingredient of the present unit formulation will be described. This tamsulosin hydrochloride was approved in Japan in July 1993 as an agent for improving dysuria of benign prostatic hyperplasia. Therefore, it is widely used in general, and its properties are very excellent in suitability as a unit preparation having low solubility in water and sustained release.

Next, the sustained release composite unit preparation according to the present invention will be described.
In the present invention, crystalline cellulose is used as a unit molding substance for producing the sustained-release composite unit preparation of the present invention containing tamsulosin hydrochloride having the above-mentioned properties as an active ingredient. By blending with lactose having a high concentration, the state of overtightening due to excess energy of moisture and high-speed stirring granulation can be alleviated, and a unit preparation having a sustained release with less fluctuation in granule density and surface area can be manufactured. In order to demonstrate this, the dissolution performance of tamsulosin hydrochloride of the present unit preparation is confirmed by a dissolution test method.

  In addition, the specific surface area calculated from the crystalline cellulose contained in the granules granulated by the high-speed stirring greatly differs depending on the amount of water added during granulation. Furthermore, considering that the mechanism controlling the sustained release of tamsulosin hydrochloride is based on the alliance with the excipient, the change in the bulk density and surface area between the tamsulosin hydrochloride and the crystalline cellulose is closely related to the release of tamsulosin hydrochloride. Therefore, in this embodiment, in order to reduce such physical fluctuation, verification was performed using various substances described below.

Here, as a unit that forms a structure that does not easily disintegrate in the digestive tract, crystalline cellulose and crystalline lactose are blended at a weight ratio of 1: 1 as unit molding substances. The size was about 350M. In addition, a lubricant is used in an amount of about 2 to 10% by weight based on the total weight of the preparation in order to speed up the flow of the spherical particles during the stirring granulation step.
In the present invention, talc is used as the lubricant. In addition to this talc, for example, calcium stearate or magnesium stearate can be used instead.

  In the dissolution control step used in the present invention, since the present unit preparation needs to be insoluble in the digestive tract, an acrylic acid-based polymer which is insoluble in an acidic solution in the same atmosphere as the digestive tract is used. A polymer, a cellulose derivative including ethyl cellulose, an aqueous suspension, an aqueous emulsifier, and a water-containing organic solvent solution are added as a granulation additive solution, and further spray-coated with the granulation additive solution to elute into the body. The degree is adjusted.

上記粉体３成分を高速撹拌造粒機に投入し、これを精密に混合した後、液体３成分を混合した溶液をスプレーしながら造粒を行なった。そして、出来上がった造粒物を14号篩に全通させた後に乾燥した。
＜対照例１＞

上記粉体２成分を高速撹拌造粒機に投入し、精密に混合した後、さらに液体３成分を混合した溶液をスプレーしながら球状物となるように造粒工程を行なった。そして、この造粒工程を経て出来上がった球状物を14号篩に全通させて乾燥した。

このことから、単位製剤としてのカプセル充填が容易な粒度である30〜60号onの収率は、対照例１とほぼ同じであるが、その中での分布は、前述の実施例１の方が分布幅は狭いと考えられる。
上記の結果を得て、次に粗充填嵩密度の測定値を以下に示す。

球状物の粒子径が大きい実施例１の方が対照例１に比べて嵩密度が低いことから、造粒後の球状物が閉まり過ぎていないことが測定結果から示唆された。 In the following, the performance of the present unit preparation was measured from various viewpoints by conducting experiments.
(1) Particle Size Distribution and Bulk Density Particle Size Distribution Test: This was carried out in accordance with the 14th revised edition of the Japanese Pharmacopoeia powder particle size measurement method.
Rough filling bulk density test: Performed using an ABD powder property measuring device (manufacturer and distributor: Tsutsui Scientific Instruments).
(Example 1)

The above three powder components were put into a high-speed stirring granulator and mixed precisely, followed by granulation while spraying a mixed solution of the three liquid components. The resulting granulated product was passed through a No. 14 sieve and dried.
<Comparative Example 1>

The two powder components were charged into a high-speed stirring granulator and mixed precisely, and then a granulation step was performed while spraying a solution obtained by mixing the three liquid components so as to form spherical particles. Then, the spherical material obtained through this granulation step was passed through a No. 14 sieve and dried.

From this, the yield of No. 30 to 60, which is a particle size that can be easily filled into capsules as a unit preparation, is almost the same as that of Comparative Example 1, but the distribution therein is smaller than that of Example 1 described above. However, it is considered that the distribution width is narrow.
After obtaining the above results, the measured values of the bulk density of the rough filling are shown below.

Since the bulk density of Example 1 in which the particle diameter of the sphere was large was lower than that of Control Example 1, the measurement results suggested that the sphere after granulation was not too closed.

（実施例２）

上記の塩酸タムスロシンからタルクまでの４成分について精密に混合し、さらに、高速撹拌造粒機内に他の成分を混合溶解したものをスプレーコーティングしながら造粒工程を行なった。そして、造粒物を14号篩に全通することにより湿式整粒を行ない、ステンレスバットに広げて乾燥した。さらに乾燥後、まず22号篩を通過させ、次に、60号篩を通過しない粒についてカプセルに詰めて溶出試験を行った。
（実施例３）
前述の実施例２の段階で製造した顆粒剤について、以下の混合液に対し流動層内においてコーティングを施した。

「結果」
同様の処方により、コーティング量を2倍・3倍としたものをそれぞれ作り、その試料をpH6.8における溶出挙動を測定した結果、次に示すグラフのような結果となった。このグラフからコーティング量をフィルム固形分として10％以上とすると、約6時間以上は直線的な溶出挙動を示し、このことから、コーティング量によって徐放速度もコントロールされることが示唆された。 (2) Dissolution test The dissolution test method of the Japanese Pharmacopoeia The test was carried out by the liquid chromatograph method using the paddle rotation speed of 50 rpm and the Japanese Pharmacopoeia liquids 1 and 2 as the test liquid by the paddle method. Was.
"Liquid chromatography measurement method"
The eluate collected at each preset time was filtered through a filter, and after adding an internal standard, 100 μl thereof was injected into a liquid chromatograph under the conditions described below. The concentration was calculated by comparison.

(Example 2)

The above four components from tamsulosin hydrochloride to talc were precisely mixed, and a granulation step was performed while spray-coating a mixture obtained by mixing and dissolving other components in a high-speed stirring granulator. The granulated product was subjected to wet granulation by passing it through a No. 14 sieve, spread in a stainless steel vat, and dried. After further drying, the particles were first passed through a No. 22 sieve, and then the particles that did not pass through a No. 60 sieve were packed in capsules and subjected to a dissolution test.
(Example 3)
The granules produced in the above-mentioned Example 2 were coated in the fluidized bed with the following mixture.

"result"
With the same formulation, the coating amount was doubled and tripled, respectively, and the elution behavior of the sample at pH 6.8 was measured. The result was as shown in the following graph. From this graph, when the coating amount is set to 10% or more as a film solid content, a linear dissolution behavior is exhibited for about 6 hours or more, which suggests that the controlled release rate is controlled by the coating amount.

FIG. 4 is a graph comparing the time-dependent concentrations of tamsulosin hydrochloride in a pH 6.8 aqueous solution depending on the coating amount in the sustained release complex unit preparation of the present invention.

Claims (4)

A unit molding substance is blended with 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride, which is a physiologically active substance, and an elution controlling agent is further added to form the compound. A sustained-release composite unit preparation obtained by granulation,
The unit molding material has lactose and crystalline cellulose as its main components, and further has a compounding ratio of lactose and crystalline cellulose in a weight ratio of 50:50 to 45:55 in a sustained release. Complex unit preparation.   The control substance for controlling the sustained release of 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride is an enteric coating of an acrylic acid polymer. 2. The sustained-release composite unit preparation according to claim 1, wherein the preparation is a mixture obtained by mixing an agent or a film-forming agent of a cellulose derivative into an aqueous suspension, an aqueous emulsifier, or a water-containing organic solvent.   The weight ratio of the 5- {2- [2- (O-ethoxyphenoxy) ethylamino] propyl} -2-methoxybenzenesulfonamide hydrochloride per unit preparation is less than 5%. Item 3. The sustained release composite unit preparation according to item 1 or 2. 4. The sustained release composite unit preparation according to claim 1, 2 or 3, wherein each unit preparation has a diameter of 0.2 mm to 1.0 mm.

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