JP4603803B2 - Controlled release pharmaceutical composition and formulation using the same - Google Patents

Description

  The present invention relates to a sustained-release pharmaceutical composition containing a physiologically active substance such as tamsulosin or a pharmaceutically acceptable salt thereof and a preparation using the same.

  The number of patients with benign prostatic hyperplasia is increasing due to aging in recent years. This prostatic hypertrophy often accompanies dysuria, and the need for drugs for treating dysuria such as tamsulosin is increasing for the treatment. In addition, in such diseases and the like, it is necessary to continuously use drugs. Currently, Harnal capsules that are marketed as drugs containing tamsulosin are designed as sustained-release preparations according to the purpose. A single administration shows efficacy.

  The sustained-release technique relating to the above-mentioned Harnal capsule is a kind selected from acrylic acid polymer, copolymer and cellulose derivative to this mixture by adding substantially 70% or more of crystalline cellulose by weight ratio in the preparation unit. Or it consists of a granular material (particle | grain) obtained by adding two or more sorts of elution control agents, and granulating (patent document 1).

Japanese Examined Patent Publication No. 7-72129

  However, in the above technique, it is necessary to use a large amount of crystalline cellulose. Therefore, the type and amount of other additives are limited, and the size of the powder containing the drug must be set to a certain level or more. There was a limit to the control of sustained release. Therefore, development of a technique capable of controlling the sustained release of tamsulosin regardless of the amount of crystalline cellulose has been demanded.

  The inventors of the present invention conducted intensive research on the sustained release of tamsulosin, and surprisingly, by incorporating one or more components selected from inorganic acids or organic acids or their metal salts and a release control base, In addition, the present inventors have found that the elution of the drug from the preparation can be controlled and the sustained release ability can be imparted without being limited by the amount of crystalline cellulose.

  That is, the present invention comprises a controlled-release pharmaceutical composition comprising one or more components selected from tamsulosin or a pharmaceutically acceptable salt thereof, an inorganic acid, an organic acid or a metal salt thereof and a release-controlling base. Is to provide.

  The present invention also provides fine granules or granules obtained by granulating the above-mentioned controlled-release pharmaceutical composition and a preparation obtained by tableting them.

  The controlled-release pharmaceutical composition of the present invention can control the dissolution of tamsulosin or a pharmaceutically acceptable salt thereof without being limited by the amount of crystalline cellulose in the preparation.

  In addition, the granules or fine granules obtained by granulating the controlled release pharmaceutical composition of the present invention are spherical and have a small range of particle size distribution.

  Therefore, the tamsulosin preparation prepared by using the controlled-release pharmaceutical composition of the present invention or a fine or granulated product of the composition has excellent performance as a sustained-release preparation.

  The controlled-release pharmaceutical composition of the present invention (hereinafter referred to as “the composition of the present invention”) comprises tamsulosin or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “tamsulosin”), an inorganic acid or an organic acid or the like. It is prepared by adding one or more components selected from metal salts and a release control base.

  Tamsulosin used in the composition of the present invention is a compound whose chemical name is 5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide. As described above, it has an effect of improving dysuria. The pharmaceutically acceptable salt is preferably tamsulosin hydrochloride. The content of tamsulosin in the composition of the present invention is not particularly limited, but is about 0.1 to 1.0 mg in view of its medicinal effect. The other physiologically active substance is not particularly limited as long as it can be used as a medicine.

  Moreover, sulfuric acid, phosphoric acid, and nitric acid are mentioned as an inorganic acid among the inorganic acids or organic acids used for this invention composition. Examples of the organic acid include sulfuric acid, phosphoric acid, nitric acid, silicic acid, acetic acid, succinic acid, citric acid, and benzoic acid. Furthermore, examples of these metal salts include salts of alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum and the aforementioned inorganic acid or organic acid. The type and amount of these can be appropriately selected depending on the combination with other additives, the degree of sustained release of the target tamsulosin, etc., but phosphoric acid and silicic acid are preferred, and their metal salts are further Particularly preferred are calcium hydrogen phosphate and / or synthetic aluminum silicate. These contents in the composition of the present invention can be appropriately adjusted in accordance with the target degree of elution, but 0.001 to 0.9 parts by weight per 1 part by weight of the unit preparation of the final product. Preferably, 0.3 to 0.6 part by weight is more preferable.

Further, the release controlling base used in the composition of the present invention includes cellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate. Hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer, carboxymethylethylcellulose, ethylcellulose and the like. Among these release control bases, it is preferable to select and use a gastric or enteric one as appropriate, and it is particularly preferable to use an enteric release control base from the viewpoint of drug efficacy. Such enteric release control bases include methacrylic acid copolymer L, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxy Examples include methyl cellulose acetate succinate. These contents in the composition of the present invention can be appropriately adjusted depending on the type of the selected release control base, but are preferably 0.01 to 0.5 parts by weight with respect to 1 part by weight of the unit preparation of the final product. 0.05-0.3 weight part is more preferable.

  The composition of the present invention can be produced by adding various inert carriers that are usually used for pharmaceutical preparation to the above-mentioned components as long as the effects of the present invention are not impaired, if necessary, and mixing them according to a conventional method. can do. Examples of such inert carriers include celluloses such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, lactose, D-mannitol, corn starch, polyvinyl pyrrolidone, talc, Examples include magnesium stearate, hydrogenated oil, polyethylene glycol, titanium oxide, tar dye, and the like. These can be used alone or in combination. Among these inert carriers, celluloses are preferable, and crystalline cellulose is more preferable.

  The composition of the present invention thus obtained can be made into a solid preparation that can be administered orally without particular limitation, such as granules, fine granules, tablets, capsules and the like. Specifically, in the case of tablets and capsules, granules or fine granules are prepared in advance from the above composition and then compression-molded with other additives into tablets, or capsules are filled as capsules. It is preferable to do.

  To produce fine granules or granules from the above composition, stirring granulation, rolling fluidized bed granulation and the like can be used, but stirring granulation is more preferable. The fine particles or granules thus obtained are, for example, round with a roundness (ratio of major axis / minor axis of the sphere) of about 0.75 or more, preferably 0.8 or more, and a particle size of 0.8. The thickness is 2 to 2.0 mm, preferably 0.3 to 1.5 mm, and more preferably 0.5 to 1.0 mm. In addition, the particle size distribution of the fine granules or granules is uniform.

  Moreover, it is also possible to coat the granules using a coating agent as appropriate. The base of the coating agent varies depending on the purpose of use. For example, cellulose-based coating bases such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, ethylcellulose, methyl acrylate / methacrylic acid Examples thereof include acrylic coating bases such as methyl copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, and methacrylic acid copolymer LD.

  In the preparation of the composition of the present invention, other additives can be appropriately added for solubilization, stabilization, coloring, weight adjustment and the like. Examples of the additive that contributes to solubilization include polysorbate 80, sodium lauryl sulfate, and cyclodextrin. Examples of the additive that contributes to stabilization include ascorbic acid, tocophenol, butylhydroxyanisole, and the like. Furthermore, examples of the colorant include tar pigments, yellow iron sesquioxide, and iron sesquioxide. Still further, additives used for weight adjustment and the like include excipients, disintegrants, binders and the like. Examples of the excipient include lactose, sugar alcohols such as D-mannitol and D-mannitol, purified white sugar, corn starch, and potato starch. Examples of the disintegrant include partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, hydroxypropyl starch, crospovidone and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic, gelatin, and pullulan.

  The preparation thus obtained has sufficient sustained release properties because the composition of the present invention contains an inorganic acid or organic acid and a release controlling base. In particular, when the preparation of the present invention is made into fine granules or granules, the shape thereof is very close to a sphere as shown in an electron micrograph described later, and the width of the particle size distribution is small, so that the elution can be controlled. Excellent and lot-to-lot variation is prevented.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all to these Examples.

Example 1
0.5 g of 5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide hydrochloride (hereinafter referred to as “tamsulosin hydrochloride”) and crystalline cellulose 165.5 g, 191 g of calcium hydrogen phosphate, and 34.5 g of methacrylic acid copolymer LD (Eudragit L30D-55: manufactured by Rohm) were added and granulated with a stirring granulator. The obtained granules were dried with a fluid bed granulator. When the obtained granule was observed with an electron microscope, it had a spherical shape with a roundness of about 0.95.

Example 2
Fine particles were obtained under the same conditions as in Example 1 except that calcium hydrogen phosphate in Example 1 was changed to 51 g of calcium hydrogen phosphate and synthetic aluminum silicate was changed to 25.4 g. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Example 3
Fine particles were obtained under the same conditions as in Example 1 except that calcium hydrogen phosphate in Example 1 was changed to 19.2 g of calcium hydrogen phosphate and synthetic aluminum silicate to 57.2 g. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Example 4
Fine granules were obtained under the same conditions as in Example 1 except that the calcium hydrogen phosphate in Example 1 was changed to 12.8 g of calcium hydrogen phosphate and the synthetic aluminum silicate was changed to 63.6 g. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Example 5
Fine granules were obtained under the same conditions as in Example 1 except that the calcium hydrogen phosphate in Example 1 was changed to 4.8 g of calcium hydrogen phosphate and the synthetic aluminum silicate was changed to 71.6 g. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Example 6
Fine granules were obtained under the same conditions as in Example 1 except that calcium hydrogen phosphate in Example 1 was changed to 1.6 g calcium hydrogen phosphate and synthetic aluminum silicate to 74.8 g. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Example 7
Fine particles were obtained under the same conditions as in Example 1 except that the calcium hydrogen phosphate in Example 1 was changed to synthetic aluminum silicate. When the obtained fine particles were observed with an electron microscope, the roundness was almost the same as in Example 1.

Comparative Example 1
Fine granules were obtained under the same conditions as in Example 1 except that the calcium hydrogen phosphate in Example 1 was changed to low-substituted hydroxypropylcellulose.

Test example 1
The dissolution of the active substance in the preparation of the present invention was tested by the dissolution test method shown below. The results are shown in FIG.

(Dissolution test method)
In accordance with the Japanese Pharmacopoeia dissolution method No. 2 paddle method, tamsulosin hydrochloride corresponding to 0.2 mg was used as the active ingredient, the paddle rotation speed was 50 rpm, and the dissolution test solution (water) was 900 ml. In addition, the HPLC method was used for the detection method of tamsulosin hydrochloride. The operating conditions of the HPLC method are shown below.

(Operating conditions)
Detector: UV absorptiometer (225 nm)
Column: Octadeci as a packing material on stainless steel tube with inner diameter of about 3.0mm x length of 150mm
Rusilylated silica gel was packed.
Column temperature: 35 ° C
Mobile phase: 0.05 mol / L perchloric acid solution / acetonitrile mixture (7: 3)
Flow rate: About 0.5mL / min

(Result)
As shown in FIG. 1, the preparation of the present invention was able to control the elution time of tamsulosin hydrochloride by changing the ratio of calcium hydrogen phosphate and synthetic aluminum silicate in the preparation.

Test example 2
The particle size distribution of the granules obtained in each Example and Comparative Example was measured using 14 mesh (M), 20 mesh, 32 mesh and 42 mesh sieves. In addition, the measuring method was implemented according to the test method of the particle size of the formulation described in the 14th revision Japanese Pharmacopoeia. The results are shown in Table 1.

  From the results of this test, it was found that the preparation according to the present invention contained organic acid salt or inorganic salt in the preparation, so that it became spherical granules with a certain size, and the distribution was uniform in a certain particle size. It was.

Test example 3
The result of observation of the preparation of Example 1 with an electron microscope is shown in FIG. As a result, it was found that the preparation of Example 1 had a very clean spherical shape with a roundness of 0.95 and had a uniform particle size.

  Since the controlled-release pharmaceutical composition of the present invention can release tamsulosin gradually, a preparation obtained by using the tamsulosin can be effectively used for treatment of dysuria in prostatic hypertrophy.

FIG. 1 is a drawing showing the relationship between the tamsulosin hydrochloride time and dissolution rate of the preparations produced in Examples 1-7. FIG. 2 is an electron micrograph of the preparation produced in Example 1 (× 50). more than

Claims (8)

Tamsulosin or a pharmaceutically acceptable salt thereof; one or more components selected from inorganic acids or organic acids selected from sulfuric acid, phosphoric acid, nitric acid, silicic acid, acetic acid, succinic acid, citric acid, and benzoic acid, or metal salts thereof; And cellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate , Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer, Carboxymethyl include controlled release base selected from methyl cellulose and ethyl cellulose; and, controlled release pharmaceutical composition characterized in that it consists of granules or granules formed by the agitation granulation method or tumbling fluidized granulation method . The controlled release pharmaceutical composition according to claim 1 , wherein the metal salt of the inorganic acid or organic acid is a metal salt selected from alkali metals, alkaline earth metals, and aluminum. The controlled-release pharmaceutical composition according to claim 1 or 2 , further comprising a cellulosic additive. The controlled-release pharmaceutical composition according to claim 3 , wherein the cellulosic additive is crystalline cellulose.   The controlled release pharmaceutical composition according to claim 1, wherein the inorganic acid is phosphoric acid or silicic acid. 6. The controlled-release pharmaceutical composition according to any one of claims 1 to 5, comprising fine granules or granules having a particle size of 0.5 to 2.0 mm. The controlled-release pharmaceutical composition according to any one of claims 1 to 6, comprising fine particles or granules having a roundness of 0.75 or more. Tamsulosin or a pharmaceutically acceptable salt thereof; one or more components selected from inorganic acids or organic acids selected from sulfuric acid, phosphoric acid, nitric acid, silicic acid, acetic acid, succinic acid, citric acid, and benzoic acid, or metal salts thereof; And cellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate , Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer, Carboxymethyl include controlled release base selected from methyl cellulose and ethyl cellulose; and, preparations of fine granules or granules formed by the agitation granulation method or tumbling fluidized granulation method in tabletting.