KR100714058B1 - Extended-releasing composition for oral administration of tolterodine l-tartrate and the process thereof - Google Patents

Abstract

The present invention relates to a sustained release oral composition of tolterodine L-tartrate which is a therapeutic agent for urinary incontinence, and a method for preparing the same. A primary drug release control layer was prepared by coating a mixture containing SR 30D (polyvinylacetate 30% aqueous dispersion, BASF), hydroxypropylmethylcellulose as a binder, and propylene glycol as a plasticizer. Multi-layer coating technique for preparing a secondary drug release control layer by coating a mixture comprising a colicoat SR 30D with a sustained release coating polymer, hydroxypropylmethylcellulose as a binder and propylene glycol as a plasticizer to control the release of the active ingredient to the core It relates to a sustained release oral composition of tolterodine L-tin salt and a method for preparing the same.

Urinary incontinence drug, Tolterodine L-Tartrate, sustained release, primary drug release control layer, secondary drug release control

Description

Extended-releasing composition for oral administration of Tolterodine L-tartrate and the process approximately}

Figure 1 shows a cross section of the primary and secondary drug release control layer according to the present invention.

FIG. 2 is a graph showing dissolution test results of tolterodine-l-tartrate preparations prepared according to Examples 1 and 2 and Comparative Examples 1 to 3 and 4 milligrams of ditrusitol SR capsules on the market.

The present invention relates to a sustained release oral composition of tolterodine L-tartrate and a method for preparing the same, and more particularly, to the active ingredient tolterodine L-tartrate, a sustained release coating polymer in a sugar sphere with an inert core. Low colicoat SR 30D, a mixture of hydroxypropylmethylcellulose as a binder, propylene glycol as a plasticizer to prepare a primary drug release control layer, a sustained release coating polymer colicoat SR 30D, hydroxypropylmethylcellulose as a binder, Sustained release oral composition of tolterodine L-tartrate with easy side effect and reduced side effects such as dry mouth by applying a multi-layer coating technique to re-coat a mixture of propylene glycol as a plasticizer on the primary drug release control layer It is about a method.

Tolterodine [(R) -N, N-diisopropyl-3- (2-hydroxy-5methylphenyl) -3-phenylpropanamine], an antagonist of the muscarinic receptor, is used for urinary incontinence and unstable or excessively activated bladder It is an important drug used to treat other symptoms. As is known so far, tolterodine L-tartrate and its active metabolite, 5-hydroxymethyl derivative of tolterodine, show side effects of dry mouth. For the preparation of tolterodine released immediately, the film-coated tablet contains 2 milligrams of tolterodine el-tartrate and the recommended dose is 2 milligrams twice daily. If the patient's dose and dose are not constant, the side effects of dry mouth appear.

Thus, sustained controlled release of tolterodine L-tartrate substantially reduces the peak serum levels of tolterodine L-tartrate and 5-hydroxymethyl, the active substance of tolterodine, while maintaining the desired effect on the bladder. Side effects such as dry mouth can be reduced when the release tablet is used in the same total dose for the same time. It is also reported that the dose of tolterodine tartrate can be increased to increase the effect on the bladder for certain acceptable side effects levels. Therefore, many studies are underway to obtain sustained-release tolterodine L-tartrate preparations with release control action.

Korean Patent Publication No. 2001-0075695 discloses an active ingredient covering (i) a core unit of water-insoluble or water-inert inert material, (ii) a first layer of a water-insoluble polymer on the core unit, and (iii) a first layer. To a second layer and (iv) a controlled release form comprising a third layer of polymer effective to control the release of the active ingredient on the second layer. In other words, in actual production, the work process is complicated and takes a lot of time.

Similarly, U. S. Patent No. 5,783, 215 describes (i) a core unit of soluble or water insoluble inert material, (ii) a first layer on a core unit comprising an active ingredient dispersed in a hydrophilic polymer, and (iii) a first layer. A multi-coating technique has been developed to avoid the interaction of the polymer of the drug-containing layer with the release controlling layer of the active ingredient in a form comprising a second layer of covering hydrophilic polymer and (iv) a third layer effective to control the release of the active ingredient. . However, this also has the disadvantage of the complexity of the work process as described above.

Therefore, the present inventors compared with the conventional formulation using a triple multiple coating technique to provide a delayed release formulation instead of sacrificing the convenience and economy of the process, the primary drug release control containing the active ingredient tolterodine L-Tartrate After the layer is prepared, the second drug release control layer is prepared using a sustained release coating polymer such as the first drug release control layer, which satisfies the process convenience, economy, side effects reduction, and drug compliance. The long-lasting tolterodine L-tartrate formulation can be provided, thus completing the present invention.

The present invention relates to a sustained release oral composition of tolterodine L-tartrate, which is a therapeutic agent for urinary incontinence, and a method for preparing the same, which reduces side effects such as dry mouth of tolterodine L-tartrate, which is immediately released, Sustained release oral composition of tolterodine L-tartrate, which is easy to manufacture by using multi-layer coating method and maintains uniformity of active ingredient by increasing the compliance with medications due to the decrease of the number of times, and the preparation method To provide that purpose.

According to a suitable embodiment of the present invention, an active ingredient which is tolterodine L-tartrate; An inert core which is at least one compound selected from sugaspeare, sugar, calcium dihydrogen phosphate dihydrate and microcrystalline cellulose; At least one compound selected from collicoat SR 30D as a sustained release coating polymer, hydroxypropylmethylcellulose as a binder, polyethylene glycol as a plasticizer, trialkyl citrate, dialkyl sebacate, triacetin, castor oil and glycerol fatty acid derivatives Provided is a sustained release oral composition of tolterodine L-tartrate consisting of a primary and secondary drug release control layer comprising a.

According to another suitable embodiment of the present invention, the inert core may be used 20 to 40 parts by weight of the shoe gas pier relative to the weight of the active ingredient.

According to another suitable embodiment of the present invention, the primary drug release control layer has 5 to 40 parts by weight of colicoat SR 30D, 0.3 to 1 part by weight of hydroxypropylmethylcellulose, and 0.1 to 1 part by weight of the plasticizer relative to the weight of the active ingredient. May be included.

According to another suitable embodiment of the present invention, 2 to 30 parts by weight of the coli coat SR 30D, 0.05 to 0.5 parts by weight of hydroxypropylmethylcellulose, 0.1 to 0.5 parts by weight of the plasticizer in the secondary drug release control layer May be included.

According to another suitable embodiment of the present invention, the plasticizer may be used propylene glycol.

The long-term oral sustained-release composition of tolterodine L-tartrate of the present invention uses tolterodine L-tartrate as an active ingredient, and tocopherol SR 30D as tolterodine L-tartrate and sustained release coating polymer in an inert core sugas peer. , By coating a mixed solution containing hydroxypropyl methyl cellulose as a binder, propylene glycol as a plasticizer to prepare a first drug release control layer, and again to control the release of the active ingredient Colicoat SR 30D with a sustained release coating polymer, binding It is characterized in that it is prepared by using a multi-layer coating technique for coating a mixture comprising hydroxypropyl methyl cellulose, propylene glycol as a plasticizer to the primary drug release control layer.

The primary drug release control layer of the tolterodine L-tartrate composition according to the present invention is 20 to 40 parts by weight of the inert core sugaspear relative to the weight of the active ingredient, 5 to 40 parts by weight of Colicoat SR 30D with a sustained release coating polymer, 0.3 to 1 part by weight of zero hydroxypropylmethylcellulose, and 0.1 to 1 part by weight of propylene glycol as a plasticizer.

The inert core may be a known common core material such as sugar gas pier, sugar, calcium dihydrogen phosphate dihydrate (trade name: Di-tab), microcrystalline cellulose (trade name: vivapur) and the like. In the present invention, "core" has a meaning encompassing known core materials unless specifically limited. Moreover, although it is not specifically limited, Sugas peer can be used suitably as the core of this invention. When the gas is less than 20 parts by weight with respect to the active ingredient in the composition according to the present invention, less gas is less than the amount of coating, so that the loss of solid content is increased, and when the content is more than 40 parts by weight, the uniformity of the drug contained is lowered and sustained release is achieved. Becomes difficult.

The primary drug release control layer surrounds the core in the form of a mixture of the drug and the primary release modulator, and primarily controls the release of the active ingredient. If the amount of Colicoat SR 30D used as the primary release controlling agent is less than 5 parts by weight of the active ingredient, it is impossible to control the sustained release of the active ingredient. If it exceeds 40 parts by weight, the release of the active ingredient is lowered below the elution standard. It becomes.

When less than 0.3 parts by weight of the hydroxypropyl methyl cellulose used as the binder is used, the amount of solids in the coating liquid coated on the inert core is large, and thus the drug content is decreased and the sustained release is difficult. When the amount of solids loss is not large compared to the case where 0.3 to 5 parts by weight is used, and the content of the water-soluble polymer is increased, the sustained release control is impossible.

Propylene glycol, a plasticizer, is less than 0.1 parts by weight of the active ingredient is hardened to form a film formed during the fluidization process may not be controlled to sustained release, when used in excess of 1 parts by weight is difficult to form a film.

The secondary drug release control layer of the tolterodine L-tartrate composition according to the present invention is 2 to 30 parts by weight of colicoat SR 30D with a sustained release coating polymer relative to the weight of the active ingredient, and 0.05 to 0.5 parts by weight of hydroxypropyl methyl cellulose as a binder. , Characterized in that it comprises 0.1 to 0.5 parts by weight of propylene glycol as a plasticizer.

When Colicoat SR 30D, the secondary release regulator of the secondary drug release control layer, is used in an amount of less than 2.5 parts by weight or more than 30 parts by weight, the degree of release of the active ingredient does not meet a certain dissolution standard.

The plasticizers used in the primary drug release control layer and the secondary drug release control layer are pharmaceuticals such as polyethylene glycol, trialkyl citrate, dialkyl sebacate, triacetin, castor oil, glycerol fatty acid derivatives, etc., in addition to propylene glycol. It can be mentioned as a plasticizer which can be used.

In the present invention, by using the sustained-release oral administration of the tolterodine L- tartrate salt can be formulated by a pharmaceutical method by mixing the essential components and other pharmaceutical additives containing the drug according to a conventional method. . The oral administration of tolterodine L-tartrate salt of the present invention may in particular have a formulation of a capsule.

The sustained release oral composition of tolterodine L-tartrate of the present invention has a uniform particle size distribution of the obtained particles and thus a small dissolution rate variation of the individual particles. In addition, the sustained release oral composition of the present invention can be controlled in a variety of forms in the desired form because the release of the drug is controlled in multiple layers through the first drug release control layer and the second release control layer, in particular the first and second release By changing the composition ratio of the regulator, the dissolution rate can be appropriately adjusted as necessary.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

Example 1

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine L-tartrate, was dissolved in 750 g of purified water. Subsequently, 200 g of colicoat SR 30D with a sustained release coating polymer, 6 g of hydroxypropylmethylcellulose as a binder, 6 g of propylene glycol as a plasticizer, and 7.25 g of talc as a lubricant were added to prepare a coating solution, which was then coated on a shoe gas pier. To prepare. However, operating conditions of the fluidized bed coater are shown in Table 1 below.

Inlet air temperature 55 ℃ Product bed temperature 41 ℃ Feeding rate 3 g / min Air flap 20% Spray nozzle pressure 1.0 bar Spray nozzle diameter 0.8 mm Dispersion plate type C type

Secondary Drug Release Control Layer

50 g of colicoat SR 30D with sustained-release coating polymer, 0.63 g of hydroxypropylmethylcellulose as a binder, 1.5 g of propylene glycol as a plasticizer and 1.38 g of talc as a lubricant were added to 62.5 g of purified water to prepare a solution. Re-coating to the coated Suga Spear to prepare a torrerodine L-tartrate sustained release oral composition having a second drug release control layer (see Figure 1). However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Example 2

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine L-tartrate, was dissolved in 750 g of purified water. Then, 75 g of Colicoat SR 30D with sustained-release coating polymer, 6 g of hydroxypropylmethylcellulose as a binder, 6 g of propylene glycol as a plasticizer, and 7.25 g of talc as a lubricant were added to prepare a coating solution, which was then coated on a shoe gas pier. To prepare. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Secondary Drug Release Control Layer

In the Sugasphere coated with the first drug release control layer, 50 g of Colicoat SR 30D as a sustained release coating polymer, 0.63 g of hydroxypropylmethylcellulose as a binder, 1.5 g of propylene glycol as a plasticizer, and 1.38 g of talc as a lubricant, 62.5 g of purified water. A tolerated sustained-release oral dosage composition of tolterodine L-tartrate was prepared by coating with a solution added thereto. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 1

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine el-tartrate, was dissolved in 750 g of purified water, and then 300 g of colicoat SR 30D with a sustained release coating polymer, 7.8 g of hydroxypropylmethylcellulose as a binder, and propylene as a plasticizer. 7.8 g of glycol and 9.3 g of talc are added to the lubricant to prepare a coating solution, which is then coated on a shoe gas pier to prepare a primary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Secondary Drug Release Control Layer

In the Sugas peer coated with the first drug release control layer, 50 g of colicoat SR 30D with a sustained release coating polymer, 0.63 g of hydroxypropylmethylcellulose as a binder, 1.5 g of propylene glycol as a plasticizer, 1.38 g of talc as a lubricant, and 62.5 g of purified water The composition was prepared by coating with a solution added to the secondary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 2

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine L-tartrate, was dissolved in 750 g of purified water, followed by 200 g of colicoat SR 30D as a sustained release coating polymer, 6 g of hydroxypropylmethylcellulose as a binder, and propylene glycol as a plasticizer. 6g, 7.25g of talc is added to the lubricant to prepare a coating solution, which is then coated on a Suga Spear to prepare a primary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 below.

Secondary Drug Release Control Layer

In the Sugasphere coated with the first drug release control layer, 100 g of colicoat SR 30D with sustained release coating polymer, 1.25 g of hydroxypropylmethylcellulose as binder, 3.0 g of propylene glycol as a plasticizer and 2.75 g of talc as a lubricant were added to 125 g of purified water. Coating with the added solution to prepare a composition with a second drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 3

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine L-tartrate, was dissolved in 750 g of purified water, followed by 200 g of colicoat SR 30D as a sustained release coating polymer, 6 g of hydroxypropylmethylcellulose as a binder, and propylene glycol as a plasticizer. 6g, 7.25g of talc is added to the lubricant to prepare a coating solution, which is then coated on a Suga Spear to prepare a primary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Secondary Drug Release Control Layer

In the Sugasphere coated with the first drug release control layer, 150 g of Colicoat SR 30D as a sustained release coating polymer, 1.87 g of hydroxypropylmethylcellulose as a binder, 4.5 g of propylene glycol as a plasticizer and 4.1 g of talc as a lubricant were added to 200 g of purified water. Coating with the added solution to prepare a composition with a second drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 4

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine el-tartrate, was dissolved in 750 g of purified water, and then 75 g of colicoat SR 30D with a sustained release coating polymer, 6 g of hydroxypropylmethylcellulose as a binder, and propylene glycol as a plasticizer. 6g, 7.25g of talc is added to the lubricant to prepare a coating solution, which is then coated on a Suga Spear to prepare a primary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Secondary Drug Release Control Layer

In the Sugasphere coated with the first drug release control layer, 100 g of colicoat SR 30D with sustained release coating polymer, 1.25 g of hydroxypropylmethylcellulose as binder, 3.0 g of propylene glycol as a plasticizer and 2.75 g of talc as a lubricant were added to 125 g of purified water. Coating with the added solution to prepare a composition with a second drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 5

Primary Drug Release Control Layer  Produce

After 325 g of Sugaspeare was fluidized in a fluidized bed coater, 10 g of the main component, tolterodine el-tartrate, was dissolved in 750 g of purified water, and then 300 g of colicoat SR 30D with a sustained release coating polymer, 7.8 g of hydroxypropylmethylcellulose as a binder, and propylene as a plasticizer. 7.8 g of glycol and 9.3 g of talc are added to the lubricant to prepare a coating solution, which is then coated on a shoe gas pier to prepare a primary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Secondary Drug Release Control Layer

In the Sugasphere coated with the first drug release control layer, 25 g of Colicoat SR 30D as a sustained release coating polymer, 0.63 g of hydroxypropylmethylcellulose as a binder, 1.5 g of propylene glycol as a plasticizer and 1.38 g of talc as a lubricant, 62.5 g of purified water The composition was prepared by coating with a solution added to the secondary drug release control layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Comparative Example 6

A 4 mg gram (tolterodine el stannate, 4 mg gram) formulation of a commercially available Pharmacia ditrusitol SR capsule was prepared.

Test Example

The dissolution test of tolterodine L-tartrate preparation prepared according to Examples 1 and 2 and Comparative Examples 1 to 5, and Comparative Example 6 was carried out under the following operating conditions, and the results are shown in Table 2. It was.

Dissolution test method: Korean Pharmacopoeia 2

Eluent: pH 6.8 phosphate buffer

Eluent temperature: 37 ℃

Speed: 100 rpm

Analysis conditions: liquid chromatograph method

Hours (hr) Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 6 0.5 10.9% 14.3%  4.5%  7.4%  3.4%  9.8% One 15.3% 18.9% 9.8% 13.4%  6.4% 16.8% 2 35.1% 39.4% 20.6% 23.2% 15.6% 38.9% 3 57.5% 65.7% 41.3% 45.3% 24.6% 61.3% 4 78.6% 83.5% 58.6% 57.6% 32.4% 80.4% 5 86.9% 91.3% 68.9% 71.5% 40.9% 89.6% 6 93.1% 94.5% 76.8% 79.4% 50.9% 94.1% 7 94.6% 96.4% 81.4% 83.2% 58.9% 97.2%

The present invention is to prepare a primary drug release control layer by coating a mixed solution containing collicoat SR 30D, hydroxypropyl cellulose, propylene glycol with a sustained release coating polymer and tolterodine el-tartrate on the inert core Shugaspeare Re-coated with a mixed solution containing Colicoat SR 30D, hydroxypropyl cellulose, and propylene glycol with a sustained release coating polymer, the sustained release of tolterodine L-tartrate formed with a primary drug release control layer and a secondary drug release control layer By preparing a type oral administration composition, a preparation that can be taken once daily can be provided, which is convenient to take, reduces side effects such as dry mouth, and tolterodine el-tin that satisfies the convenience of the process and uniformity of the product. Provided is a sustained release oral composition of an acid salt. In addition, the tolterodine L-tartrate oral administration composition of the present invention has an excellent effect as a sustained release formulation since the active ingredient is released in close proximity to the zero-order.

Claims (5)

Active ingredient which is tolterodine L-tartrate; An inert core which is at least one compound selected from sugaspeare, sugar, calcium dihydrogen phosphate dihydrate and microcrystalline cellulose; Sustained release oral administration of tolterodine L-tartrate with primary and secondary drug release control layers comprising 30% aqueous polyvinylacetate as a sustained release coating polymer, hydroxypropylmethylcellulose as a binder, and propylene glycol as a plasticizer Composition. The sustained-release oral dosage composition of tolterodine L-tartrate according to claim 1, wherein the inert core is 325 parts by weight of Sugaspear with respect to 10 parts by weight of the active ingredient. According to claim 1, wherein the first drug release control layer comprises 200 parts by weight of polyvinylacetate 30% aqueous dispersion 200 or 75 parts by weight, 6 parts by weight of hydroxypropyl methyl cellulose, 6 parts by weight of propylene glycol based on 10 parts by weight of the active ingredient Sustained release oral composition of tolterodine L-tartrate, characterized in that. According to claim 1, wherein the secondary drug release control layer comprises 50 parts by weight of 30% aqueous polyvinyl acetate, 0.63 parts by weight of hydroxypropyl methyl cellulose, 1.5 parts by weight of propylene glycol based on 10 parts by weight of the active ingredient Sustained release oral composition of tolterodine L-tartrate. delete

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