KR100592512B1 - Extended Release Formulation of Tamsulosin or Pharmaceutically Acceptable Salt for Treating Evacuatory Insufficiency - Google Patents

Abstract

The present invention relates to a therapeutic agent for sustained-release urination disorder comprising tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient, the present invention relates to an agent for controlling the dissolution of the drug including an acrylate polymer or copolymer and poloxamers Sustained release urination disorder treatment comprising, and

A primary release control system comprising tamsulosin or a pharmaceutically acceptable salt thereof, and a primary dissolution control agent for the drug, including acrylate polymers (including copolymers) and poloxamers; And a method for preparing a sustained-release urination disorder comprising a secondary release control system by coating the primary release control system with a coating solution including at least a secondary dissolution control agent and a method of manufacturing the same.

The therapeutic agent according to the composition of the present invention is simple to manufacture, and in the case of coating after granulating the therapeutic agent of the present invention, it is possible to precisely control the initial release pattern by adjusting the amount of coating.

Description

Extended release formulation of Tamsulosin or Pharmaceutically Acceptable Salt for Treating Evacuatory Insufficiency

The present invention relates to a therapeutic agent for sustained-release urination disorder containing tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient, and more particularly, to a sustained-release type and a solid dispersion prepared simply by spray drying. In addition, the present invention relates to a therapeutic agent for sustained-release urination disorder in which the initial release pattern is precisely controlled by granulating and coating such a solid dispersion, and a method of manufacturing the same.

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.

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. Intensive bladder contraction increases bladder internal pressure and compresses the mucous membranes between the thick muscle fibers, making it difficult to drain urine during urination. 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 in the urethra and prostate, and reduces the prostate pressure in the urethral pressure curve It is widely used as an excellent agent for improving urination disorders caused by enlarged prostate [see; UROLOGY 58 (Suppl 6A): 42-48, 2001].

Korean Laid-Open Patent Publication 2002-0016944 treats tamsulosin or a pharmaceutically acceptable salt thereof as an active ingredient as a therapeutic agent for lower urinary tract disease. Lower urinary tractosis is a symptom of urination disorder following the functional obstruction of the lower urinary tract of men and women. Urinary tract is also included. 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. Already a day of Yamanouchi Pharmaceuticals ^? Capsules (0.2 mg as tamsulosin hydrochloride) and FLOMAX ^™ capsules (0.4 mg as tamsulosin hydrochloride) from Boehringer Ingelheim are commercially available in a sustained release formulation administered once daily.

Korean Patent Laid-Open Publication Nos. 86-0006984, 02-0016944 and Japanese Patent Laid-Open No. 62-9 introduce the preparation of a sustained release preparation of tamsulosin hydrochloride. According to this, crystalline cellulose is used as the unit forming material, and water-insoluble high molecular materials such as acrylic acid polymers or copolymers or cellulose derivatives used in the form of an aqueous suspension, an aqueous emulsifier, and an aqueous organic solvent solution. Commercially available are Eudragit L30D-55 (methacrylic acid copolymer LD), Eudragit E30D (ethyl acrylate methyl methacrylate copolymer emulsion), Aquacoat ECD-30 (ethylcellulose aqueous) A method for producing granules by centrifugal fluid granulator, filling a capsule into capsules, and the like to form a capsule is disclosed. However, the above-mentioned formulations have a high release amount of the initial drug, while the release pattern is low after 4 to 5 hours, and thus very difficult to control release.

It is an object of the present invention to provide a therapeutic agent for urination disorders which is simply produced by spray drying as a sustained release type.

Another object of the present invention is to provide a therapeutic agent for treating urination disorder by precisely controlling the release pattern even after the initial and 4 to 5 hours by performing coating after granulating the urination disorder treatment agent and adjusting the amount of the coating.

It is still another object of the present invention to provide a method for preparing a therapeutic agent for urination disorder of a granule formulation having a controlled release pattern.

The therapeutic agent for sustained-release urination disorder of the first aspect of the present invention for achieving the above object includes tamsulosin or a pharmaceutically acceptable salt thereof, and an acrylate polymer (copolymer) as a dissolution control agent of the drug. The same) or a cellulose derivative alone or in combination of two or more thereof, and a treatment for sustained-release urination disorder comprising poloxamers.

The treatment for sustained-release urination disorder according to the second aspect of the present invention includes tamsulosin or a pharmaceutically acceptable salt thereof, an acrylate polymer and a cellulose derivative alone or a mixture of two or more thereof, as a dissolution control agent of the drug, and poloxa A primary emission control system comprising a head; The primary release control system is coated with a coating solution containing at least a secondary dissolution control agent to include a sustained release urination disorder treatment consisting of a secondary release control system.

The present invention also includes a method for preparing a sustained-release urination disorder treatment comprising the following steps.

(a) a primary dissolution control agent for the drug, including tamsulosin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable acrylate polymer and a cellulose derivative alone or in combination of two or more thereof, and poloxamers Spray-dissolving in a suitable solvent;

(b) adding an excipient and a binder to the spray dried mixture to granulate; And

(c) coating the granules with a coating solution in which at least a secondary dissolution control agent is dissolved in a suitable solvent

Hereinafter will be described in detail a sustained-release urination disorder treatment agent according to the first aspect of the present invention.

Tamsulosin or a pharmaceutically acceptable salt thereof, preferably hydrochloride (tamsulosin hydrochloride), is added within a range of safe amounts that do not cause adverse effects on the human body. For example, the recommended daily dosage disclosed in Korean Patent Laid-Open No. 2001-53221 is disclosed.

Acrylate polymers that can be used as elution control agents are currently commercially available, for example, polymethacrylate methylmethacrylate copolymer (trade name: Eudragit L-100), polyethylacrylate methylmethacrylate trimethylammonio Ethyl methacrylate chloride copolymer (trade name: Eudragit RL-100, RS-100), polymethacrylate ethyl acrylate copolymer (trade name: Eudragit L30D-55), ethyl acrylate methyl methacrylate trimethyl Copolymer of ammonioethyl methacrylate chloride (trade name: Eudragit RL30D), copolymer of ethyl acrylate methylmethacrylate trimethyl ammonioethyl methacrylate chloride (trade name: Eudragit RS30D), polyethylacrylate Methylmethacrylate copolymer (trade name Eudragit NE30D).

Examples of cellulose derivatives include ethylcellulose's aqueous suspending agent (trade name: Aquacoat ECD-30, Surrelease), AnyCoat and the like.

Poloxamers as elution control agents are α-hydro-ω-hydroxypoly (oxyethylene) poly (oxypropylene) poly (oxyethylene) block copolymers as a series of block copolymers of ethylene oxide and propylene oxide. More generally poloxamers are already known as polyethylene-propylene glycol copolymers or polyoxyethylene-polyoxypropylene copolymers.

The poloxamers used in the present invention preferably contain 60 to 90% by weight of polyoxyethylene part, more preferably 70 to 80% by weight. The polyoxyethylene fraction is hydrophilic, while the polyoxypropylene fraction is hydrophobic. All poloxamers are chemically similar in composition, but differ only in the relative amounts of propylene oxide and ethylene oxide in the structure.

Particularly usable materials for the present invention are poloxamer 188, poloxamer 124, poloxamer 237, poloxamer 338, poloxamer 407, and the like, more preferably poloxamer 188. More detailed information on poloxamers can be obtained from the technical data sheet provided by BASF (Ireland).

Such dissolution control agents may be provided in the form of a powder, an aqueous suspension, an aqueous emulsion, or a solvent in a hydrous organic solvent solution.

When added in powder form, it does not require special limitation, but is preferably added in an amount of 30 wt% or less, and in the form of an aqueous liquid, it does not require special limitation, but is preferably added in an amount of 50 to 150 wt% or less.

Also in the case of an aqueous suspension, preferably 2 to 5% by weight of polyethylene glycol, propylene glycol, glycerol, dimethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citric acid Salts, triacetin, castor oil and the like are added.

The composition ratio of the acrylate polymer and the cellulose derivative alone or two or more mixed components and poloxamers added as the dissolution control agent does not require special limitation, but is preferably from 10: 1 to 3, more preferably from 10: 1. The weight ratio of.

The method for preparing a sustained-release urination disorder treatment according to the first aspect of the present invention may be used a conventional method using a spray dryer. Examples of specific manufacturing processes are as follows. first,

(1) Preparation of Solution A

Tamsulosin hydrochloride is dissolved in a suitable organic solvent. The organic solvent is not particularly limited as long as it can dissolve tamsulosin hydrochloride. Examples are water, ethanol and a mixed solvent of water and ethanol.

(2) Preparation of Solution B

As the elution control agent, a mixture ratio of an acrylate copolymer (e.g., at least one component selected from Eudragit L-100, Eudragit RS-100, or RL-100) and poloxamers (e.g. poloxamer 188) is preferably used. 10: 1-3, More preferably, it is made into the weight ratio of 10: 1, and is made to melt | dissolve in a suitable organic solvent. At this time, examples of the organic solvent that can be used may be composed of a single component or a mixed solvent of two or more components, such as ethanol, acetone, dichloromethane.

(3) Preparation of Solid Dispersion

When the solution A and the solution B are mixed, the content of the total solvent is preferably about 100 to 150 when the weight of tamsulosin hydrochloride is 1. Then, the solution is spray-dried under the conditions of 55 ~ 60 ℃ using a conventional spray dryer to prepare a primary controlled release fine particles.

The solid dispersion according to the first aspect of the invention may then be formulated into any formulation such as injections, powders, granules, tablets, suppositories, and the like.

Hereinafter, the treatment for sustained-release urination disorder according to the second aspect of the present invention will be described in detail.

The therapeutic agent according to the second aspect of the present invention is based on the case of formulating the therapeutic agent according to the first aspect into granules. In formulating granules, various excipients (e.g., CMC, calcium phosphate, lactose, etc.) which are commonly added pharmaceutically, and various binders (e.g., polyvinylpyrrolidone (PVP), methylcellulose, ethylcellulose At least one component selected from the group of cellulose derivatives including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, alginic acid, sodium alginate, acacia, guar gum, polymethacrylate, and gelatin aqueous solution). .

Once manufactured into granules, a two-step release control system is implemented in which the granules are coated with a coating liquid containing a secondary dissolution control agent as a main component.

The secondary dissolution control agent may be used alone or a mixture of two or more of the acrylate polymer and cellulose derivative. Thus, polymethacrylate methyl methacrylate copolymer (trade name: Eudragit L-100), polyethyl acrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (trade name: Eudragit RL-100 , RS-100), polymethacrylate ethyl acrylate copolymer (trade name: Eudragit L30D-55), copolymer of ethyl acrylate methyl methacrylate trimethylammonioethyl methacrylate chloride (trade name: Eudragit RL30D), copolymer of ethyl acrylate methyl methacrylate trimethylammonioethyl methacrylate chloride (trade name: Eudragit RS30D), polyethyl acrylate methyl methacrylate copolymer (trade name: Eudragit NE30D), ethyl Single or two or more selected from cellulose aqueous suspending agents (trade name: Aquacoat ECD-30, Surrelease), any coat, etc. Contains mixed ingredients.

The secondary dissolution control agent constituting the coating layer is preferably to include 10 to 100 when the weight of the drug to 1. The reason for this is that when the secondary dissolution control agent is added below 10, the initial release may be high, and when the secondary dissolution control agent is added above 100, the dissolution rate may be lowered. It should be noted that not.

In addition, the coating solution may further include a fatty acid for accurate release control. Examples of such fats may include at least one component in fatty alcohols, fatty acid esters or waxes.

Examples of the alcohol include cetyl alcohol and cetostearyl alcohol.

Fatty acid esters include fatty acid glycerol (trade name: Plesyrol ATO5, Completol 888 ATO, company name: Katte Bonded).

Waxes include Bee wax, Carnauba wax and the like.

The fats are preferably included when the weight of the drug is 1 to about 1 to 20.

Preferably, the secondary dissolution inhibitor and the fats are formed in a ratio of 10: 1 to 3.

The solvent for forming the coating liquid is not limited to a particular kind as long as it is sufficient to dissolve the acrylate copolymer and the fatty acids. Examples of such an organic solvent may be composed of a single component or a mixed solvent of two or more components from ethanol, acetone, dichloromethane and the like.

The coating process is carried out using a known fluidized bed spray coating machine for the coating liquid prepared as described above. The sprayer can use either a bottom spray system or a top spray system, and specific operating conditions are as described in the following examples.

Hereinafter, the content of the present invention will be described in more detail with reference to Examples. However, these examples are only presented to understand the content of the present invention, and the scope of the present invention should not be construed as being limited to these embodiments.

<Example 1>

1 g of tamsulosin hydrochloride was dissolved in 200 ml of ethanol, a mixture of 100 g of Eudragit L-100 or RL and 10 g of poloxamer 188 was dissolved in 500 ml of ethanol and mixed with each other.

The above liquid mixture was spray dried to obtain a solid dispersion in the form of fine powder particles. 100 g of solid dispersion was taken and mixed with 540 g of CMC and 60 g of lactose as excipients, and 900 ml of 5% gelatin aqueous solution was mixed with a binder to prepare granules and air-dried.

To prepare a coating solution 900ml of Table 1 and coating the granules 500g with a fluid bed spray coating machine (Fluid Bed Coating Machine: GLATT, Germany) having the operating conditions of Table 2.

TABLE 1 Coating Composition

menstruum ethanol ingredient Eudragit RL-100 10% by weight, cetyl alcohol 2% by weight, triacetin 2% by weight

<Table 2> Operating Conditions of Fluidized Bed Spray Coating Machine

Device name GPCG-1 Equipment condition type Bottom spray Temperature Inlet: 55-60 ° C. Product: 35-40 ° C. Outlet: 33-38 ° C. Pump speed 7-10 ml / min pressure Nozzle: 2.5 bar Exhaust air flap-25 to 30%

<Example 2>

500 g of CMC was mixed with 100 g of the solid dispersion prepared in Example 1, granules were prepared in 1000 ml of a 5% PVP aqueous solution as a binder, and air-dried.

Granules prepared by the above process using No. 14 and No. 35 sieves were sized and selected into three parts as follows.

[A]: Pass through sieve 14 and remain in sieve 35. Medium

[B]: what remains in No. 14 sieve. .... biggest size

[C]: Passed through No. 35 sieve. .... the smallest size

300 g of granules [A] of the granules thus prepared and screened were subjected to fluidized bed spray coating with 240 ml of the coating solution of Example 1.

<Example 3>

300 g of [A] granules of Example 2 were subjected to fluidized bed spray coating with 480 ml of the coating solution of Example 1.

<Example 4>

200 g of [B] granules of Example 2 were taken and fluidized bed spray coating was performed with 360 ml of the coating solution of Example 1.

Example 5

200 g of [C] granules of Example 2 were taken and fluidized bed spray coating was performed with 240 ml of the coating solution of Example 1.

<Example 6>

200 g of [C] granules of Example 2 were subjected to fluidized bed spray coating with 360 ml of the coating solution of Example 1.

Example 7 Preparation of Sustained-Release Tablet

50 g of the solid dispersion of Example 1 and 250 g of CMC were mixed, and then 500 ml of a 5% PVP aqueous solution was mixed as a binder to prepare granules, and then a fluidized bed spray coating was performed with 500 ml of the coating solution of Table 3 below.

TABLE 3 Coating Composition

menstruum ethanol ingredient Eudragit RL-100 10% by weight, cetyl alcohol 2% by weight

100 g of the coated granules were weighed to equally mix 24.5 g of CMC-Ca and 500 mg of magnesium stearate to prepare a tablet with a tablet press.

The tablet obtained by the above process contains 0.2 mg of tamsulosin per tablet when the tablet weight is 250 mg per tablet.

Evaluation of the coated granules and tablets prepared under the above conditions was carried out through the dissolution test disclosed in the following experimental example.

Experimental Example Dissolution Test

About 200-250 mg of the coated granule formulation (containing about 0.2 mg of tamsulosin hydrochloric acid) was weighed into a capsule, and then tested according to the second dissolution test method of the Korean Pharmacopoeia General Test Method. The number of revolutions was 100 rpm and the temperature was 37 ± 0.5 ° C. A test solution was prepared by adding 1 ml of polysorbate 80 (twin 80) [3 → 200] to 500 ml of the first solution of the disintegration test. Take 10 ml of the eluent 2 hours after the start of the dissolution test, and use it as the first test solution. Then, change the test solution to 500 ml of pH 7.2 phosphate buffer solution. The eluate after time was taken as a third test liquid.

In the above procedure, the sample solution was taken and then supplemented with the same amount of test solution.

The sample solution was first filtered through a 0.45 μm membrane filter, and then the drug content was quantified by HPLC under the following operating conditions. Each sample was taken and tested.

By the same procedure, the tablets were subjected to dissolution test in units of 1 tablet (250 mg, containing 0.2 mg of drug).

<Table 4> Operation Conditions

Device name Shimadzu LC-10AD Detector UV detector 225nm column Polaris C18-A5u (PN 2000-250 × 0.46) Mobile phase water: ACN (1: 1) Injection volume 20 μl

TABLE 5 Dissolution Test Results

Sample First sample solution (pH 1.2) 2nd sample solution (pH 7.2) Third sample solution (pH 7.2) Example 1 31.8 ± 3.4 70.5 ± 4.5 75.6 ± 8.5 Example 2 37.4 ± 3.2 70.2 ± 1.9 80.0 ± 2.6 Example 3 35.3 ± 4.1 70.2 ± 4.8 77.9 ± 4.8 Example 4 32.8 ± 2.6 68.7 ± 3.9 76.2 ± 2.9 Example 5 39.7 ± 2.3 68.5 ± 2.6 75.3 ± 2.9 Example 6 33.5 ± 3.0 66.3 ± 3.3 72.6 ± 4.4

The therapeutic agent according to the present invention is controlled release, and is simply produced by spray drying. In the case of coating the granules of the present invention after granulation, by controlling the amount of coating, it is possible to precisely control the release pattern after the initial to 4-5 hours.

Claims (16)

Tamsulosin or a pharmaceutically acceptable salt thereof, Polymethacrylate methylmethacrylate copolymer (trade name: Eudragit L-100) as the acrylate polymer, polyethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (trade name: Eudragit RL -100, RS-100) single or two kinds of mixed components selected from; A sustained-release urination disorder treatment comprising a dissolution control agent of the drug is a solid dispersion formed by spray-drying poloxamers together. The method of claim 1, A therapeutic agent composed of a acrylate polymer and a cellulose derivative alone or in a mixture of two or more, and poloxamers in a ratio of 10: 1 to 3 delete The method of claim 1, The agent is a therapeutic agent which is a granule Tamsulosin or a pharmaceutically acceptable salt thereof, Polymethacrylate methylmethacrylate copolymer (trade name: Eudragit L-100) as the acrylate polymer, polyethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (trade name: Eudragit RL -100, RS-100) single or two kinds of mixed components selected from; A primary release control system of the drug, which is a solid dispersion formed by spray-drying poloxamers together; And Polymethacrylate methyl methacrylate copolymer (trade name: Eudragit L-100), polyethyl acrylate methyl methacrylate trimethylammonioethyl methacrylate chloride as secondary dissolution control agent in the primary release control system A therapeutic agent for sustained-release urination disorder comprising a secondary release control system coated with a coating liquid containing a single or two mixed components selected from a copolymer (trade name: Eudragit RL-100, RS-100). The method of claim 5, Acrylate polymers and poloxamers are therapeutic agents in a ratio of 10: 1 to 3 delete delete The method of claim 5, The coating liquid constituting the second release control system comprises at least one component of fatty alcohol, fatty acid ester or wax as fat. The method of claim 9, Secondary Dissolution Control Agents and Fatty Acids are Treated at a Ratio of 10: 1 to 3 Tamsulosin or a pharmaceutically acceptable salt thereof, Polymethacrylate methylmethacrylate copolymer (trade name: Eudragit L-100) as the acrylate polymer, polyethylacrylate methylmethacrylate trimethylammonioethyl methacrylate chloride copolymer (trade name: Eudragit RL -100, RS-100) single or two kinds of mixed components selected from; Spray drying the first dissolution control agent of the drug including poloxamers in ethanol; Granulating by adding an excipient and a binder to the spray dried mixture; And Polymethacrylate methyl methacrylate copolymer (trade name: Eudragit L-100), polyethyl acrylate methyl methacrylate trimethylammonoethyl methacrylate chloride copolymer (trade name: Eudra as a secondary elution control agent) RL-100, RS-100) A method for producing a sustained-release urination disorder treatment comprising a tamsulosin as an active ingredient comprising the step of coating the granules with a coating liquid containing a single or two mixed components selected from. The method of claim 11, A method for producing an acrylate polymer and poloxamers in a ratio of 10: 1 to 3 delete delete The method of claim 11, The coating solution further comprises at least one component among fatty alcohols, fatty acid esters or waxes as fats. The method of claim 11, Secondary dissolution control agent and fats are prepared in a ratio of 10: 1 to 3