JP2005162737A - Sustained release medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a sustained release medicinal composition containing tamsulosin hydrochloride, having effectiveness equal to or more than that of oral sustained release formulations (the present formulations) containing tamsulosin hydrochloride supplied to medical suites, increasing a dose with suppressing harmful consequences such as adverse effects (e.g., orthostatic hypotension and the like) and giving no restriction in taking meals by request, and a method for dosing tamsulosin hydrochloride to reduce adverse effects accompanied by treatment or prevention based on α<SB>1</SB>receptor blocking action. <P>SOLUTION: The sustained release medicinal composition contains tamsulosin or its pharmaceutically permissible salt and expresses ≥0.4 ratio of the serum tamsulosin concentration (C<SB>min</SB>) at 24 hours after administration over the maximum serum tamsulosin concentration (C<SB>max</SB>) (C<SB>min</SB>/C<SB>max</SB>) after orally administering the formulation. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a sustained-release pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof. Specifically, the present invention comprises tamsulosin or a pharmaceutically acceptable salt thereof, and a carrier for sustained-release pharmaceutical composition, and after oral administration of the composition to a specific maximum plasma drug concentration The present invention relates to a sustained-release pharmaceutical composition characterized by exhibiting a plasma drug concentration ratio of about 24 hours. The present invention also relates to a method for administering tamsulosin hydrochloride for reducing side effects associated with treatment or prevention based on an adrenergic α receptor blocking action.

Tamsulosin or a salt thereof is known to have an adrenergic α-receptor blocking action, and in particular, its hydrochloride salt (tamsulosin hydrochloride) has an alpha-receptor blocking action in the urethra and prostate, and the prostate pressure in the urethral pressure curve. It is widely used as a drug that improves the urination disorder associated with benign prostatic hyperplasia. Recently, drainage disorders associated with neurogenic bladder and lower urinary tract disorders (urination disorders associated with functional obstruction of the lower urinary tract, with no obvious organic or neurological abnormalities in the lower urinary tract Effectiveness against dysuria (for example, International Publication No. 00/00187 pamphlet (corresponding European Patent Publication No. 1088551), International Publication No. 01/10436 Pamphlet (corresponding European Publication No. 1203582) reference).

The following information is included in the package insert of the product as side effect information regarding tamsulosin hydrochloride. That is, as a side effect, adverse reactions (including abnormal laboratory values) suspected to be related to this drug occurred in 104 cases (2.2%) out of 4,724 cases surveyed at the time of approval in Japan and after marketing. However, the main ones were dizziness and stomach discomfort (at the time of re-examination application), and serious side effects include fainting and loss of consciousness (frequency unknown): transient loss of consciousness associated with decreased blood pressure. Other side effects include: Psychiatric & nervous system: dizziness, dizziness (less than 0.1-5%), dizziness, headache, drowsiness (less than 0.1%), irritation (frequency unknown), cardiovascular system: It is described that they are hypotension, orthostatic hypotension, blood pressure, tachycardia, palpitation (less than 0.1%), and arrhythmia (frequency unknown). Furthermore, as for the pharmacokinetics of tamsulosin, the plasma concentration is 0.1 to 0.6 mg of this drug orally administered to healthy adults, and the plasma unchanged concentration peaked at 7 to 8 hours after administration, and the half-life was It was 9.0 to 11.6 hours, C _max and AUC increased almost in proportion to the dose, and when this drug was orally administered for 7 consecutive days, the half-life was slightly extended, but the plasma concentration transition was It is described that the steady state was reached on the fourth day.

Tamsulosin is an alpha-receptor blocker, and when administered with lactose trituration, side effects such as orthostatic hypotension have been observed. Once-per-day sustained-release preparations (Flomax / Harnal / Omnic (both registered trademarks)) are provided in the medical field (for example, see Japanese Patent Publication No. 7-72129, corresponding US Pat. No. 4,772,475) ). Sustained-release preparations utilizing such preparation techniques are administered at a dose of 0.1 mg to 0.2 mg / day in Japan and 0.4 mg to 0.8 mg / day in Europe and the United States.

As side effects, about 5% of erectile ejaculation disorders, hypotension, and feeling of wandering have been reported in Europe and the United States. Although the current formulation is a formulation that reduces the side effects caused by α-receptor blocking action and shows an excellent sustained release effect, the current formulation still has improvement due to fluctuation factors such as fluctuation of pharmacokinetics when administered under fasting conditions. There is room for.

On the other hand, α receptor blockers include prazosin, terazosin, alfuzosin, doxazosin and the like. Since both drugs were originally used as antihypertensive agents, there is a gradual increase method that requires about 4-6 weeks until orthostatic hypotension is seen as a side effect or the therapeutic amount is reached. It is a drug that has limited clinical usage and dosage, such as being used.

As a sustained-release preparation containing the above α-receptor blocker (prazosin or alfuzosin), the drug is poorly absorbed in the colon region and the plasma drug concentration is extremely lowered, so that the drug is maintained at a precise rate. The drug release control preparation that exhibits a so-called zero-order release is inappropriate, and suppresses side effects such as orthostatic hypotension and achieves a good therapeutic effect. Invention relating to a preparation that releases the second part and continuously releases the second part of the drug in the colonic region (for example, WO 94/27582 (corresponding to European Patent No. 0 700 285) In view of the decrease in drug absorption in the colon, such formulation technology employs technical means to compensate for the decrease in absorption by increasing the drug release rate in the lower gastrointestinal tract. However, since these preparations are basically time-controlled, time-released, there is still room for improvement in order to improve their absorption in the colon. When it is easily absorbed in the lower gastrointestinal tract, the plasma drug concentration becomes high, and there is a concern that it may cause side effects such as severe hypotension, so there is still room for improvement.

On the other hand, with regard to tamsulosin, clinical development is being expanded with other indications for improving dysuria, so that the dose administered for treatment or prevention is expected to be 0.8 mg or more.

In addition, the current preparation containing tamsulosin hydrochloride has a restriction of post-meal administration. However, in light of the current business people or the life patterns of the elderly, QOL (Quality of Life), and compliance, there is a need for the development of a formulation that does not restrict dietary intake (the bioavailability does not change depending on the presence or absence of a meal). ing.

International Publication No. 00/00187 Pamphlet International Publication No. 01/10436 Pamphlet Japanese Patent Publication No.7-72129 WO94 / 27582 pamphlet

Therefore, compared with the oral sustained-release preparation containing tamsulosin hydrochloride currently provided in the medical field, the efficacy is equal or better and adverse events such as side effects (eg orthostatic hypotension) A sustained-release pharmaceutical composition capable of reducing, further increasing the dose, and optionally restricting food intake, and a method for administering tamsulosin hydrochloride that reduces side effects associated with treatment or prevention based on α-receptor blocking action Development is still desired.

In view of the above situation, the present inventors first conducted various studies using a novel hydrogel sustained-release preparation created by the applicant company, and as a result, the maximum plasma tamsulosin concentration (C _max ) after oral administration of the preparation On the other hand, preparations that show a plasma tamsulosin concentration (C _min ) ratio (C _min / C _max ratio) of about 0.4 or more at about 24 hours after administration are more than equivalent to current preparations in clinical trials. And found that side effects can be significantly reduced compared to current formulations. It was also found that no significant difference was observed in pharmacokinetic parameters regardless of dietary conditions.
In addition, in clinical trials conducted for the purpose of developing different indications with the hydroforming preparations, the present inventors have found that a high-content preparation of tamsulosin hydrochloride (1.0 mg or 1.5 mg) is a placebo (non-active ingredient). It was found that the adverse event profile was similar to that in the administration group.
Despite various factors affecting both drug dissolution and absorption, a correlation often exists between in vitro drug dissolution time from a formulation and bioavailability.
The establishment of this correlation has been reported in many patents and papers, and the drug elution profile from a drug product is generally used to explain the bioavailability of a drug contained in a special drug product. That is, the drug elution time of various preparations is one of important and basic characteristics to be considered when determining whether or not the drug release properties of special preparations should be evaluated in vivo. Sustained release preparations have a larger dose than normal preparations, and sustained release is achieved based on a special release control mechanism. In other words, the drug release mechanism functioning equally between the preparations on an empty stomach (before meal intake) and after meal (after meal intake) is an extremely important factor in considering bioequivalence. is there.

The dissolution test is used as reinforcing data for evaluating the equivalence (similarity) of the controlled release mechanism between preparations or for evaluating bioequivalence. For both purposes, if the dissolution behavior of the drug product is the same, it is considered that the performance of both drugs can be estimated to some extent within the range of individual and inter-individual variation when administered to a living body. Yes.

Based on the in vitro and in vivo correlation theory, the same drug dissolution profile under similar dissolution test conditions, even if it is a drug based on other formulation technologies, It is thought to show pharmacokinetic parameters. Therefore, a formulation showing pharmacokinetic parameters similar to that of the hydrogel-forming formulation has the same or better efficacy than the current formulation and can be expected to reduce the occurrence of adverse events. In addition, an increase in dose or elimination of dietary restrictions is expected. Based on such an idea, the present invention has been completed by producing a preparation showing an elution profile similar to that of the hydrogel-forming preparation.

That is, the present invention
1. containing tamsulosin or a pharmaceutically acceptable salt thereof, and a carrier for sustained-release pharmaceutical composition, about 24 hours after administration with respect to the maximum plasma tamsulosin concentration (C _max ) after oral administration A sustained-release pharmaceutical composition characterized in that the ratio of plasma tamsulosin concentration (C _min ) (C _min / C _max ratio) is about 0.4 or more,
2. The sustained-release pharmaceutical composition according to 1 above, wherein a value obtained by dividing C _min by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is greater than about 10 × 10 ⁻⁶ mL ⁻¹ .
3. The sustained release pharmaceutical composition according to 1 or 2 above, wherein C _min is about 4 ng / mL or more,
4. The sustained release according to any one of 1 to 3 above, wherein the value obtained by dividing C _max by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 40 × 10 ⁻⁶ mL ⁻¹ or less. Active pharmaceutical composition,
5. The sustained release according to any one of 1 to 4 above, wherein a value obtained by dividing C _max by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 30 × 10 ⁻⁶ mL ⁻¹ or less. Active pharmaceutical composition,
6. The sustained release pharmaceutical composition according to any one of 1 to 5 above, wherein C _max is about 20 ng / mL or less,
7. The sustained release pharmaceutical composition according to any one of 1 to 6 above, wherein the adverse event profile is not significantly different from placebo,
8. The sustained-release pharmaceutical composition according to any one of 1 to 7 above, wherein the pharmacokinetic parameters obtained from the change in plasma tamsulosin concentration are not significantly different when taken before or after taking a meal. Stuff,
9. The sustained release pharmaceutical composition according to any one of 1 to 8 above, which is a sustained release hydrogel-forming preparation,
10. The sustained release pharmaceutical composition according to any one of 1 to 8 above, which is an osmotic pump type preparation,
11. The sustained release pharmaceutical composition according to any one of 1 to 8 above, which is a gel preparation comprising a combination of a plurality of gums,
12. The sustained-release pharmaceutical composition according to any one of 1 to 8 above, which is a multilayer tablet formulation comprising a drug nucleus and a controlled release layer arranged geometrically,
13. The sustained release pharmaceutical composition according to any one of 1 to 8 above, which is a gastric retention preparation using a swellable polymer,
14. The sustained release pharmaceutical composition according to any one of 1 to 8 above, which is a matrix preparation using a water-soluble polymer,
15. Even after administration of a pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition, tamsulosin is released in vivo, even after 8 to 24 hours. A method for maintaining the plasma concentration of tamsulosin or a pharmaceutically acceptable salt thereof in an effective range by absorption,
16. Using tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition, the plasma of about 24 hours after administration was compared with the maximum plasma tamsulosin concentration (C _max ) after oral administration. 16. The method according to 15 above, wherein the ratio of medium tamsulosin concentration (C _min ) (C _min / C _max ratio) is about 0.4 or more,
17. The method according to 15 or 16 above, wherein the value obtained by dividing C _min by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is greater than about 10 × 10 ⁻⁶ mL ⁻¹ .
18. The method according to any one of 15 to 17 above, wherein C _min is about 4 ng / mL or more.
19. The method according to any one of the above 15 to 18, wherein a value obtained by dividing C _max by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 40 × 10 ⁻⁶ mL ⁻¹ or less.
20. The method according to any one of 15 to 19 above, wherein a value obtained by dividing C _max by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 30 × 10 ⁻⁶ mL ⁻¹ or less.
21. The method according to any one of 15 to 20 above, wherein C _max is about 20 ng / mL or less,
22. The method according to any one of 15 to 21 above, wherein the adverse event profile is not significantly different from placebo,
23. The method according to any one of the above 15 to 22, wherein the pharmacokinetic parameter obtained from the change in plasma tamsulosin concentration is not significantly different when taken before or after taking the meal,
24. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained-release pharmaceutical composition according to any one of 15 to 23 above, which is a sustained-release hydrogel-forming preparation. Described method,
25. The method according to any one of 15 to 23 above, wherein the pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is an osmotic pump type preparation. ,
26. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a gel preparation comprising a combination of a plurality of gums according to any one of 15 to 23 above. Described method,
27. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained-release pharmaceutical composition is a multi-layered tablet formulation comprising a drug nucleus and a controlled release layer arranged geometrically. The method according to any one of 15 to 23,
28. Any of the above 15 to 23, wherein the pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a gastric retention preparation using a swellable polymer. The method according to paragraph 1,
29. Any one of the above 15 to 23, wherein the pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a matrix preparation using a water-soluble polymer. The method described in
I will provide a.

The term “C _max ” means the maximum plasma drug concentration obtained after administration of the unit formulation in vivo.
The term “C _min ” means the drug concentration in plasma about 24 hours after administration of the unit preparation in vivo.
The term “AUC” means the area under the curve of the plasma drug concentration-time profile obtained after administration of the unit preparation in vivo.
The term “pharmacokinetic parameter” means C _max , AUC, maximum plasma concentration attainment time (T _max ), etc. determined from changes in plasma drug concentration obtained after administration of a unit preparation in vivo. .
The term “sustained release” means that the concentration of tamsulosin in plasma is within the effective range for treatment or prevention of diseases based on α-receptor blocking action over a period of about 6 to 8 hours, or more, 12 hours or more. As such, it means that tamsulosin or a pharmaceutically acceptable salt thereof is continuously released.
The term “usage” means a sustained release comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained release pharmaceutical composition for the treatment or prevention of a certain disease based on the adrenergic receptor blocking action. It means a method of using a pharmaceutical composition for a patient. For example, “take after meal” means to take about 30 minutes after taking a meal. In addition, “no restriction on food intake” means, for example, when taking a preparation that does not change the bioavailability regardless of whether or not food is consumed and is not affected by food, 30 minutes) or pre-meal (about 30 minutes before ingestion) means that there are no restrictions on taking the drug product. Furthermore, "taken under fasting" means taking without eating a meal for at least 8 hours.
The term “biologically equivalent” means that the 90% confidence interval of the ratio of the mean value of the test formulation to the control formulation for AUC and C _max falls within the range of 80-125%.
The term “side effect” means an action different from the original effect of tamsulosin used for treatment or prevention of a disease based on an adrenergic receptor blocking action.
The term “bioavailability” refers to the rate and amount of unchanged or active metabolite entering the systemic blood.
The term “biologically equivalent formulation” means a formulation with equivalent bioavailability.

  The sustained-release pharmaceutical composition of the present invention and the method for administering tamsulosin are equivalent to or better than the oral sustained-release preparation containing tamsulosin hydrochloride currently provided in the medical field, and Reduce adverse events such as side effects (eg orthostatic hypotension). Furthermore, the composition and administration method have an excellent effect that the dose can be increased and there is no restriction on food intake. Therefore, the sustained-release pharmaceutical composition and administration method of the present invention are highly useful as an oral sustained-release preparation or method containing tamsulosin hydrochloride.

The oral sustained release pharmaceutical composition of tamsulosin or a pharmaceutically acceptable salt thereof according to the present invention will be described in detail below.

The pharmaceutical composition of the present invention is characterized in that it exhibits a specific _Cmin / _Cmax . By adopting such characteristics, the sustained-release pharmaceutical composition of the present invention can produce tamsulosin or its The pharmacologically acceptable salt can be continuously released, and as a result, the occurrence of adverse events can be reduced.

Tamsulosin is referred to as (R) (−)-5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide and is represented by the following structural formula.

Tamsulosin or a salt thereof is known to have an α receptor blocking action. In particular, its hydrochloride (tamsulosin hydrochloride) has an alpha receptor blocking action on the urethra and prostate, and reduces prostate pressure on the urethral pressure curve. It is widely used as a drug that lowers and improves dysuria associated with benign prostatic hyperplasia. In addition, tamsulosin hydrochloride is a clinically extremely useful drug because it is clinically confirmed to be effective in treating lower urinary tract disease.

The compound was first disclosed in JP 56-110665 along with its pharmaceutically acceptable salt. Tamsulosin can form pharmaceutically acceptable acid and base addition salts with a wide range of inorganic and organic acids or bases. Such salts also form part of the present invention. For example, salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, salts with organic acids such as fumaric acid, malic acid, citric acid and succinic acid, salts with alkali metals such as sodium and potassium, calcium and magnesium, etc. And a salt with an alkaline earth metal. Most preferred in the present invention is hydrochloride. These salts can be produced by conventional methods.

The dose of tamsulosin or a pharmaceutically acceptable salt thereof is appropriately determined depending on the individual case in consideration of the administration route, disease symptoms, age of the administration subject, sex, etc. In particular, the amount is not particularly limited as long as it is effective for the treatment or prevention of a specific disease. Such a dose is usually an amount effective for treating or preventing a disease based on an α receptor blocking action, and is, for example, 0.1 to 2 mg, preferably 0.1 to 1.5 mg, and more preferably 0.1 to 1.2 mg. And even more preferably 0.4 to 0.8 mg. For example, when used as an agent for improving dysuria associated with benign prostatic hyperplasia, the dose is 0.1 mg to 0.2 mg / day in Japan and 0.4 mg to 0.8 mg / day in Europe and America. In addition, when tamsulosin or a pharmaceutically acceptable salt thereof is used as an indication other than a dysuria improving agent, a dose exceeding 0.8 mg, for example, a dose of up to about 2 mg is also considered.

Tamsulosin or a pharmaceutically acceptable salt thereof used in the present invention can be easily obtained by the production methods described in JP-A-56-110665 and JP-A-62-114952, or in accordance therewith. It is. In addition to the above publication, International Publication No. 2002/68382, Korean Publication No. 2002-85278, International Publication No. 2003/35608, International Publication No. 2003/37850, or International Publication No. 2003 / It can also be obtained by the manufacturing method described in the pamphlet of No. 37851.

The maximum plasma concentration (C _max ) of tamsulosin and its pharmaceutically acceptable salt as defined in the present invention is the same as the carrier for tamsulosin or its pharmaceutically acceptable salt, and sustained-release pharmaceutical composition Is the maximum plasma concentration of tamsulosin when orally administered, and 0.4 mg of tamsulosin is initially administered orally, the value is about 20 ng / mL or less.

When 0.4 mg of tamsulosin hydrochloride is administered every day, the C _max is preferably about 20 ng / mL or less, more preferably about 16 ng / mL, and even more preferably about 12 ng / mL. Further, when 0.8 mg of tamsulosin hydrochloride is administered every day, the C _max is preferably about 40 ng / mL or less, more preferably about 32 ng / mL, and even more preferably about 24 ng / mL. Furthermore, when 1.2 mg of tamsulosin hydrochloride is orally administered every day, the C _max is preferably about 60 ng / mL or less, more preferably about 48 ng / mL, and even more preferably about 36 ng / mL.
The current tamsulosin preparation has a maximum plasma concentration of about 10 ng / mL when 0.4 mg is orally administered after ingestion, and a maximum plasma concentration of about 17 ng / mL by oral administration before ingestion. The expression of orthostatic hypotension and the like caused by tamsulosin is considered to involve the maximum plasma concentration and the rate at which the plasma concentration increases. In this respect, further sustained release of drug release from the preparation is useful.
In general, the maximum plasma concentration (C _max ) obtained after oral administration varies depending on the dose of the drug. The value obtained by dividing C _max defined in the present invention by the dose of tamsulosin or a pharmaceutically acceptable salt thereof (C _max / dose) is a value obtained by normalizing C _max by the dose. It is considered as a useful parameter for considering the pharmacokinetics of a drug when it is administered using the above-mentioned dose.
When the preparation of the present invention is orally administered, this value (C _max / dose) is about 40 × 10 ⁻⁶ mL ⁻¹ or less. Preferably it is about 30 × 10 ⁻⁶ mL ⁻¹ or less. When the value is larger than these values, there is a concern about the occurrence of side effects such as orthostatic hypotension.

As the minimum plasma concentration (C _min ) of tamsulosin and a pharmaceutically acceptable salt thereof defined in the present invention, tamsulosin or a pharmaceutically acceptable salt thereof is used as a carrier for sustained-release pharmaceutical compositions. means plasma concentration of tamsulosin after 24 hours when orally administered, is represented by C _min (ng / mL). In the case of tamsulosin, the value is about 4 ng / mL or more. The significance of the numerical values is based on clinical findings confirmed for efficacy and side effects in many cases. For example, when tamsulosin hydrochloride 0.4 mg is orally administered as an agent for improving urination disorder associated with prostatic hypertrophy together with a sustained-release pharmaceutical composition carrier, it is about 4 ng / mL or more. C _min varies depending on the dose of the drug. The value obtained by dividing C _min defined in the present invention by the dose of tamsulosin or a pharmaceutically acceptable salt thereof (C _min / dose) is a value obtained by normalizing C _min by the dose. It is considered as a useful parameter for considering the pharmacokinetics of a drug when it is administered using the above-mentioned dose. When the preparation of the present invention is orally administered, this value (C _min / dose) is greater than about 10 × 10 ⁻⁶ mL ⁻¹ . When the value is smaller than this value, there is a concern that a sufficient pharmacological effect for use as a therapeutic agent for dysuria associated with benign prostatic hyperplasia cannot be expected.

For tamsulosin and its pharmaceutically acceptable salts, the ratio of the minimum plasma tamsulosin concentration to the maximum plasma tamsulosin concentration is expressed as the ratio C _min / C _max . The C _min / C _max ratio defined in the present invention is about 0.4 or more and less than 1. If the C _min / C _max ratio is less than about 0.4, side effects such as orthostatic hypotension may appear as seen when the current preparation is taken before meal intake.
Note that the C _min / C _max ratio in the current tamsulosin preparation is about 0.222 ± 0.015 before ingestion and about 0.355 ± 0.113 after ingestion.

As described above, the range of plasma tamsulosin concentration is that when tamsulosin and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a carrier for sustained-release pharmaceutical composition are orally administered, The active ingredient tamsulosin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it maintains a plasma tamsulosin concentration that is pharmacologically effective for treating or preventing a disease.

The determination of tamsulosin hydrochloride in human plasma is not particularly limited as long as it is a method for determining tamsulosin hydrochloride concentration in plasma. For example, the method described below is mentioned. :
1. Yoshiaki Soeishi et al., “Sensitive method for the determination of amsulosin in human plasma using high-performance liquid chromatography with fluorescence detection”, Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 533, 1990, pp. 291- 296,
2. Hiroshi Matsushima et al., ≡Highly sensitive method for the determination of tamsulosin hydrochloride in human plasma dialysate, plasma and urine by high-performance liquid chromatography≡electrospray tandem mass spectrometry≡, Journal of Chromatography B: Biomedical Sciences and Applications, Vol 695, 2, 1997, pp. 317-327.
Further details include the following methods. :
Blood samples are collected from each patient at preset times. Plasma samples are collected by centrifugation at 1500 G (3500 rpm) for 10 minutes at 4 ° C. and stored at −70 ° C. until analysis. These plasma samples are subjected to tamsulosin quantitative analysis based on a method by reverse phase high performance liquid chromatography after liquid-liquid extraction. Drug detection is performed with a fluorescence detector.

In the present invention, tamsulosin is used as a carrier for sustained-release pharmaceutical compositions contained in orally administered preparations together with tamsulosin or a pharmaceutically acceptable salt thereof, and tamsulosin is maintained at an effective concentration for the treatment or prevention of diseases. There is no particular limitation as long as it is a carrier or pharmaceutical formulation or pharmaceutical technology. As a carrier (or pharmaceutical formulation or pharmaceutical technology) constituting such a composition / component, for example, (A) the formulation gels almost completely during the stomach and small intestine retention in the upper digestive tract, and also in the colon in the lower digestive tract. Sustained release hydrogel-forming preparation with drug release ability, (B) Osmotic pump type preparation, (C) Gel preparation combining multiple gums, (D) Geometrically arranged drug nucleus and release control Examples include a multilayer tablet formulation comprising layers, (E) a gastric retention formulation using a swellable polymer, and (F) a matrix formulation using a water-soluble polymer. All compositions or formulation techniques related to such formulation technology are incorporated into the present invention.

(A) Sustained release hydrogel-forming preparations used as carriers for sustained release pharmaceutical compositions include additives for allowing water to penetrate into the preparation (both gelling agents, gelling accelerators, hydrophilic bases) However, in the present specification, it is hereinafter abbreviated as “hydrophilic base”) and a polymer material forming a hydrogel (hydrogel-forming polymer material).

The “hydrophilic base” is not particularly limited as long as the polymer substance that forms the hydrogel used in the pharmaceutical composition can be dissolved before gelation. Such a hydrophilic base is preferably one having an amount of water required to dissolve 1 g of the base of 5 ml or less (20 ± 5 ° C.), more preferably 4 ml or less (same temperature). Yes, the higher the solubility in water, the higher the effect of allowing water to enter the preparation. Examples of such hydrophilic bases include polyethylene glycol (PEG: for example, trade names PEG400, PEG1500, PEG4000, PEG6000, PEG20000 (manufactured by NOF Corporation)), polyvinylpyrrolidone (PVP: for example, trade name PVP K30 BASF). Highly water-soluble polymers such as D-sorbitol and xylitol, sucrose, anhydrous maltose, D-fructose, dextran (for example, dextran 40), glucose and other sugars, polyoxyethylene curing Castor oil (HCO: Cremophor RH40 (BASF), HCO-40, HCO-60 (Nikko Chemicals)), polyoxyethylene polyoxypropylene glycol (for example, Pluronic F68 (Asahi Denka)) or polyoxy Surfactants such as ethylene sorbitan higher fatty acid esters (Tween: eg Tween 80 (manufactured by Kanto Chemical Co., Ltd.)) and sodium chloride Or salts such as magnesium chloride, organic acids such as citric acid and tartaric acid, amino acids such as glycine, β-alanine and lysine hydrochloride, and amino sugars such as meglumine. Particularly preferred are PEG6000, PVP, D-sorbitol and the like. The hydrophilic base of the pharmaceutical composition can be used alone or in combination of two or more.

The blending ratio of the hydrophilic base includes the characteristics of the drug (solubility, therapeutic effect, etc.) and its content, the solubility of the hydrophilic base, the characteristics of the polymer forming the hydrogel, or the patient at the time of administration. Although it depends on various factors such as the state of the above, a ratio that allows gelation almost completely while the preparation stays in the upper part of the digestive tract is preferable. The time for which the preparation stays in the upper gastrointestinal tract varies depending on the species and varies from individual to individual, but is about 2 hours after administration in dogs and about 4 to 5 hours after administration in humans (Br. J. Clin. Pharmacology). (1988) 26, 435-443). In the case of humans, the ratio is preferably such that the preparation can be completely gelled 4 to 5 hours after administration. Generally, it is about 5 to 80% by weight, preferably about 5 to 60% by weight, based on the whole preparation. When the content of the hydrophilic base is low, gelation does not proceed to the inside, and release in the colon is not sufficient. On the other hand, if the content is too high, gelation proceeds in a short time, but the gel tends to collapse, drug elution is accelerated, there is a possibility that sufficient sustained release cannot be achieved, and the amount of the base also increases. Each of the preparations has drawbacks such as an increase in size.

As the hydrogel-forming polymer used, it is able to withstand the contraction movement of the gastrointestinal tract accompanying food digestion and transfer to the colon below the gastrointestinal tract while maintaining a certain shape while the preparation is almost completely gelled. It is necessary to have properties such as viscosity at the time of gelation to such an extent that it can be performed.

As the hydrogel-forming polymer substance to be used, those having a high viscosity at the time of gelation are preferable. For example, a 1% aqueous solution (25 ° C.) having a viscosity of 1000 cps or more is particularly preferable. The properties of the polymer substance depend on its molecular weight (weight average molecular weight), and the polymer substance that forms a hydrogel applicable to the preparation is preferably a higher molecular weight, more preferably an average molecular weight of 2 million or more. May have an average molecular weight of 4 million or more. Examples of such a polymer substance include polyethylene oxide (PEO) having a molecular weight of 2 million or more (for example, trade name Polyox WSR-303 (average molecular weight: 7 million, viscosity: 7500-10000 cps (1% aqueous solution 25 ° C.)), Polyox WSR Coagulant (average molecular weight 5 million, viscosity: 5500-7500cps (same)), Polyox WSR-301 (average molecular weight: 4 million, viscosity: 1650-5500cps (same)), Polyox WSR-N-60K (average molecular weight: 2 million, viscosity: 2000-4000 cps (2% aqueous solution at 25 ° C)), all manufactured by Union Carbide), hydroxypropylmethylcellulose (HPMC) (for example, trade name Metroise 90SH100000 (viscosity: 4100-5600cps (1% aqueous solution at 20 ° C)) Metroise 90SH50000 (viscosity: 2900-3900cps (same)), Metrolose 90SH30000 (viscosity: 25000-35000cps (2% aqueous solution 20 ° C)), Shin-Etsu Chemical Co., Ltd.), carboxymethylcellulose sodium (CMC-Na) (for example, products Name Sun Rose F-150MC (Average molecular weight: 200,000, viscosity 1200-1800cps (1% aqueous solution 25 ° C)), Sunrose F-1000MC (average molecular weight: 420,000, viscosity 8000-12000cps (same)), Sunrose F-300MC (average molecular weight: 300,000, viscosity 2500-3000cps (same) manufactured by Nippon Paper Industries Co., Ltd.), hydroxyethyl cellulose (HEC) (for example, trade name HEC Daicel SE850 (average molecular weight: 1.48 million, viscosity 2400-3000CPS (1% aqueous solution 25 ° C)) HEC Daicel SE900 (average molecular weight: 1.56 million, viscosity: 4000-5000 cps (same)) manufactured by Daicel Chemical Industries, Ltd.) or carboxyvinyl polymer (for example, Carbopol 940 (average molecular weight of about 2.5 million) BF Goodrich Chemical) Etc. PEO having an average molecular weight of 2 million or more is preferable. When it is necessary to maintain the release for a long period of time, for example, 12 hours or more, a higher polymer, preferably an average molecular weight of 4 million or higher or higher viscosity, preferably a 1% aqueous solution having a viscosity of 25 cps or higher Molecules are preferred. These polymer substances forming the hydrogel can be used alone or in combination of two or more. Also, a mixture composed of two or more kinds of polymer substances and having properties suitable for the above as a whole can also be suitably used as the polymer substance forming the hydrogel.

In humans, in order to have the ability to release a drug in the colon, a part of the gelled preparation remains in the colon at least 6 to 8 hours after administration, more preferably at least 12 hours. It is necessary. In order to form a hydrogel preparation having such properties, it varies depending on the size of the preparation, the type of polymer substance, the nature of the drug and additives for allowing water to enter the tablet, the content, etc. Generally, in preparations of 600 mg or less per tablet, the polymer substance forming hydrogel is 10 to 95% by weight, preferably 15 to 90% by weight, based on the whole preparation, and blended per tablet. The amount is preferably 70 mg or more, preferably 100 mg or more in a tablet. If the amount is less than this, it may not be able to withstand erosion in the digestive tract over a long period of time, and sufficient sustained release may not be achieved.

When polyethylene oxide is used as the polymer substance that forms the hydrogel, yellow ferric oxide and / or red ferric oxide is added in an amount that does not change the drug release characteristics over time.

Yellow iron sesquioxide or red iron sesquioxide can be used alone or in combination.

The blending ratio of yellow iron sesquioxide and / or red iron sesquioxide used is not particularly limited as long as it is an amount that usually stabilizes a matrix-type controlled-release preparation and does not change the drug release characteristics. Such a ratio is preferably 1 to 20% by weight, more preferably 3 to 15% by weight, based on the total amount of the preparation. In the “physical mixing in the matrix” of yellow ferric oxide and / or red ferric oxide, the content is preferably 1 to 20% by weight, more preferably 3 to 15% by weight, based on the total amount of the preparation. For example, in red ferric oxide, 5 to 20% by weight is preferable and 10 to 15% by weight is more preferable with respect to the total amount of the preparation. In yellow ferric oxide, 1 to 20% by weight is preferable, and 3 to 10% by weight is more preferable. When yellow ferric oxide and / or red ferric oxide is blended by “film coat”, it is preferably 0.3 to 2%, more preferably 0.5 to 1.5% based on the tablet weight. At this time, the concentration of yellow ferric oxide or red ferric oxide in the film is preferably 5 to 50%, more preferably 10 to 20%.

Here, “physical mixing in matrix” means, for example, that drug, polyethylene oxide and iron sesquioxide are uniformly dispersed, and the drug and iron sesquioxide are homogeneously contained in PEO which is the main base of the controlled release preparation. Means to be distributed. “Film coat” means, for example, that the above-mentioned iron sesquioxide is dissolved or suspended in a water-soluble polymer solution such as hydroxypropylmethylcellulose, and a separately prepared tablet is coated with a thin film. The yellow ferric oxide and / or red ferric oxide can usually be present anywhere in the formulation. For example, in a film such as a film coat, in a granulated product such as granulation, or in a matrix (for example, in the vicinity of polyethylene oxide).

The method for producing such a sustained-release pharmaceutical composition preparation is not particularly limited as long as it can produce a normal hydrogel-forming preparation. For example, a tableting method in which a drug, a hydrophilic base, a hydrogel-forming polymer substance, and, if necessary, additives such as yellow iron sesquioxide and / or red iron sesquioxide are added and mixed, and compression-molded, capsule compression filling Examples thereof include an extrusion molding method, an injection molding method, and the like in which the mixture is melted and solidified after molding. In addition, after the molding, a usual sugar coating, coating treatment such as film coating, etc. can be applied. Or you may fill a capsule after shaping | molding.

(B) Osmotic pump type formulation:
The osmotic pump type formulation allows permeation of the liquid through a semipermeable membrane that allows free diffusion of the liquid but does not allow free diffusion of the drug or osmotic agent. It is a preparation that utilizes pressure. Thus, the action of the osmotic system is pH independent, and the drug product can pass through the gastrointestinal tract and continuously release the drug at a constant rate over a long period of time even in environments with different pH values. Characterized by points.

The formulation is described in “Osmotic drug delivery: a review of the patent literature” written by Santus and Baker, Journal Reported in Journal of Controlled Release, 35, p.1-21, (1995). In addition, for this preparation, U.S. Patent 3,845,770, U.S. Patent 3,916,899, U.S. Patent 3,995,631, U.S. Patent 4,008,719, U.S. Patent 4,111,202, U.S. Patent No. U.S. Patent No. 4,160,020, U.S. Patent No. 4,327,725, U.S. Patent No. 4,519,801, U.S. Patent No. 4,578,075, U.S. Patent No. 4,681,583, U.S. Patent No. 5,019,397 and U.S. Patent No. 5,156,850 It is described in the specification, and all the contents described in the specification are incorporated into the specification.

The osmotic pump type preparation is composed of a drug layer containing tamsulosin or a pharmaceutically acceptable salt thereof (preferably hydrochloride) and a push layer containing a double layer tablet type compression core. It is a preparation formed by coating a semipermeable membrane that penetrates but does not permeate drugs, osmotic agents, or osmopolymers. The semipermeable membrane is provided with at least one drug delivery orifice for connecting the inside of the preparation and the external environment. Therefore, in an osmotic pump type preparation, after ingestion orally, a liquid such as water permeates through the semipermeable membrane and penetrates into the preparation, and the generated osmotic action causes tamsulosin to pass through the drug delivery port for a long time. It has a mechanism that it is released continuously at a constant rate.

The drug layer contains tamsulosin or a pharmaceutically acceptable salt (preferably hydrochloride) thereof in a mixture with a pharmaceutically acceptable additive.

The push layer contains osmotic active component (s), but will not contain tamsulosin or a pharmaceutically acceptable salt thereof, as will be described in detail later. The osmotic active ingredient (s) in the push layer is typically composed of an osmotic agent and one or more osmopolymers. As used herein, “osmopolymer” means a polymer having a relatively large molecular weight that swells upon liquid absorption to release tamsulosin through the drug delivery port.

As the semipermeable membrane to be used, the permeability of an external liquid such as water or biological fluid is high, but the permeability of tamsulosin, osmotic agent, osmopolymer, etc. is particularly impermeable. Not limited. Such a semipermeable membrane is essentially non-erodible and insoluble in vivo.

Examples of the polymer used for forming the semipermeable membrane include a semipermeable homopolymer and a semipermeable copolymer. Cellulose polymers such as cellulose esters, cellulose ethers, and cellulose ester-ethers are used as the polymer material. As the cellulosic polymer, those having an anhydroglucose unit degree of substitution (DS) of more than 0 and 3 or less are used. Degree of substitution (DS) means the average number of hydroxyl groups originally present on an anhydroglucose unit that is substituted by a substituent or converted to another group. Anhydroglucose units are groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate, semi-permeable polymer-forming groups, etc. Here, the organic component can be partially or fully substituted with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms).

Semi-permeable compositions are typically cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono- , One or more selected from the group consisting of di- and tri-alkenylates, mono-, di- and tri-alloyates and the like. Representative polymers include cellulose acetate having a DS of 1.8-2.3 and acetyl content of 32-39.9%, cellulose diacetate having a DS of 1-2, acetyl content of 21-35%, and DS of 2-3. And cellulose triacetate having an acetyl content of 34 to 44.8%. More specific cellulosic polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 38.5%, cellulose acetate propionate having an acetyl content of 1.5-7% and an acetyl content of 39-42%, 2.5 Cellulose acetate propionate having acetyl content of ~ 3%, average propionyl content of 39.2 ~ 45%, and hydroxyl content of 2.8 ~ 5.4%, DS of 1.8, acetyl content of 13-15%, and 34 ~ 39% Cellulose acetate butyrate having a butyryl content, cellulose acetate butyrate having a acetyl content of 2 to 29%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%, a cellulose triac having a DS of 2.6 to 3 Rates, eg, cellulose trivalate, cellulose trilamate, cellulose Tripalmitate, cellulose trioctanoate and cellulose tripropionate, cellulose diester having a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, etc., or Examples of the mixed cellulose ester include cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, and cellulose acetate heptanoate. Semi-permeable polymers are described in U.S. Pat. No. 4,077,407, and the polymers are described in Encyclopedia of Polymer Science and Technology Vol. 3, 325- 354 (1964), Interscience Publishers Inc., New York, NY, can be synthesized and obtained. As the blending ratio of the polymer used, the external liquid permeability such as water and biological fluid is high, but the permeability of tamsulosin, osmotic agent, osmopolymer, etc. is particularly an amount that can be made substantially impermeable. Although not limited, it is preferably 6 to 20 W / W%, more preferably 8 to 18 W / W%, based on the weight of the two-layer compression core composed of the drug layer and the push layer.

As the semipermeable polymer for forming the semipermeable membrane, cellulose acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose dimethylamino acetate, semipermeable polyurethane, semipermeable sulfonated polystyrene, or From anions and cations disclosed in U.S. Patent 3,173,876, U.S. Patent 3,276,586, U.S. Patent 3,541,005, U.S. Patent 3,541,006, and U.S. Patent 3,546,142. Selective semipermeable polymer formed by coprecipitation and crosslinked, disclosed in US Pat. No. 3,133,132, semipermeable polymer, semipermeable polystyrene derivative, semipermeable poly (sodium styrenesulfonate) Semi-permeable poly (vinylbenzyltrimethyla Moniumukurorido), and the semipermeable wall expressed as hydrostatic pressure difference or osmotic pressure difference per atmosphere at the time of passing through the shows 10 ^-5 to 10 ^-2 liquid permeability (cc ml / cm hr atm) semipermeable A functional polymer. These polymers are described in U.S. Pat. No. 3,845,770, U.S. Pat. No. 3,916,899 and U.S. Pat. No. 4,160,020, and are also described in Handbook of Common Polymers, Scott ( Scott) and Roff, 1971, reported to CRC Press, Cleveland, OH.

The semipermeable membrane may contain a flux-regulating agent. As used herein, “flux modifier” means a substance added to help adjust the liquid permeability or volume through the semipermeable membrane. That is, the “flux adjusting agent” includes a substance having an action of improving the flux (hereinafter referred to as a flux improving agent) or a substance having an action of reducing the flux (hereinafter referred to as a flux reducing agent). The flux enhancer is essentially hydrophilic and the flux lowering agent is essentially hydrophobic. Examples of the flux adjusting agent include polyhydric alcohol, polyalkylene glycol, polyalkylene diol, and alkylene glycol polyester. Typical flux improvers include polyethylene glycol 300, 400, 600, 1500, 4000, 6000, etc .; low molecular weight glycols such as polypropylene glycol, polybutylene glycol, and polyamylene glycol; polyalkylene diols such as poly ( 1,3-propanediol), poly (1,4-butanediol), poly (1,6-hexanediol) and the like; fatty acids such as 1,3-butylene glycol, 1,4-pentamethylene glycol, 1, 4-hexamethylene glycol and the like; alkylene triols such as glycerin, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; esters such as ethylene glycol dipropio Nate, ethylene glycol butylene , Butylene glycol dipropionate, glycerol acetate esters; including. Preferred flux improvers include propylene glycol bifunctional block copolymers polyoxyalkylenes or derivatives thereof known as pluronics (trade name) (BASF). Typical flux reducing agents include phthalates substituted with alkyl or alkoxy or substituted with both alkyl and alkoxy groups, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and [di (2-ethylhexyl) phthalate ], Aryl phthalates such as triphenyl phthalate, and butyl benzyl phthalate; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, etc .; insoluble oxides such as titanium oxide; in the form of powder, granules, etc. Polymers such as polystyrene, polymethylmethacrylate, polycarbonate, and polysulfone; esters such as citrate esterified with long chain alkyl groups; inert and water impermeable fillers; cellulosic Including; a permeable membrane forming material compatibility of the resin, such as.

The blending amount of the “flux adjusting agent” contained in the semipermeable membrane is about 0.01 to about 20 W / W% or more.

In the semipermeable membrane, in order to impart plasticity, flexibility and elongation properties to the semipermeable membrane, to make the semipermeable membrane not brittle, or to impart tear strength, For example, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, straight chain phthalate having 6 to 11 carbon atoms, di-isononyl phthalate, di-isodecyl phthalate and the like may be contained. Such plasticizers include non-phthalates such as triacetin, dioctyl azelate, epoxidized tallate, triisooctyl trimellitate, triisononyl trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, etc. Is mentioned.

The blending amount of the plasticizer contained in the semipermeable membrane is about 0.01 to 20 W / W% or more.

The push layer used is in a contact laminate arrangement with the drug layer. The push layer includes an osmopolymer that absorbs and swells aqueous or biological fluids to extrude tamsulosin or a pharmaceutically acceptable salt thereof through the exit of the formulation. As used herein, “osmopolymer” means a polymer that interacts with water or an aqueous biological liquid and has a function of highly swelling or expanding. Such osmopolymer is preferably a hydrophilic polymer that is swellable and exhibits a volume increase of 2 to 50 times. The osmopolymer may or may not be cross-linked, but in a preferred embodiment, it is at least lightly cross-linked to produce a polymer network that is too large to exit the formulation. Is preferred. The amount of “osmopolymer” used depends on factors such as the characteristics and content of the drug in the drug layer, but the drug in the drug layer can be eluted at a desired dissolution rate by swelling. The amount is not particularly limited, but is preferably 30 mg or more, more preferably 50 mg or more. The blending ratio is 40 to 80 W / W% with respect to the weight of the push layer.

As the “osmopolymer” used, a poly (alkylene oxide) having a number average molecular weight of 1,000,000 to 15,000,000 represented by polyethylene oxide, or a poly (alkali carboxymethyl cellulose) having a number average molecular weight of 500,000 to 3,500,000 (wherein The alkali is sodium, potassium or lithium). In addition, for example, osmopolymers, including polymers that form hydrogels, such as Carbopol®, acidic carboxy polymers, acrylic polymers cross-linked with polyallyl sucrose known as carboxypolymethylene, molecular weight 250,000-4,000,000 carboxyvinyl polymers; Cyanamer® polyacrylamide; crosslinked water-swellable indene maleic anhydride polymer; Good-rite® polyacrylic acid with a molecular weight of 80,000-200,000 Aqua-Keeps®, acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucans; and the like. Polymers forming the hydrogel are described in U.S. Pat.No. 3,865,108, U.S. Pat.No. 4,002,173, U.S. Pat.No. 4,207,893, and Handbook of Common Polymers, Scott Reported to Lof, Chemical Rubber Co., Cleveland, OH.

The osmagent used (also referred to as osmotic solute or osmotically effective agent) includes a drug layer containing tamsulosin or a pharmaceutically acceptable salt thereof. It may be contained in both layers of the push layer, and is not particularly limited as long as it shows an osmotic pressure gradient through the semipermeable membrane. Such osmotic agents include sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, acidic potassium phosphate, mannitol, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates One or two or more components selected from the group consisting of: The amount of the osmotic agent used is 15 to 40 W / W% based on the weight of the push layer.

Suitable solvents for manufacturing the formulation component include aqueous or inert organic solvents that do not deleteriously affect the materials used in the system. The solvent broadly includes components selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, alicyclic, aromatic, heterocyclic solvents and mixtures thereof. To do. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n -Heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, Contains inorganic salts such as toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, sodium chloride and calcium chloride Sex solvents include, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene chloride and methanol, and ethylene chloride and methanol, the.

The drug layer to be used is composed of a pharmaceutical composition comprising a pharmacologically effective amount of tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained release pharmaceutical composition. Such a carrier for sustained release pharmaceutical composition may contain a hydrophilic polymer.
Such a hydrophilic polymer provides an action of releasing tamsulosin or a pharmaceutically acceptable salt thereof at a constant release rate. Such polymers include poly (alkylene oxide) having a number average molecular weight of 100,000 to 750,000, such as poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide) and poly (hexylene oxide); number average molecular weight of 40,000 to 400,000 poly (carboxymethylcellulose), typically poly (alkali carboxymethylcellulose), poly (sodium carboxymethylcellulose), poly (potassium carboxymethylcellulose), or poly (lithium carboxymethylcellulose). The drug composition has a number average molecular weight of 9,200-125,000 hydroxypropylalkylcellulose, typically hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose to improve the delivery characteristics of the formulation; And poly (vinyl pyrrolidone) having a number average molecular weight of 7,000 to 75,000 may be included to improve the flow properties of the formulation. Among such polymers, poly (ethylene oxide) having a number average molecular weight of 100,000 to 300,000 is particularly preferable. The blending ratio of the hydrophilic polymer to be used depends on factors such as the physicochemical characteristics and content of the drug contained, but is 40 to 90 W / W% as compared to the weight of the drug layer.

If desired, a surfactant or disintegrant may be incorporated in the drug layer. Examples of the surfactant include those having an HLB value of about 10 to 25, such as polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxy Examples thereof include ethylene-20-sorbitan monopalmitate, polyoxyethylene-20-monolaurate, polyoxyethylene-40-stearate, and sodium oleate. Disintegrants may be selected from starches, clays, celluloses, algins and gums and crosslinked starches, celluloses and polymers. Typical examples include corn starch, potato starch, croscarmelose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum and the like.

Pan coating can be used to produce a formulation prior to the step of installing an exit orifice for drug release on the surface of the formulation. In a pan coating system, a composition that forms a semipermeable membrane is applied by spraying the semipermeable membrane onto the surface of a bilayer compression core composed of a drug layer and a push layer that roll in a rotating pan. (Coated). Moreover, it can be used to coat the compressed core with a semipermeable membrane by a well-known and common technique in this technical field. After coating the semi-permeable membrane, the semi-permeable membrane is dried in a forced air oven or a temperature / humidity controlled oven to dry the semi-permeable membrane and remove the solvent (s) used for coating from the formulation. Can be removed. The drying conditions here can be appropriately selected based on available equipment, ambient conditions, solvent, coating agent, coating thickness, and the like.

The sustained-release pharmaceutical composition is produced by a method known per se. For example, the formulation can also be produced by wet granulation techniques. As for the wet granulation technique, an organic solvent such as denatured anhydrous alcohol is used as a granulation solution, and a drug and a carrier for a sustained-release pharmaceutical composition are blended. The remaining components can be dissolved in a part of the granulating solution such as the above solvent, and the wet mixture prepared separately is gradually added with continuous mixing in the drug mixture with the drug mixture. Next, the granulating solution is added until a wet mixture is formed, and the wet mass mixture is sieved through a pre-installed screen on an oven tray. The mixture is then dried in a forced air oven at a temperature around 24 ° C. to 35 ° C. for about 18 to about 24 hours. Next, the size of the dried granule is adjusted. Next, a lubricant such as magnesium stearate is added to the drug granules, and the granules are placed in a finely ground jar and mixed in a jar mill for about 10 minutes. The composition is pressed in layers, for example on a Manesty® press or a Korsch LCT press. The bilayer core first presses the drug-containing layer and then presses the push layer composition, similarly produced by wet granulation techniques, against the drug-containing layer. Open one or more outlets at the drug layer end of the formulation. And optionally a water-soluble overcoat (which may be colored (eg, Opadry colored coating) or transparent (eg, Opadry clear)) is applied over the formulation to provide a finished formulation Also good.

The sustained release pharmaceutical formulation is provided with at least one outlet. The drug is uniformly released from the formulation by the compressed core through this outlet (s). The outlet can be provided during manufacture of the formulation or during drug delivery by the formulation in the liquid environment of use. The terms “exit”, “delivery port” or “drug delivery port”, and other similar terms used herein, are terms selected from the group consisting of a passage, an opening, an orifice, and a bore. Is included. The expression also includes a mouth formed from a substance or polymer that erodes, dissolves or is leached from the outer wall. This material or polymer is, for example, erodible poly (glycolic acid) or poly (lactic acid) in a semipermeable membrane; gelatinous filament; water-removable poly (vinyl alcohol); leachable compounds such as inorganic and organic Fluid removable pore formers selected from the group consisting of salts, oxides or carbohydrates may be included. The outlet (s) leaches one or more components selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate, and mannitol In this case, the outlet of the pores having such a size that the controlled release of the drug can be controlled is provided. The outlet can have any shape, such as circular, rectangular, square, oval, etc., for constant release of drug from the formulation. The formulation is placed with one or more outlets at regular intervals or on one or more surfaces of the formulation. The outlet diameter is not particularly limited as long as it enables controlled drug release in cooperation with the compression core, but is preferably 0.3 mm to 0.6 mm. Drilling through the semipermeable membrane is used to form the outlet, including mechanical drilling or laser drilling. Such outlets or devices that form such outlets are disclosed in US Pat. No. 3,916,899 by Theeuwes and Higuchi, or in US Pat. No. 4,088,864 by Tewes et al. All of the contents described in those patents are incorporated.

(C) As a carrier for a sustained-release pharmaceutical composition used in a gel preparation in which a plurality of gums are combined, a sustained release comprising a heteropolysaccharide gum and a homopolysaccharide capable of crosslinking the heteropolysaccharide gum when presented to an environmental fluid Releasable excipients and inert diluents selected from, for example, monosaccharides, disaccharides, polyhydric alcohols, or mixtures thereof, and the drug for at least about 24 hours when the dosage is presented to the environmental fluid And a pharmaceutically acceptable water-soluble cationic cross-linking agent for providing sustained release. “Environmental fluid” includes, in addition to body fluids such as blood and gastrointestinal fluids, aqueous solutions such as those used for in vitro dissolution tests.

As described in U.S. Pat.No. 4,994,276, U.S. Pat.No. 5,128,143, and U.S. Pat.No. 5,135,757, combinations of heteropolysaccharides and homopolysaccharides exhibiting synergism, such as two or A heterodisperse excipient consisting of a combination of more polysaccharide gums has a higher viscosity than either gum alone and results in rapid hydration, and the resulting gel forms faster and harder It is known to be.

The “heteropolysaccharide” used is defined as a water-soluble polysaccharide containing two or more sugar units. Such a heteropolysaccharide is not particularly limited as long as it has a branched or helical configuration and has excellent water absorption characteristics and high viscosity. Such heteropolysaccharides are preferably xanthan gum and its derivatives, such as deacylated xanthan gum, carboxymethyl ether, and propylene glycol esters. Preferred is a high molecular weight (> 10 ⁶ ) heteropolysaccharide, xanthan gum.

The “homopolysaccharide” used is defined as a single polysaccharide consisting of one type of monosaccharide. Such a homopolysaccharide is not particularly limited as long as it can form a crosslink with a heteropolysaccharide. Examples of such homopolysaccharide include galactomannan gum (polysaccharide consisting only of mannose and galactose). Preferably, locust bean in which galactose is substituted with mannose at a relatively high ratio is used.

The combination of “heteropolysaccharide” and “homopolysaccharide” is particularly preferably a combination of xanthan gum and locust bean gum. The blending ratio of “heteropolysaccharide” and “homopolysaccharide” is not particularly limited as long as it is an amount effective for increasing the desired gel strength. As such a ratio, the ratio of heteropolysaccharide gum to galactomannan gum is about 3: 1 to about 1: 3, more preferably about 1: 1.

Homopolysaccharides are not limited to galactomannan gum; sustained release excipients can include about 1 to about 99 W / W% heteropolysaccharide gum and about 99 to about 1 W / W% homopolysaccharide. Made of gum. The blending ratio of the gum is about 30 to about 60 W / W%, preferably about 35 to about 50 W / W%, based on the total weight of the sustained-release pharmaceutical composition.

The ratio of tamsulosin or pharmaceutically acceptable salt to gum is usually about 1: 1 to about 1: 5, preferably about 1: 1.5 to about 1: 4.

The water-soluble cationic crosslinking agent to be used is not particularly limited as long as it is pharmaceutically acceptable and is a monovalent or polyvalent metal cation. As such a crosslinking agent, inorganic salts such as various alkali metals and / or alkaline earth metals such as sulfates, chlorides, borates, bromides, citrates, acetates and lactates are preferable. More specifically, the crosslinking agent includes calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium hydrogen carbonate, calcium chloride, Examples include magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, and sodium fluoride. As the above-mentioned polyvalent metal cation, a divalent one is preferable. The salt is preferably calcium sulfate or sodium chloride.

The blending ratio of the water-soluble cationic crosslinking agent is preferably about 1 to about 20 W / W% with respect to the total weight of the sustained-release pharmaceutical composition. Optimally, the crosslinker is about 10 W / W% based on the pre-pharmaceutical weight.

The inert diluent used is not particularly limited as long as it is pharmaceutically acceptable. Such diluents include, for example, monosaccharides, sugars including disaccharides, or polyhydric alcohols, cellulose derivatives, and / or mixtures of the foregoing. Specific examples include sucrose, dextrose, lactose, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, fructose, xylitol, sorbitol, and mixtures thereof. Of these, it is preferred to use soluble formulation diluents such as lactose, dextrose, sucrose, or mixtures thereof.

The aforementioned sustained-release pharmaceutical composition is produced as a pharmaceutically acceptable oral solid dosage form such as a tablet. Such sustained-release pharmaceutical composition includes (1) an inert diluent that can be pharmaceutically acceptable for (1) a heteropolysaccharide gum and a homopolysaccharide capable of crosslinking the heteropolysaccharide gum when presented to an environmental fluid. (2) wet granulate these mixtures, (3) dry the granulated granules, and (4) pulverize the dried granules to provide a controlled release with the desired particle size. (5) granulate this sustained release excipient with tamsulosin or a pharmaceutically acceptable salt thereof, (6) dry the resulting granules, and then ( 7) Inert excipients (eg lubricant) are added and the mixture is then compressed into eg (8) tablets. In yet another embodiment, a sustained release excipient and a mixture of tamsulosin or a pharmaceutically acceptable salt thereof together with a solution of a hydrophobic substance in an amount sufficient to delay its hydration without destroying the gum. Granulate. Thereafter, further inert excipients (eg lubricants) are added and the mixture is compressed into eg tablets.

Wet granulation is a uniform mixing of a predetermined amount of heteropolysaccharide gum, homopolysaccharide gum, cationic cross-linking agent and inert diluent, and then adding a wetting agent such as water, propylene glycol, glycerol or alcohol. A wet mass is produced, and after drying, the mass is pulverized using a general apparatus to prepare a granulated product having a predetermined particle size.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and the like, and sodium stearyl fumarate (Edward Mendell Co., Inc., trade name PruvR) is particularly suitable. . The amount of the lubricant is about 0.5 to about 3 W / W% based on the total weight of the sustained-release pharmaceutical composition. As a method for blending the hydrophobic substance into the sustained-release excipient, for example, a granulated material is further granulated with the above-mentioned flow product using a solution in which the hydrophobic substance is dissolved and / or dispersed in an organic solvent. Can be mentioned.

Examples of the hydrophobic substance include ethyl cellulose, acrylic and / or methacrylic acid polymers or copolymers, hydrogenated vegetable oils, zein, or pharmaceutically acceptable hydrophobic cellulose substances such as alkyl celluloses. Can be mentioned. The amount of the hydrophobic substance added is preferably from about 1 to about 20 W / W%, more preferably from about 3 to about 12 W / W%, even more preferably from the total weight of the sustained-release pharmaceutical composition. About 5 to about 10 W / W%.

As an optimal combination of various components, xanthan gum as “heteropolysaccharide” and locust bean megam as “homopolysaccharide” are about 35 W / W% with respect to the total weight of the sustained-release pharmaceutical composition in a ratio of about 1: 1. -About 50W / W%, calcium sulfate as a "water-soluble cationic cross-linking agent" about 10W / W% or less, dextrose as about 35W / W% as an "inert diluent", and "hydrophobic substance" And about 5 W / W%-about 10 W / W% of ethyl cellulose.

(D) As a carrier for a sustained-release pharmaceutical composition used in a multilayer tablet formulation comprising a drug nucleus and a release control layer arranged geometrically, it comprises a drug-containing layer and a release control layer. Become:
a) in contact with an environmental fluid produced by compressing a mixture or granule comprising 5 to 90 W / W% (preferably 10 to 85 W / W%) of a water-soluble polymer in the layer A first layer (layer 1) having the property of expanding,
b) Consisting of a water-soluble polymer and other auxiliary substances, adjacent to the first layer, having properties suitable for compression moldability and designed to release a bioactive substance within a predetermined time A second layer (layer 2) containing tamsulosin or a pharmaceutically acceptable salt thereof (preferably hydrochloride), and
c) Tamsulosin from (layer 2) or a pharmaceutically acceptable salt thereof (preferably consisting of a water-soluble polymer that generally gels and / or swells and then optionally disintegrates, as appropriate. Is the third layer (layer 3) attached to (layer 2), which has the function of controlling the release of hydrochloride)
A sustained-release pharmaceutical composition (compression-molded product such as a tablet) comprising two or three layers. “Environmental fluid” includes, in addition to body fluids such as blood and gastrointestinal fluids, aqueous solutions such as those used in elution tests.

  The above sustained release pharmaceutical composition comprises a drug (layer 2), a drug-free or optionally a drug as described in US Pat. No. 4,839,177 and US Pat. No. 5,422,123. It is characterized in that the release rate of the drug from the pharmaceutical preparation is controlled by being sandwiched between the contained (Layer 1) and (Layer 3). In addition, as described in US Pat. No. 5,780,057 and US Pat. No. 6,149,940, the sustained-release pharmaceutical composition is brought into contact with body fluid (layer 1) or (layer 3). Similarly, (layer 2) swells after at least one of the swells rapidly, i.e. the volume of the pharmaceutical composition increases significantly, so that the pharmaceutical composition remains in the stomach for a longer period of time and the active substance contained Is known to have a function of being eluted and absorbed by a method controlled in the upper digestive tract.

(Layer 1) and (Layer 3) may have the same composition and the same functional properties, or they may have different compositions and different properties. When (Layer 1) and (Layer 3) are composed of the same functional properties and composition, their amount and thickness sandwiching (Layer 2) may be varied. At least one of (Layer 1) and (Layer 3) acts as a barrier for the elution of the active substance, that is, impermeant that tamsulosin or its salt (preferably hydrochloride) contained in (Layer 2) does not elute or diffuse And at least one of the layers has the characteristic of rapidly expanding, i.e. its volume increasing rapidly. (Layer 3) optionally contains a drug and can also be supplementarily imparted with a drug release different from (Layer 2).

  The amount of tamsulosin or a pharmaceutically acceptable salt thereof (preferably hydrochloride) is as described above.

The water-soluble polymer used in (Layer 1), (Layer 3) and (Layer 2) is not particularly limited as long as it is pharmaceutically acceptable and biocompatible. Such water soluble polymers may gradually dissolve and / or gradually gel in an aqueous liquid and / or gel quickly or at different rates and then optionally disintegrate. Specific examples of such water-soluble polymers include hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose having a molecular weight of 1,000 to 4,000,000, hydroxypropylcellulose having a molecular weight of 2,000 to 2,000,000, carboxyvinyl polymers, chitosans, mannans, galacto Mannans, xanthans, carrageenans, amylose, alginic acid, salts and derivatives thereof, pectin, acrylates, methacrylates, acrylic / methacrylic acid copolymers, polyanhydrides, polyamino acids, poly (methyl vinyl ether) / Maleic anhydride) polymers, polyvinyl alcohols, glucans, scleroglucans, carboxymethylcellulose and its derivatives, ethylcellulose, methylcellulose Alternatively including general water-soluble cellulose derivatives. Preferred is hydroxypropylmethylcellulose having a molecular weight of 3,000 to 2,000,000. The amount of the water-soluble polymer of (Layer 1) and (Layer 3) is usually 5 to 90 W / W%, preferably 10 to 85 W / W%, more preferably 20 to 80 W / W based on its weight. W%. The amount of the water-soluble polymer of (Layer 2) is usually 5 to 90 W / W%, preferably 10 to 85 W / W%, based on its weight.

In the production process of (Layer 1) and (Layer 3), in order to rapidly increase the volume of the pharmaceutical preparation having the above water-soluble polymer, a water-soluble excipient that promotes the degree of wetting of the layer is used. Can do. Such water soluble excipients include cross-linked polyvinyl pyrrolidone, low or medium molecular weight hydroxypropyl cellulose and hydroxypropyl methyl cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl starch and salts thereof, and divinylbenzene / methacrylic acid It is preferably selected from the group of so-called excipients that disintegrate very rapidly, such as potassium copolymers.
The blending amount of the excipient is 1 to 90 W / W% or less, preferably 5 to 50 W / W% of the layer.
If necessary, surfactants (anionic, cationic and nonionic surfactants) can be used to improve the degree of wetting, so that environmental fluids and tablets can be more quickly and easily adapted. Thus, the pharmaceutical composition, particularly the gel-forming layer can be gelled more rapidly. Such substances include sodium lauryl sulfate, sodium ricinoleate, sodium tetradecyl sulfonate, sodium dioctyl sulfosuccinate, cetomagrogol, poloxamer, glycerin monostearate, polysorbate, sorbitan monolaurate, lecithin or Any other pharmaceutically acceptable surfactant and the like. If necessary, other substances that regulate hydration can also be used. Such substances include water soluble diluents such as mannitol, lactose, starches of various origins, sorbitol, xylitol, microcrystalline cellulose and / or substances that generally facilitate the penetration of water or aqueous liquids into pharmaceutical compositions, Or hydrophobic, such as ethyl cellulose, glycerin monostearate, palmitate, hardened or non-hardened vegetable oil (eg, hardened castor oil, wax, monoglyceride, diglyceride, triglyceride) to delay the penetration of water or aqueous liquids into the pharmaceutical formulation Selected from sexual diluents. Preferably, ethyl cellulose or hydrogenated vegetable oil is selected as the hydrophobic diluent.
The amount of the hydrophobic diluent added to (Layer 1) and (Layer 3) is usually 1 to 60 W / W%, preferably 5 to 40 W / W%, more preferably 10 to 30W / W%.

The sustained-release pharmaceutical composition includes magnesium stearate, talc, stearic acid, glycerin monostearate, polyoxyethylene glycol having a molecular weight of 400 to 7,000,000, hydrogenated castor oil, glycerin behenate, monoglyceride, diglyceride, triglyceride and the like. Fluidizing agents such as lubricants, colloidal silica or any other silica, binders, buffers, absorbents, and other pharmaceutically acceptable additives may be included.

The tablet comprising the sustained-release pharmaceutical composition is produced by a method in which powders and / or granules are mixed using a known production technique and compression-molded. A pharmaceutical composition (for example, a tablet) consisting of two or three layers can be produced by a tableting method known per se. The tablets of the present invention can be manufactured, for example, using a rotary press capable of manufacturing “multilayer” tablets. The tableting pressure is usually 7-50 KN (or kilonewtons). When producing a tablet on a small scale, each powder and / or granule can be prepared using a mortar and pestle, and a tablet consisting of two or three layers can be produced using an oil press type tableting machine. The thickness of each layer of the tablet may vary depending on the content of the active substance, but is preferably in the range of 0.2 to 8 mm, more preferably 1 to 4 mm. The pharmaceutical compositions (eg tablets) of the present invention are polymeric materials, for example for the purpose of protecting the tablets or for the purpose of slowing the initial release of the active substance released from the pharmaceutical composition. A coating layer coated with may be applied to the pharmaceutical composition. The coating may be soluble in an acidic solution or may be permeable so that the tablet releases the active substance after a predetermined time. Such a coating can be applied by a method known per se by using an organic or aqueous solution.

The pharmaceutical composition (eg, tablet) rapidly increases its volume upon contact with gastrointestinal fluid and / or liquid in the gastrointestinal tract. This increase in volume is determined and may be limited to a single layer or several layers of the tablet. Such pharmaceutical compositions (eg tablets) are characterized in that at the end of 2 hours the volume of at least one layer increases by 1.5 times, preferably at least 3 times the initial volume. The pharmaceutical composition may be in the form of gelatin capsules consisting of tablets or small tablets or small tablets. Also, at least two small tablets may be combined in the same pharmaceutical composition. These may be packaged, for example, in wafer capsules or gelatin capsules. When the pharmaceutical composition consists of small tablets, each of these may have a different or identical composition.

(E) Gastric retention formulation using swellable polymer The carrier for the sustained-release pharmaceutical composition used is composed of a high-molecular-weight water-soluble polymer that swells upon absorption of water. Such polymers can be used individually or in combination.

The sustained-release pharmaceutical composition carrier is described in, for example, U.S. Patent No. 6,340,475, U.S. Patent No. 5,972,389, U.S. Patent No. 5,582,837, U.S. Patent No. 5,007,790. The specification incorporates all the contents described in the specification.

The “high molecular weight water-soluble polymer that swells upon absorption of water” used is pharmaceutically acceptable, swells without any dimensional limitation upon absorption of water, and can release the drug continuously. Not limited. Such a polymer is preferably a polymer having a weight molecular weight of about 4,500,000 or more, more preferably a polymer having a weight molecular weight of about 4,500,000 to about 10,000,000, and a polymer having a weight molecular weight of about 5,000,000 to about 8,000,000 is particularly suitable.

Such polymers include cellulose polymers and their derivatives, polysaccharides and their derivatives, polyalkylene oxides, cross-linked polyacrylic acids and their derivatives. The term “cellulose” here represents a linear polymer of anhydroglucose. A preferred cellulose polymer is an alkyl substituted cellulose polymer that dissolves in the gastrointestinal tract. Preferred alkyl-substituted cellulose derivatives are those substituted with alkyl groups of 1 to 3 carbon atoms each. Such polymers include, for example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. Preferred viscosities include those having a viscosity in the range of about 100 to about 110,000 cps as a 2% aqueous solution at 20 ° C. Other types include those whose viscosity is in the range of about 1,000 to about 4,000 cps as a 1% aqueous solution at 20 ° C. Particularly preferred alkyl substituted celluloses are hydroxyethyl cellulose and hydroxypropyl methylcellulose. A presently preferred hydroxyethyl cellulose is NATRASOL® 250HX NF.

Particularly preferable examples of such a polymer include polyalkylene oxide derivatives. More preferable polyalkylene oxide is polyethylene oxide, which means a linear polymer of unsubstituted ethylene oxide. Preferred polyethylene oxides are those having a weight average molecular weight in the range of about 900,000 to about 8,000,000. Preferred viscosity ranges include those having a viscosity in the range of about 50 to about 2,000,000 cps as a 2% aqueous solution at 20 ° C. The presently preferred polyethylene oxide is POLYOX®, which can include grade WSR Coagulant and grade WSR 303.

Further examples of such polymers include both natural and modified (semi-synthetic) polysaccharide gums, such as dextran, xanthan gum, gellan gum, welan gum, and rhamsan gum. Xanthan gum is preferred. The most useful crosslinked polyacrylic acids are similar in their properties to those described above for alkyl-substituted cellulose and polyalkylene oxide polymers. Preferred crosslinked polyacrylic acids are those having a viscosity in the range of about 4,000 to about 40,000 cps as a 1% aqueous solution at 25 ° C. The currently preferred example is Carbopol (CAR
BOPOL® NF grade 971P, 974P and 934P, or WATER LOCK®, a copolymer of starch, acrylate and acrylamide.

The weight ratio of tamsulosin or pharmaceutically acceptable salt to "high molecular weight water soluble polymer that swells upon water absorption" is in the range of about 15:85 to about 80:20, preferably about 30. : 70 to about 80:20, more preferably in the range of about 30:70 to about 70:30.

The sustained-release pharmaceutical composition is produced as a pharmaceutically acceptable oral solid dosage form such as a tablet, particle, tablet or particle encapsulated in a capsule. The presently preferred dosage form is, for example, that 2 or 3 drug-containing polymer particles (pellets) are encapsulated in a No. 0 gelatin capsule. The size of the pellet to enclose two pellets in a No. 0 gelatin capsule is 6.6 mm or 6.7 mm (or more generally 6.5 mm to 7 mm) and 9.5 mm or 10.25 mm (or More generally, a length of 9 mm to 12 mm) is preferred. The size of the pellet for enclosing three pellets in a No. 0 gelatin capsule is preferably 6.6 mm in diameter and 7 mm in length. A pellet for enclosing two pellets in a No. 00 gelatin capsule preferably has a diameter of 7.5 mm and a length of 11.5 mm. A pellet for enclosing three pellets in a No. 00 gelatin capsule preferably has a diameter of 7.5 mm and a length of 7.5 mm. Another presently preferred dosage form is a tablet having a size of 18 mm to 22 mm in length, 6.5 mm to 7.8 mm in width and 6.2 mm to 7.5 mm in height, with preferred tablet length, width and height. The combination is 20 mm long, 6.7 mm wide, and 6.4 mm high. These are merely examples, and the shape and size can vary to a considerable extent.

Granular drug / polymer mixtures or drug-impregnated polymer matrices can be produced by various mixing, subdivision and fabrication techniques by methods known per se. For example, direct compression, injection or compression molding using a suitable mortar can be mentioned. A lubricant may be added during compression molding. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and the like, and magnesium stearate is particularly preferable. The blending amount of the lubricant is 0.25 to 3 W / W%, preferably less than 1 W / W%, based on the total weight of the sustained-release pharmaceutical composition. Further, as other lubricants, hydrogenated vegetable oil, hydrogenated and refined stearic acid and palmitic acid triglyceride are preferable, and the blending amount is about 1 to 5 W / weight relative to the weight of the sustained-release pharmaceutical composition. W%, most preferably about 2 W / W%.

As an optimal combination of the above-mentioned various components, a sustained release pharmaceutical composition of polyethylene oxide having a weight average molecular weight in the range of about 2,000,000 to about 7,000,000 as a “high molecular weight water-soluble polymer that swells upon absorption of water” Examples include about 90 to about 97 W / W% based on the total weight, and formulating less than about 2 W / W% magnesium stearate as the “lubricant” based on the total weight of the sustained-release pharmaceutical composition. Further, for example, as a combination of two kinds of water-soluble polymers, for example, polyethylene oxide having a weight average molecular weight in the range of about 900,000 to about 7,000,000 and a 20% 2% aqueous solution having a viscosity of about 3 to about 10,000 cps. It is mentioned that about 48 W / W% of each of the hydroxypropylmethylcelluloses having a mixing ratio of about 1: 1 is included.

(F) Matrix formulation using water-soluble polymer The matrix tablet using water-soluble polymer is a sustained-release pharmaceutical composition carrier in which the drug is uniformly dispersed in a water-soluble polymer base such as hydroxypropylmethylcellulose. is there.

  This matrix preparation is described in, for example, WO 93/16686 pamphlet, and all of the contents described in the above specification are incorporated into this specification.

Hydroxypropyl methylcellulose, which is a water-soluble polymer, hydrates when contacted with water and forms a hydrogel layer on the tablet surface. The gel layer containing the drug formed on the tablet surface gradually dissolves and erodes to release the drug. This tablet has the characteristic of sustained release of the drug by repeating this contact with water, formation of a gel layer containing the drug, and dissolution / erosion of the gel layer.

The sustained-release pharmaceutical composition carrier to be used has a feature that a sustained-release excipient comprising a water-soluble polymer, other inert diluent, and a physiologically active substance are uniformly dispersed. The water-soluble base used is not particularly limited as long as it gradually gelates and / or erodes and / or dissolves and / or disintegrates when presented to the environmental fluid. Such water-soluble bases include hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose having a molecular weight of 1,000 to 4,000,000, hydroxypropylcellulose having a molecular weight of 2,000 to 2,000,000, carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthan , Carrageenans, amylose, alginic acid, salts and derivatives thereof, pectin, acrylates, methacrylates, acrylic / methacrylic acid copolymers, polyanhydrides, polyamino acids, poly (methyl vinyl ether / maleic anhydride ) Polymers, polyvinyl alcohols, glucans, scleroglucans, carboxymethylcellulose and its derivatives, ethylcellulose, methylcellulose, and general water Sexual cellulose derivatives. Preferably, it is a hydroxypropyl methylcellulose having a molecular weight of 1000 to 2,000,000 or a carboxyvinyl polymer having a 0.5% aqueous solution (25 ° C.) of 3,000 to 45,000 cps, more preferably a viscosity (25%) of hydroxypropylmethylcellulose having a molecular weight of 10,000 to 1,000,000 or a 0.5% aqueous solution. C) is a carboxyvinyl polymer having a 4,000 to 40,000 cps. The amount of the water-soluble polymer is 5 to 95 W / W%, preferably 10 to 90 W / W%, more preferably 30 to 85 W / W% per unit of the preparation.

In the pharmaceutical composition, various pharmaceutical excipients are appropriately used and formulated. Such a pharmaceutical excipient is not particularly limited as long as it is pharmaceutically acceptable and used as a pharmaceutical additive. For example, a diluent, a binder, a disintegrant, a sour agent, a foaming agent, an artificial sweetener, a fragrance, a lubricant, a colorant and the like are used. Diluents are from the following groups of substances: mannitol, lactose, starches of various origins, sorbitol, xylitol, microcrystalline cellulose and / or water soluble diluents that generally facilitate the penetration of water or aqueous liquids into pharmaceutical formulations. Selected. Examples of the binder include hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, gum arabic and the like. Examples of the disintegrant include corn starch, starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose. Examples of the sour agent include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include baking soda. Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin. Examples of the fragrances include lemon, lemon lime, orange and menthol. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like. In addition, these pharmaceutical excipients can be appropriately added in an appropriate amount, alone or in combination.

A tablet comprising the pharmaceutical composition can be produced by a method known per se. Such tablets are very commonly used and can be manufactured according to tableting methods known to those skilled in the art. Usually, the working tableting force is in the range of 3-20 KN (or kilonewtons). When producing tablets on a small scale, according to the method described in more detail in the examples, each powder and / or granule is prepared using a mortar and pestle, and an oil press type tableting machine is used. Tablets can also be produced.

The method for administering tamsulosin or a pharmaceutically acceptable salt thereof for reducing side effects associated with treatment or prevention based on the α receptor blocking action of the present invention is described in the description of the invention relating to the sustained-release pharmaceutical composition. The method can be implemented.

EXAMPLES Hereinafter, although an Example, a test example, and an experiment example are given and this invention is demonstrated further, this invention is not limited to these Examples.

Example A (sustained release hydrogel-forming preparation)
Example A-1
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. While stirring with a magnetic stirrer, 1.6 parts of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron Corporation) is suspended (partially dissolved) and sprayed. A liquid was prepared. Charge 56.16 parts of PEG6000 and 300 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) to a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), intake temperature 25 ° C, spray rate 5 g / min, spray / The particle size was adjusted by spraying the spray liquid at a drying cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding and mixing 1.8 parts of magnesium stearate to 361.6 parts of this dried sized product, this mixture was compressed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 8.5 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 181.7 mg to obtain a controlled release preparation (tablet) of the present invention.

Example A-2
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. Under stirring with a magnetic stirrer, 1.6 parts of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron) was suspended (partially dissolved) and sprayed. A liquid was prepared. Next, 76.16 parts of PEG6000 and 400 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) were charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), the intake air temperature was 25 ° C, and the spray rate was 5 g / min. The sizing was performed by spraying the spray solution at a spray / dry cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding and mixing 2.4 parts of magnesium stearate to 481.6 parts of this dried granulated product, this mixture was compressed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 9 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 242 mg to obtain a preparation (tablet) of the present invention.

Example A-3
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. Under stirring with a magnetic stirrer, 1.6 parts of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron) was suspended (partially dissolved) and sprayed. A liquid was prepared. Next, 96.16 parts of PEG6000 and 500 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) were charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), the intake air temperature was 25 ° C, and the spray rate was 5 g / min. The sizing was performed by spraying the spray solution at a spray / dry cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding 3 parts of magnesium stearate to 601.6 parts of this dried granulated product, this mixture was mixed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 9.5 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 302.3 mg to obtain a preparation (tablet) of the present invention.

Example A-4
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. Under stirring with a magnetic stirrer, 1.0 part of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron Corporation) was suspended (partially dissolved). A spray solution was prepared. Charge 76.16 parts of PEG6000 and 400 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), intake temperature 25 ° C, spraying speed 5 g / min, spray / The particle size was adjusted by spraying the spray liquid at a drying cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding and mixing 2.4 parts of magnesium stearate to 481.0 parts of this dried granulated product, this mixture was compressed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 9 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 241.7 mg to obtain a controlled release preparation (tablet) of the present invention.

Example A-5
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. Under stirring with a magnetic stirrer, 2.0 parts of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron Corporation) is suspended (partially dissolved) and sprayed. A liquid was prepared. Charge 76.16 parts of PEG6000 and 400 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), intake temperature 25 ° C, spraying speed 5 g / min, spray / The particle size was adjusted by spraying the spray liquid at a drying cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding 2.4 parts of magnesium stearate to 482.0 parts of this dried sized product, this mixture was compressed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 9 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 242.2 mg to obtain a controlled release preparation (tablet) of the present invention.

Example A-6
3.84 parts of PEG6000 was dissolved in 10.56 parts of water with stirring using a magnetic stirrer. Under stirring with a magnetic stirrer, 0.5 part of tamsulosin hydrochloride pulverized in advance using a hammer mill (sample mill AP-S, 1 mm screen, manufactured by Hosokawa Micron) was suspended (partially dissolved) and sprayed. A liquid was prepared. Next, 76.16 parts of PEG6000 and 400 parts of PEO (product name POLYOX ^™ WSR-303, Dow Chemical) were charged into a fluidized bed granulator (FLOW COATER, manufactured by Freund Corporation), the intake air temperature was 25 ° C, and the spray rate was 5 g / min. The sizing was performed by spraying the spray solution at a spray / dry cycle of 20 seconds / 40 seconds. After sizing, this sized product was dried at an intake air temperature of 40 ° C. for 30 minutes. After adding 2.4 parts of magnesium stearate to 480.5 parts of this dried sized product and mixing, this mixture was compressed using a rotary tableting machine (HT P-22, manufactured by Hata Iron Works) with a 9 mmφ punch. Tableting was performed at 400 kgf / kg and a tablet weight of 241.5 mg to obtain a preparation (tablet) of the present invention.

Test Example A1 (dissolution test)
The drug release characteristics from each preparation of Examples A-1 to A-5 are evaluated by the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). Using 900 mL of purified water as a test solution, without using a sinker, the paddle rotation speed is 200 rpm. Sampling is performed at each time, and tamsulosin hydrochloride in the sampling solution is quantified by HPLC equipped with a UV spectrophotometer (225 nm). The results are shown in Table 1.

(Results and discussion)
Sustained drug release of tamsulosin hydrochloride was demonstrated by using polyethylene oxide as the hydrogel-forming base and PEG as the hydrophilic base. The dissolution rate could be controlled by the blending amount of polyethylene oxide and PEG. As shown in the experimental examples below, in clinical trials using Example A-2 (or A-4,5,6), the efficacy is equal to or greater than that of the current formulation, and the side effects are compared with those of the current formulation. Decreasing results were obtained. Therefore, it is expected that the formulation showing the same pharmacokinetic parameters as in Example A-2 orally administered will have the same or better efficacy than the current formulation at the same dose and reduce the occurrence of adverse events. Is done. It is also expected to increase the dose or eliminate restrictions on food intake.

Example B (osmotic pump type formulation)
Step 1: Production of mixed powder constituting drug layer containing active substance A mixed powder comprising 0.80 mg of tamsulosin hydrochloride and having the following composition ratio was prepared and used for production of a two-layer compression core.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR N80) 100 mg
Hydroxypropyl methylcellulose (HPMC2910) 6 mg
Magnesium stearate 1.00 mg
115.00 mg total

In the above composition, the drug and various additives were weighed and prepared by mixing well using a mortar and pestle until homogenized.
Step 2: Manufacture of push layer A mixed powder having the following composition was prepared and used for the manufacture of a two-layer compressed core.
Polyethylene oxide (Polyox ^TM WSR Coagulant) 60 mg
NaCl 30 mg
Hydroxypropyl methylcellulose (HPMC2910) 4 mg
Red ferric oxide 1 mg
Magnesium stearate 0.5 mg
95.5 mg total

In the above composition, various additives were weighed and mixed well using a mortar and pestle until homogenized.

Step 3: Manufacture of two-layer compression core consisting of drug layer and push layer A two-layer compression core was prepared using an oil press tableting machine. Molded using a mortar with a diameter of 8.0 mm × 9.6 R. The mixed powder for push layer was filled in the mortar, and the mixed powder for drug layer was laminated on the upper layer, followed by compression molding to obtain a two-layer compressed core containing 0.8 mg of tamsulosin hydrochloride.

Process 4: Preparation of semipermeable membrane and membrane coating
PEG4000 and cellulose acetate (94: 6 (W / W%)) were dissolved in a mixed solvent of dichloromethane and methanol (9: 1 (W / W%)). This coating solution has a solids content of about 4% when used. This coating solution is applied to the two-layer compression core produced as described above using a breathable coating machine (Hi-Coater HCT-30, manufactured by Freund Sangyo Co., Ltd.) so that the coating component is 10 W / W% of the weight of the two-layer compression core. Spray coated until

Step 5: Drilling Holes were formed on the drug layer side of the tablet coated with the semipermeable membrane as described above using a 0.4 mm diameter injection needle (27G). Similarly, the preparations of Examples B-2 to B-13 described in Table 2 and Table 3 were produced.

Test example B (dissolution test)
Test Example B-1: According to the method of Test Example A, the release properties of the preparations of Examples B1 to B13 were evaluated. The results are shown in Table 4. In addition, the elution rate after the elution start when the lag time from the elution profile to the elution start was determined and the lag time was set to 0 was calculated and shown in Table 5.

(Results and discussion)
The osmotic pump type preparations showed a lag time of about 2 hours (a time period during which no drug release was observed) in order to start the drug release. It shows a sustained drug release profile after the start of elution. The elution rate at 3 hours after the start of elution when the lag time is 0 is from 14% to 33%, after 7 hours, from 32% to 78%, after 12 hours In any of the preparations, a sustained-release pharmaceutical composition having an elution profile of 55% or more and having an elution profile similar to that of Example A-2. Therefore, it is considered that the same dose shows the same pharmacokinetic parameters as A-2, and the efficacy is equivalent or better than that of the current preparation, and the occurrence of adverse events is expected to be reduced. It is also expected to increase the dose or eliminate restrictions on food intake.

Example C (gel formulation combining multiple gums)
Example C-1
The powder consisting of the various composition units shown below weighs 5 parts of locust bin gum (Sanki, Sanace M175), 5 parts of xanthan gum (Nitta, VS900), 7 parts of dextrose (Wako) and 1 part of calcium sulfate (Kanto Chemical). Taken and mixed thoroughly using a mortar and pestle until homogenized. Further, 2 mL of purified water was divided into 2 portions (1 mL × 2 times) and gradually adjusted to the prepared mixed powder, and the mixture was granulated by thoroughly stirring and mixing using Daikin. The obtained granulated product was sieved using 16 mesh (0.59 μm) and dried for 12 h at a constant temperature of 40 ° C. to obtain granulated powder A.
After adding tamsulosin hydrochloride and lactose to granulated powder A, 10% ethylcellulose solution (100 mg / mL) dissolved in methanol is gradually added dropwise, and the resulting mixture is stirred and mixed thoroughly using milk dedication. Obtained. The granulated powder B was dried for 12 hours at a constant temperature of 40 ° C., filled in a mortar, and compressed with an oil press tableting machine using a punch with a diameter of 8.0 mm × 8.0 R and a tableting pressure of 1000 kg / 杵. As a result, a tablet having a weight of 202.00 mg was produced.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Locust Bingham (Tricrystal, Sanace M175) 50.00 mg
Xanthan gum (Nitta, VS900) 50.00 mg
Dextrose 70.00 mg
Calcium sulfate 10.00 mg
Ethylcellulose 14.00 mg
202.00 mg total

Example C-2
After adding tamsulosin hydrochloride and lactose to granulated powder A, 10% ethylcellulose solution (100 mg / mL) dissolved in methanol is gradually added dropwise, and the resulting mixture is stirred and mixed thoroughly using Milk Dedicated to give granulated powder C. Obtained. The granulated powder C was dried for 12 hours at a constant temperature of 40 ° C., filled in a mortar, and compressed with an oil press tableting machine using a punch with a diameter of 8.0 mm × 8.0 R and a tableting pressure of 1000 kg / 杵. As a result, a tablet having a weight of 396.00 mg was produced.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Locust Bingham (Tricrystal, Sanace M175) 100.00 mg
Xanthan gum (Nitta, VS900) 100.00 mg
Dextrose 140.00 mg
Calcium sulfate 20.00 mg
Ethylcellulose 28.00 mg
Total 396.00 mg

Example C-3
After adding tamsulosin hydrochloride and lactose to granulated powder A, 10% ethylcellulose solution (100 mg / mL) dissolved in methanol is gradually added dropwise, and the resulting mixture is stirred and mixed thoroughly using Milk Dedicated to give granulated powder D. Obtained. The granulated powder D was dried at 40 ° C under constant temperature for 12 hours, filled in a mortar, and compressed with an oil press tableting machine using a punch with a diameter of 8.0 mm × 8.0 R and a tableting pressure of 1000 kg / 杵. As a result, a tablet having a weight of 590.00 mg was produced.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Locust Bingham (Tricrystal, Sanace M175) 150.00 mg
Xanthan gum (Nitta, VS900) 150.00 mg
Dextrose 210.00 mg
Calcium sulfate 30.00 mg
Ethylcellulose 42.00 mg
590.00 mg total

Test example C (dissolution test)
Test Example C-1: According to the method of Test Example A, the release properties of the preparations of Example C1-C3 were evaluated. The results are shown in Table 6.
(Results and discussion)

Sustained drug release was demonstrated by using gels that combined multiple gums. The drug release rate from this formulation can be controlled by the amount of locust bin gum and xanthan gum, and shows a drug release rate of about 54% to about 88% 7 hours after the start of elution, similar to Example A-2 It was a sustained release pharmaceutical composition having an elution profile. Therefore, it is considered that the same dose shows the same pharmacokinetic parameters as A-2, and the efficacy is equivalent or better than that of the current preparation, and the occurrence of adverse events is expected to be reduced. It is also expected to increase the dose or eliminate restrictions on food intake.

Example D (Multilayer Tablet Formulation Composed of Geometrically Arranged Drug Core and Controlled Release Layer)
Example D-1: Production process of trilayer tablet containing tamsulosin hydrochloride 1A: Production of mixed powder constituting layer 2 containing active substance A mixed powder comprising 0.80 mg of tamsulosin hydrochloride and comprising the following composition units: Produced and used for the production of layer 2 which is the middle layer of trilayer tablets.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Mannitol 10.00 mg
Hydroxypropyl methylcellulose (HPMC 90SH-15000) 10.00 mg
Polyvinylpyrrolidone 3.20 mg
Microcrystalline cellulose 66.55 mg
Magnesium stearate 1.00 mg
Colloidal silica 1.25 mg
100.00 mg total

The powder consisting of the above composition units is prepared by weighing the required amount of active substance, mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC 90SH-15000), polyvinyl-pyrrolidone, magnesium stearate and colloidal silica, mortar and pestle Prepare by mixing well until homogenized.

Step 1B: Manufacture of granules constituting layer 1 (drug-free layer 1) used for drug release control Manufacture of granules consisting of the following composition units, and manufacture of layer 1 which is the uppermost layer of the three-layer tablet Used for.
HPMC (90SH-15000) 80.96 mg
Hydrogenated castor oil 13.71 mg
Yellow iron oxide 0.25 mg
Ethylcellulose 5.08 mg
100.00 mg total

The production process consists of weighing the required amount of hydroxypropyl methylcellulose (HPMC 90SH-15000), hydrogenated castor oil and yellow iron oxide and mixing well using a mortar and pestle until homogenized. Granules are prepared by wetting a homogeneous powder mixture with a 10% W / V ethylcellulose based alcohol solution, drying the homogeneously moist mass at 40 ° C. and then sieving.

Step 1C: Manufacture of granules constituting layer 3 (layer 3 not containing drug) used for drug release control Manufacture of granules consisting of the following composition units, and manufacture of layer 3 which is the lowest layer of the three-layer tablet Used for.
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Granules used for the production of layer 3 which is the lowest layer of the three-layer tablet are produced according to the method described in Example D-1 (Step 1B).

Process 1D: Manufacture of three-layer tablets (compression molding)
Trilayer tablets are prepared with an oil press tableting machine. Use a punch with a diameter of 8.0 mm x 9.6 R and a tableting pressure of 1000 kg / 杵. Fill the mortar with the granule of layer 3 described in the section 1C, and tap lightly so that the upper surface becomes flat. A mixed powder containing the active substance of the layer 2 described in the section 1A is filled thereon and lightly tapped so that the upper surface is flat. Further, the granule of layer 1 described in the section 1B is further filled into a mortar and compression molded to produce a three-layer tablet having an average weight of 350.00 mg and containing 0.80 mg of tamsulosin hydrochloride. Layer 1 and layer 3 may be filled in a reverse order and compression molded.

Examples D-2 to D-13: Production of a three-layer tablet containing tamsulosin hydrochloride Step 2A: Production of a mixed powder constituting layer 2 containing an active substance Intermediate layer of a three-layer tablet having 0.80 mg of tamsulosin hydrochloride The mixed powder used for the production of the layer 2 is produced according to the method described in Example D-1 (Step 1A). Tables 7 and 8 show the formulations of Examples D-2 to D-13.

Step 2B: Production of Granules Constructing Layer 1 Used for Drug Release Control (Layer 1 not Containing Drug) Granules used for production of Layer 1 which is a drug release control layer were prepared in Example D-1 (Step 1B ). Tables 9 and 10 show the formulations of Examples D-2 to D-13.

Step 2C: Manufacture of granules constituting layer 3 used for drug release control (layer 3 not containing drug) The granules used for the manufacture of layer 3 which is a drug release control layer were prepared in Example D-1 (Step 1B). ). Tables 11 and 12 show the formulations of Examples D-2 to D-13.

Process 2D: Manufacture of three-layer tablets (compression molding)
Trilayer tablets containing tamsulosin hydrochloride 0.80 mg are prepared according to the method described in Example D-1 (Step 1D).

Example D-14: Production of three-layer tablet containing tamsulosin hydrochloride 3A: Production of mixed powder constituting layer 2 containing active substance Contains 1.20 mg of tamsulosin hydrochloride and is an intermediate layer of a three-layer tablet The mixed powder used for the production of layer 2 is produced according to the method described in Example D-1 (Step 1A).
Tamsulosin hydrochloride 1.20 mg
Lactose 10.80 mg
Mannitol 15.00 mg
HPMC (90SH-15000) 15.00 mg
Polyvinylpyrrolidone 4.80 mg
Microcrystalline cellulose 99.83 mg
Magnesium stearate 1.50 mg
Colloidal silica 1.87 mg
150.00 mg total

Step 3B: Manufacture of granules constituting layer 1 (layer 1 not containing drug) used for drug release control The granules used for the manufacture of layer 1 which is a drug release control layer consisted of the following composition units: Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 80.96 mg
Hydrogenated castor oil 13.71 mg
Yellow iron oxide 0.25 mg
Ethylcellulose 5.08 mg
100.00 mg total

Step 3C: Manufacture of granules constituting layer 3 (layer 3 not containing drug) used for drug release control The granules used for the manufacture of layer 3 which is a drug release control layer consisted of the following composition units: Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Process 3D: Manufacture of three-layer tablets (compression molding)
According to the method described in Example D-1 (Step 1D), a three-layer tablet having an average weight of 400.00 mg and containing 1.20 mg of tamsulosin hydrochloride is produced.

Example D-15: Production of Trilayer Tablets Containing Tamsulosin Hydrochloride Step 4A: Production of Mixed Powder Constructing Layer 2 Containing Active Substance Containing 1.60 mg of tamsulosin hydrochloride, The mixed powder used for the production of a certain layer 2 is produced according to the method described in Example D-1 (Step 1A).
Tamsulosin hydrochloride 1.60 mg
Lactose 14.40 mg
Mannitol 20.00 mg
HPMC (90SH-15000) 20.00 mg
Polyvinylpyrrolidone 6.40 mg
Microcrystalline cellulose 133.10 mg
Magnesium stearate 2.00 mg
Colloidal silica 2.50 mg
200.00 mg total

Step 4B: Manufacture of granule constituting layer 1 used for drug release control (layer 1 not containing drug) The granule used for the manufacture of layer 1 which is a drug release control layer is composed of the following composition units. Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 80.96 mg
Hydrogenated castor oil 13.71 mg
Yellow iron oxide 0.25 mg
Ethylcellulose 5.08 mg
100.00 mg total

Step 4C: Manufacture of granules constituting layer 3 (drug-free layer 3) used for drug release control The granules used in the manufacture of layer 3 as a drug release control layer consisted of the following composition units: Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Process 4D: Manufacture of three-layer tablets (compression molding)
According to the method described in Example D-1 (Step 1D), a three-layer tablet having an average weight of 450.00 mg and containing 1.60 mg of tamsulosin hydrochloride is produced.

Examples D-16 to C-17: Manufacturing process of trilayer tablet containing tamsulosin hydrochloride 5A: Preparation of mixed powder constituting layer 2 containing active substance Trilayer tablet containing 0.80 mg of tamsulosin hydrochloride The mixed powder used for the production of the intermediate layer 2 is produced according to the method described in Example D-1 (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Mannitol 10.00 mg
HPMC (90SH-15000) 10.00 mg
Polyvinylpyrrolidone 3.20 mg
Microcrystalline cellulose 66.55 mg
Magnesium stearate 1.00 mg
Colloidal silica 1.25 mg
100.00 mg total

Step 5B: Manufacture of granule constituting layer 1 used for drug release control (layer 1 not containing drug) The granule used for the manufacture of layer 1 which is a drug release control layer is composed of the following composition units. Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-4000) 20.24 mg
HPMC (90SH-15000) 20.24 mg
Hydrogenated castor oil 6.85 mg
Yellow iron oxide 0.13 mg
Ethylcellulose 2.54 mg
Total 50.00 mg

Step 5C: Manufacture of granule constituting layer 3 (layer 3 not containing drug) used for drug release control The granule used for the manufacture of layer 3 which is a drug release control layer is composed of the following composition units. Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Process 5D: Manufacture of three-layer tablets (compression molding)
Trilayer tablets are prepared with an oil press tableting machine. In Example D-16, a 7.0 mm × 8.4 R diameter punch was used, and in Example 17, a 9.5 mm × 11.4 R punch was used, and the tableting pressure was 1000 kg / kg. Fill the mortar with the granule of layer 3 described in the section 5C, and tap lightly so that the upper surface becomes flat. A mixed powder containing the active substance of the layer 2 described in the section 5A is filled thereon and lightly tapped so that the upper surface is flat. Further, the granule of layer 1 described in the section 5B is further filled into a mortar and compression molded to produce a three-layer tablet having an average weight of 300.00 mg and containing 0.80 mg of tamsulosin hydrochloride.

Example D-18: Production of Trilayer Tablets Containing Tamsulosin Hydrochloride Step 6A: Production of Mixed Powder Constructing Layer 2 Containing Active Substance Containing 0.80 mg of tamsulosin hydrochloride in the middle layer of the trilayer tablet The mixed powder used for the production of a certain layer 2 is produced according to the method described in Example D-1 (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Mannitol 10.00 mg
HPMC (90SH-15000) 10.00 mg
Polyvinylpyrrolidone 3.20 mg
Microcrystalline cellulose 66.55 mg
Magnesium stearate 1.00 mg
Colloidal silica 1.25 mg
100.00 mg total

Step 6B: Production of granule constituting layer 1 used for drug release control (layer 1 containing no drug) The granule used for the production of layer 1 which is a drug release control layer is composed of the following composition units. Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 80.96 mg
Hydrogenated castor oil 13.71 mg
Yellow iron oxide 0.25 mg
Ethylcellulose 5.08 mg
100.00 mg total

Step 6C: Manufacture of granules constituting layer 3 (drug-free layer 3) used for drug release control The granule used for the manufacture of layer 3 which is a drug release control layer is composed of the following composition units. Prepared according to the method described in example D-1 (step 1B).
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Process 6D: Manufacture of three-layer tablets (compression molding)
Trilayer tablets with a diameter of 8.0 mm are prepared with an oil press tableting machine. The tableting pressure is 1000 kg / kg. Fill the mortar with the granule of layer 3 described in the section 6C, lightly tapping so that the upper surface is flat, and then lightly press with a convex scissor of the same diameter. On top of that, the mixed powder containing the active substance of layer 2 described in the section 6A is filled and lightly pressed with a scissors having a diameter of 8.0 mm × 9.6 R. Furthermore, the granule of layer 1 described in the section 6B was filled in a mortar and compression-molded using a punch having a diameter of 8.0 mm × 9.6 R, thereby having an average weight of 350.00 mg, and tamsulosin hydrochloride 0.80 Trilayer tablets containing mg are produced. Layer 1 and layer 3 may be filled in a reverse order and compression molded.

Example D-19: Production of bilayer tablet containing tamsulosin hydrochloride Step 7A: Production of mixed powder constituting layer containing active substance Mixed powder used for production of layer having 0.80 mg tamsulosin hydrochloride Prepared according to the method described in example D-1 (step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Mannitol 10.00 mg
HPMC (90SH-15000) 10.00 mg
Polyvinylpyrrolidone 3.20 mg
Microcrystalline cellulose 66.55 mg
Magnesium stearate 1.00 mg
Colloidal silica 1.25 mg
100.00 mg total

Step 7B: Production of granules constituting a layer used for drug release control (a layer not containing a drug) A drug release control layer, and a granule comprising the following composition units is Example D-1 (Step 1B) In accordance with the method described in 1.
HPMC (90SH-15000) 121.45 mg
Hydrogenated castor oil 20.56 mg
Yellow iron oxide 0.38 mg
Ethylcellulose 7.61 mg
150.00 mg total

Process 7C: Manufacture of double-layer tablets (compression molding)
The bilayer tablet is prepared with an oil press tableting machine. Use a punch with a diameter of 8.0 mm x 9.6 R and a tableting pressure of 1000 kg / 杵. Fill the mortar with granules of the drug-free layer described in section 7B and tap lightly so that the top surface is flat. On top of that, the mixed powder containing the active substance of the layer containing the physiologically active substance described in the section 7A is filled and compression-molded, so that it has an average weight of 250.00 mg and contains 0.80 mg of tamsulosin hydrochloride A bilayer tablet is produced.

Test example D (dissolution test)
Test Example D-1: According to the method of Test Example A, the release properties of the preparations of Example D1-D18 were evaluated, and the results are shown in Table 13 and Table 14.
(Results and discussion)

Sustained drug release was shown by sandwiching a drug-containing layer between two controlled release layers not containing a drug to form a multilayer tablet. The drug release rate from this formulation is the molecular weight of HPMC used in the controlled release layer, the thickness of the controlled release layer, the addition of ethylcellulose into the controlled release layer, the HPMC content and the molecular weight in the drug containing layer, the thickness of the drug containing layer, It was controllable by the geometry of the drug-containing layer and the diameter size of the multilayer tablet. In addition, the dissolution rate 7 hours after the start of dissolution shows a dissolution rate of 38% or more and 70% or less for all preparations, and is a sustained release pharmaceutical composition having the same dissolution profile as Example A-2. Therefore, it is considered that the same dose shows the same pharmacokinetic parameters as A-2, and the efficacy is equivalent or better than that of the current preparation, and the occurrence of adverse events is expected to be reduced. It is also expected to increase the dose or eliminate restrictions on food intake.

Example E: (Gas retention formulation using swellable polymer)
Example E-1
Powders composed of various composition units were prepared by weighing tamsulosin hydrochloride, polyethylene oxide and magnesium stearate and mixing well until homogenized using a mortar and pestle. The prepared mixed powder is filled into a mortar and compressed into tablets with a diameter of 7.0 mm x 8.4 R using an oil press tableting machine at a compression pressure of 1000 kg / kg to produce a tablet with a weight of 276.00 mg. did.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR N60K) 266.00 mg
Magnesium stearate 2.00 mg
Total 276.00 mg

Example E-2
A mixed powder containing tamsulosin hydrochloride and polyethylene oxide and consisting of the following composition units was compression-molded using a pestle having a diameter of 6.0 mm × 6.0 R according to the method described in Example E-1, and the weight was 143.00 mg. Tablets were produced.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg
Magnesium stearate 2.00 mg
143.00 mg total

Example E-3
A mixed powder comprising tamsulosin hydrochloride and polyethylene oxide and consisting of the following composition units was compression-molded using a 7.0 mm × 8.4 R punch with a weight of 276.00 mg according to the method described in Example E-1. Tablets were produced.

Example E-4
A mixed powder consisting of the following composition units containing tamsulosin hydrochloride and two different polyethylene oxides (product names: Polyox ^™ WSR 303 and Polyox ^™ WSR 1105) with different molecular weights has a diameter according to the method described in Example 1. A tablet having a weight of 276.00 mg was produced by compression molding using a 7.0 mm × 8.4 R punch.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg
Polyethylene oxide (Polyox ^TM WSR 1105) 133.00 mg
Magnesium stearate 2.00 mg
Total 276.00 mg

Example E-5
A mixed powder comprising the following composition unit containing tamsulosin hydrochloride and blended with polyethylene oxide and hydroxypropylmethylcellulose (TC5E) was used with a 7.0 mm × 8.4 R diameter candy according to the method described in Example E-1. A tablet having a weight of 276.00 mg was produced by compression molding.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg
Hydroxypropyl methylcellulose (TC5E) 133.00 mg
Magnesium stearate 2.00 mg
Total 276.00 mg

Example E-6
A mixed powder composed of the following composition unit containing tamsulosin hydrochloride and blended with polyethylene oxide and hydroxypropylmethylcellulose (90SH-10000) was crushed with a diameter of 7.0 mm × 8.4 R according to the method described in Example E-1. The tablets with a weight of 276.00 mg were manufactured by compression molding.
Tamsulosin hydrochloride 0.80 mg
Lactose 7.20 mg
Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg
Hydroxypropyl methylcellulose (90SH-10000) 133.00 mg
Magnesium stearate 2.00 mg
Total 276.00 mg

Test Example E: Dissolution Test Test Example E-1: According to the method of Test Example A, the release properties of the preparations of Example E1-E6 were evaluated. The results are shown in Table 15.
(Results and discussion)

Sustained drug release was demonstrated by gastric retention formulation using swellable polymers. The drug release rate from this preparation can be controlled by the combination of molecular weight of polyethylene oxide, blending amount and multiple water-soluble polymers, and shows a drug release rate of about 43% to about 66% 7 h after the start of elution. The sustained-release pharmaceutical composition had an elution profile similar to that of Example A-2. Therefore, it is considered that the same dose shows the same pharmacokinetic parameters as A-2, and the efficacy is equivalent or better than that of the current preparation, and the occurrence of adverse events is expected to be reduced. It is also expected to increase the dose or eliminate restrictions on food intake.

Example F: (Matrix formulation using water-soluble polymer)
Example F-1: Production process of hydroxypropylmethylcellulose (HPMC) matrix tablet containing tamsulosin hydrochloride Step 1A: Production of mixed powder containing active substance A mixed powder comprising 0.80 mg of tamsulosin hydrochloride and comprising the following composition units: To manufacture.
Tamsulosin hydrochloride 0.80 mg
Lactose 149.20 mg
Hydroxypropyl methylcellulose (60SH-10000) 200.00 mg
350.00 mg total

A powder consisting of the above composition units is prepared by weighing the required amounts of active substance, mannitol and hydroxypropylmethylcellulose (HPMC 60SH-10000) and mixing well using a mortar and pestle until homogenized.

Process 1B: Manufacture of HPMC matrix tablets (compression molding)
HPMC matrix tablets are prepared with an oil press tableting machine. Use a punch with a diameter of 9.5 mm × 11.4 R and a tableting pressure of 500 kg / 杵. A mixed powder containing the active substance described in the section 1A is filled and compression-molded to produce a matrix tablet having an average weight of 350.00 mg and containing 0.80 mg of tamsulosin hydrochloride.

Example F-2: Production of HPMC matrix tablet containing tamsulosin hydrochloride Step 2A: Production of mixed powder containing active substance Mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared in Example F- Prepared according to the method described in 1 (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 149.20 mg
HPMC (90SH-4000) 200.00 mg
350.00 mg total

Process 2B: Manufacture of HPMC matrix tablets (compression molding)
A matrix tablet having an average weight of 350.00 mg and containing tamsulosin hydrochloride 0.80 mg is prepared according to the method described in Example F-1 (Step 1B).

Example F-3: Production of HPMC matrix tablet containing tamsulosin hydrochloride Step 3A: Production of mixed powder containing active substance Mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared in Example F- Prepared according to the method described in 1 (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 149.20 mg
HPMC (90SH-100000) 200.00 mg
350.00 mg total

Process 3B: Manufacture of HPMC matrix tablets (compression molding)
A matrix tablet having an average weight of 350.00 mg and containing tamsulosin hydrochloride 0.80 mg is prepared according to the method described in Example F-1 (Step 1B).

Example F-4: Production of HPMC matrix tablet containing tamsulosin hydrochloride Step 4A: Production of mixed powder containing active substance A mixed powder comprising 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared in Example F- Prepared according to the method described in 1 (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 49.20 mg
HPMC (90SH-15000) 350.00 mg
400.00 mg total

Process 4B: Manufacture of HPMC matrix tablets (compression molding)
A matrix tablet having an average weight of 400.00 mg and containing tamsulosin hydrochloride 0.80 mg is prepared according to the method described in Example F-1 (Step 1B).

Example F-5: Manufacturing Process of HPMC Matrix Tablets Containing Tamsulosin Hydrochloride Step 5A: Preparation of Mixed Powder Containing Active Substance Mixed powder containing 0.80 mg tamsulosin hydrochloride and comprising the following composition units was prepared as Example F -1 according to the method described in (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 249.20 mg
HPMC (60SH-10000) 100.00 mg
350.00 mg total

Process 5B: Manufacture of HPMC matrix tablets (compression molding)
According to the method described in Example F-1 (Step 1B), a matrix tablet having an average weight of 350.00 mg and containing 0.80 mg of tamsulosin hydrochloride is produced.

Example F-6: Production of HPMC matrix tablet containing tamsulosin hydrochloride Step 6A: Production of mixed powder containing active substance Mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following compositional units was prepared as Example F -1 according to the method described in (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 199.20 mg
HPMC (60SH-10000) 150.00 mg
350.00 mg total

Process 6B: Manufacture of HPMC matrix tablets (compression molding)
A matrix tablet having an average weight of 350.00 mg and containing tamsulosin hydrochloride 0.80 mg is prepared according to the method described in Example F-1 (Step 1B).

Example F-7: Production of HPMC matrix tablet containing tamsulosin hydrochloride Step 7A: Production of mixed powder containing active substance Mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared as Example F -1 according to the method described in (Step 1A).
Tamsulosin hydrochloride 0.80 mg
Lactose 49.20 mg
HPMC (60SH-10000) 300.00 mg
350.00 mg total

Process 7B: Manufacture of HPMC matrix tablets (compression molding)
A matrix tablet having an average weight of 350.00 mg and containing tamsulosin hydrochloride 0.80 mg is prepared according to the method described in Example F-1 (Step 1B).

Test example F (dissolution test)
Test Example F-1: According to the method of Test Example A, the release properties of the preparations of Examples F1 to F7 were evaluated. The results are shown in Table 16.
(Results and discussion)

Sustained drug release was demonstrated by using hydroxypropylmethylcellulose (HPMC) as the water-soluble polymer. The dissolution rate 7 hours after the start of dissolution shows a dissolution rate of 38% or more and 85% or less for all preparations, and is a sustained-release pharmaceutical composition having the same dissolution profile as Example A-2. Therefore, it is considered that the same dose shows the same pharmacokinetic parameters as A-2, and the efficacy is equivalent or better than that of the current preparation, and the occurrence of adverse events is expected to be reduced. It is also expected to increase the dose or eliminate restrictions on food intake.

Experimental Example 1: Comparison of Current Formulation and Formulation of the Present Invention in a Single Administration To a healthy male subject, 0.4 mg once a day of the current formulation (Flomax®) or the formulation of Example A-2 The dose was administered orally before meal intake (fasted). After administration, blood is collected over time, the plasma tamsulosin concentration is measured, and the ratio of the plasma tamsulosin concentration (C _min ) 24 hours after administration to the maximum plasma tamsulosin concentration (C _max ) (C _min / C _max ) And are shown in Table 17.
(Results and discussion)

At the time of administration of the current preparation, the C _min / C _max value was 0.161 on average, whereas it was 0.709 for the preparation of the present invention. Therefore, it has been shown that controlling the release of tamsulosin from the preparation is useful for controlling the transition of plasma tamsulosin concentration within a preferable range. Many of the orthostatic hypotension often observed when taking α-receptor blockers are considered to occur transiently with a rapid increase in plasma concentration after the first dose. Therefore, increasing C _min / C _max and maintaining a constant blood concentration is useful for reducing the occurrence of side effects and sustaining the effect. Is considered possible. The _Cmin / _Cmax of the A-2 preparation in a single administration is significantly larger than that of the current preparation (p <0.01), and it can be expected to reduce the occurrence of side effects and sustain the effect as compared with the current preparation.

Experimental Example 2: Comparison between the present preparation and the preparation of the present invention in continuous administration Prior to meal intake (fasted) or after meal intake in healthy male subjects, the current preparation (Omnic / Flomax (registered trademark)) or the preparation of Example A-2 Was orally administered once a day at a dose of 0.4 mg per person for at least 5 days. In the pre-meal administration of the current preparation, after administration on the 7th day, in the post-meal administration, after the administration of the 6th day, in the A-2 preparation administration, both before and after the intake of the meal. Blood was collected and plasma tamsulosin concentration was measured. Determine the maximum plasma tamsulosin concentration (C _max) and plasma tamsulosin concentration at 24 hours after administration (C _min), and calculates a ratio of the _{C min (C min / C max} ) for the C _max, as shown in Table 18 .
(Results and discussion)

C _max was significantly increased with the current preparation before meal intake and after meal intake (p <0.01), but the A-2 preparation had no significant dietary effect. In addition, the C _min / C _max ratio was significantly decreased in the pre-meal administration of the current preparation compared to the post-meal administration (p <0.01). Did not admit. Furthermore, C _min / C _max after ingestion of the current preparation was smaller than when the A-2 preparation was administered.
Based on the above results, the A-2 formulation is a product that is not affected by diet, and is expected to improve compliance, reduce the incidence of side effects, and maintain sustained effects compared to the current formulation. . Therefore, it was shown that setting C _min / C _max to about 0.4 or more is useful in designing a tamsulosin preparation that is not easily affected by diet.

Experimental Example 3: Adverse Event Profile in Phase III Clinical Trial
In a clinical study on female patients with overactive bladder symptoms (frequent urine, urgency or urge urinary incontinence) aged 18 to 70 years, the preparation of the present invention (Examples A-4, 5, 6) ) Was orally administered once a day at a dose of 0.25 mg to 1.5 mg for 6 weeks. The adverse event profile of the group administered with 1.5 mg of tamsulosin hydrochloride as the sustained-release preparation of the present invention was not significantly different from that of the group administered with placebo. Therefore, when oral administration of tamsulosin preparations, it has been shown that controlling pharmacokinetic parameters within a specific range is useful for enabling high dose administration without increasing the incidence of side effects. It was done.

Experimental Example 4: Adverse Event Profile in Phase III Clinical Trial After a placebo was administered to male patients with lower urinary tract symptoms for 2 weeks, the current formulation or the formulation of Example A-2 was administered at a dose of 0.4 mg once a day. Orally for 12 weeks. The study was conducted in a double-blind manner to investigate the occurrence of adverse events.
(Results and Discussion)
As a result of comparing the A-2 formulation administration group with the current formulation administration group, the adverse event profile of the A-2 formulation administration group is improved compared to the current formulation administration group, and the effect is particularly abnormal ejaculation (abnormal ejaculation) And postural hypotension (orthostatic hypotension). Therefore, it was shown that controlling the pharmacokinetic parameters within a specific range at the time of oral administration of the tamsulosin preparation is useful for suppressing the incidence of side effects.

  The sustained-release pharmaceutical composition and administration method of the present invention are more effective than the oral sustained-release preparations containing tamsulosin hydrochloride currently provided in the medical field, and have side effects. Reduce adverse events such as orthostatic hypotension. Furthermore, it is useful as an excellent oral sustained-release preparation and method in which the dose can be increased and there is no restriction on food intake.

It is a figure which shows the drug release characteristic from each formulation of Example A. It is a figure which shows the drug release characteristic from each formulation of Example B. FIG. 3 is a graph showing drug release characteristics from each formulation of Example C. FIG. 4 shows drug release characteristics from each formulation of Example D. FIG. 4 shows drug release characteristics from each preparation of Example E. FIG. 6 shows drug release characteristics from each preparation of Example F.

Claims (29)

It contains tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition, and is about 24 hours after administration in the plasma with respect to the maximum plasma tamsulosin concentration (C _max ) after oral administration. A sustained-release pharmaceutical composition, wherein the ratio of tamsulosin concentration (C _min ) (C _min / C _max ratio) is about 0.4 or more. C _min tamsulosin or sustained-release pharmaceutical composition according to claim 1 divided by the dose of a pharmaceutically acceptable salt thereof is greater than about 10 × 10 ^-6 mL ^-1. The sustained-release pharmaceutical composition according to claim 1 or 2, wherein C _min is about 4 ng / mL or more. The sustained release property according to any one of claims 1 to 3, wherein a value obtained by dividing _Cmax by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 40 x ^10-6 mL- ¹ or less. Pharmaceutical composition. The sustained release property according to any one of claims 1 to 4, wherein a value obtained by dividing _Cmax by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 30 x ^10-6 mL- ¹ or less. Pharmaceutical composition. The sustained-release pharmaceutical composition according to any one of claims 1 to 5, wherein C _max is about 20 ng / mL or less. The sustained release pharmaceutical composition according to any one of claims 1 to 6, wherein the adverse event profile is not significantly different from that of placebo. The sustained-release pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmacokinetic parameters obtained from the change in plasma tamsulosin concentration do not differ significantly when taken before or after taking the meal. . The sustained-release pharmaceutical composition according to any one of claims 1 to 8, which is a sustained-release hydrogel-forming preparation. It is an osmotic pump type formulation, The sustained release pharmaceutical composition of any one of Claims 1-8. The sustained-release pharmaceutical composition according to any one of claims 1 to 8, which is a gel preparation comprising a combination of a plurality of gums. The sustained-release pharmaceutical composition according to any one of claims 1 to 8, which is a gastric retentive preparation using a swellable polymer. The sustained-release pharmaceutical composition according to any one of claims 1 to 8, which is a multi-layer tablet formulation comprising a drug core and a controlled release layer arranged geometrically. The sustained-release pharmaceutical composition according to any one of claims 1 to 8, which is a matrix preparation using a water-soluble polymer. Even after administration of a pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained-release pharmaceutical composition, tamsulosin is released and absorbed in vivo. A method for maintaining the plasma concentration of tamsulosin or a pharmaceutically acceptable salt thereof within an effective range. Using tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition, tamsulosin in plasma at about 24 hours after administration with respect to the maximum plasma tamsulosin concentration (C _max ) after oral administration of the preparation The method according to claim 15, wherein the concentration (C _min ) ratio (C _min / C _max ratio) is about 0.4 or more. The method of claim 15 or 16 divided by the dose of C _min tamsulosin or a pharmaceutically acceptable salt thereof is greater than about 10 × 10 ^-6 mL ^-1. The method according to any one of claims 15 to 17, wherein C _min is about 4 ng / mL or more. The method according to any one of claims 15 to 18, wherein the value obtained by dividing _Cmax by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 40 x ^10-6 mL- ¹ or less. 20. The method according to any one of claims 15 to 19, wherein a value obtained by dividing _Cmax by the dose of tamsulosin or a pharmaceutically acceptable salt thereof is about 30 x ^10-6 mL- ¹ or less. 21. The method according to any one of claims 15 to 20, wherein _Cmax is about 20 ng / mL or less. The method according to any one of claims 15 to 21, wherein the adverse event profile is not significantly different from placebo. The method according to any one of claims 15 to 22, wherein the pharmacokinetic parameters obtained from the change in plasma tamsulosin concentration do not differ significantly when taken before or after taking a meal. 24. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a sustained-release hydrogel-forming preparation. the method of. The method according to any one of claims 15 to 23, wherein the pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is an osmotic pump type preparation. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained-release pharmaceutical composition is a gel preparation comprising a combination of a plurality of gums. the method of. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for sustained-release pharmaceutical composition is a gastric retention preparation using a swellable polymer. The method according to item. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a multi-layered tablet formulation comprising a drug core and a controlled release layer arranged geometrically. 24. The method of any one of -23. 24. The pharmaceutical composition comprising tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for a sustained-release pharmaceutical composition is a matrix preparation using a water-soluble polymer. The method described.

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