DE202004009563U1 - Sustained release pharmaceutical composition containing tamsulosin comprises specific dissolution profile ensuring high activity without side-effects, useful for treating urinary disorders such as benign prostate hyperplasia - Google Patents

Abstract

A sustained release pharmaceutical composition (A) comprising tamsulosin (I) (or its salt) and a carrier (II) such that in Japanese Pharmacopoeia dissolution test 2 (paddle method; 200 rpm) the degree of release of (I) 7 hours after the start of dissolution is 20-85%, is new. ACTIVITY : Cytostatic; Uropathic. No biological data given. MECHANISM OF ACTION : alpha -Adrenergic receptor blocker. No biological data given.

Description

The The present invention relates to a pharmaceutical composition for sustained release, the tamsulosin or a pharmaceutical permissible Contains salt of it. In particular, the present invention relates to a pharmaceutical Sustainable release composition characterized by is that they have tamsulosin or a pharmaceutically acceptable salt of it and a carrier for the contains sustainably released pharmaceutical composition and a has a specific drug release profile.

Tamsolusin or a salt thereof is known to give and have an adrenaline α-receptor blocking effect, and in particular the hydrochloride (the tamsolusin hydrochloride) is known to have an α-receptor blocking effect for urethra and prostate Areas and has been widely used as a drug that lowers prostate pressure in the urethral pressure profile and alleviates the urinary disorder associated with prostate enlargement. Recently, its efficacy has also been demonstrated in relation to the excretion disorder associated with a neurogenic bladder and lower uropathy (which is a urinary disorder associated with lower urinary tract dysfunction and a urinary disorder that is neither clear organic) Disorder is accompanied by a neurological abnormality in the lower urinary tract) (see, for example, International Laid-Open No. 00/00187 (corresponding EP 1 088 551 ) and International Application No. 01/10436 (accordingly EP 1 203 582 )).

The following information is given in the product information leaflet with regard to the information about the counter reactions of tamsulosin hydrochloride. For example, with respect to the backlash, it is described that 104 cases (2.2%) of backlash (including abnormal clinical data) likely related to the present agent were observed among 4,724 cases for research results post-approval and post-marketing surveillance market launch in Japan. It describes that most of the cases related to dizziness and stomach discomfort (when used for re-examination), weakness and loss of consciousness (ambiguous frequency) and transitional loss of consciousness as a result of a negative pressure that occurred as a serious backlash, and that further backlashes related to dizziness and discontinuity (0.1 to less than 5%), orthostatic syncope, headache and drowsiness (less than 0.1%) and a disorder (ambiguous frequency) in the psychoneural and negative pressure, postural negative pressure, blood pressure, tachycardia and palpitation (less than 0 , 1%) and arrhythmia (ambiguous frequency) in the circulatory area. Also, regarding the pharmacokinetics of tamsulosin, it is described that when 0.1 to 0.6 mg of the present agent was orally administered to healthy adult volunteers, the plasma concentrations of the unchanged drug peaked 7 to 8 hours after the administration and whose half-life was 9.0 to 11.6 h, that C _max and AUC also increased almost in proportion to the dose administered, and that although the half-life was prolonged somewhat over 7 days when the present agent was administered orally repeatedly, the plasma concentration profiles reached steady state on day 4.

Tamsulosin is an α-receptor blocking agent. When this agent was administered in the form of a powder triturated with lactose, backlashes such as postural negative pressure were induced, and therefore, until now, a sustained release preparation (Flomax / Harnal / Omnic (all registered trademarks )), in which counter reactions such as postural negative pressure are suppressed, have been used in the actual determination of the medicine by using the variously particulate, sustainably released preparation (see, for example, JP-B-7-72129, accordingly US 4,772,475 ). The sustainably released preparation, in which such a technical procedure is used for pharmaceutical preparations, is administered at a dose of 0.1 to 0.2 mg per day in Japan and from 0.4 to 0.8 mg per day in Europe and America used.

Regarding the Backlash was over Erectile and ejaculation disorders, Negative pressure, feelings of discontinuity etc. to an extent of about 5% reported in Europe and America. Although the current preparation has excellent sustainable release properties, whereby by an α-receptor blocking action caused counter reactions are reduced, which currently shows preparation used deviation factors such as changes pharmacokinetics under a hungry condition or under real conditions and is still room for improvement.

On the other hand, there are α-receptor blocking agents such as prazosin, terazosin, alfuzosin and doxazosin. All of these drugs were originally used as negative pressure drugs and therefore show and result in postural negative pressure as a counter-reaction, and a progressively increasing ver are used in which it takes about 6 to 8 weeks to give the therapeutic drug levels in the plasma, so that they are drugs that are limited in their use and administration in the clinical setting.

Regarding the above-mentioned sustained-release preparations containing an α-receptor blocking agent (prazosin or alfuzosin), the drugs are only slightly absorbed in the intestinal region, which is why they are not appropriate, since the drug concentration in the plasma when the drugs are prepared is included controlled release is extremely reduced, which shows a so-called zero-order drug release, in which the drug is released precisely at a constant rate in a sustainable manner. Therefore, in order to suppress the counter-reactions such as postural negative pressure and to achieve a good therapeutic effect, an invention is described which relates to a preparation in which the first part of the medicine in the upper gastrointestinal tract and the second part of the medicine in a more sustainable manner Are released in the intestinal area (see, for example, International Laid-Open WO 94/27582 (corresponding EP 0 700 285 ). These pharmaceutical preparations are only able to compensate for the reduction in drug absorption by increasing the rate of drug release in the lower gastrointestinal tract because of the low drug absorption in the intestine. However, such preparations are based on a time-controlled drug delivery system, and improvement is still needed to increase drug absorption in the intestine. In addition, if the α-receptor blocking agent is easily and well absorbed in the lower part of the gastrointestinal tract as well as in the intestine, the drug concentrations in the plasma increase, and consequently there is a fear of induction of counter-reactions such as serious negative pressure, for whatever reason there is still room for improvement.

Because against, regarding Tamsulosin, whose clinical development is being broadened to include more Obtaining indications of the drug is therefore also predicted that the tamsulosin dose levels for therapy or prevention Will increase 0.8 mg or more.

Further exists in the current preparations, the tamsulosin hydrochloride contain a restriction on administration after meals that whose dosage concerns. However, there still exists with regard on the life patterns and the QOL (Quality of Life) of business people or currently older people and in terms of tolerability taking medication, a need to develop preparations without limitation of food intake in connection with the dosage of Medicament (i.e. that there is no food effect on bioavailability gives).

attention is also directed to WO 00/00187, WO 01/10436, JP-B-7-72129 and on WO 94/27582.

Therefore there is still a need to develop a sustained release pharmaceutical preparation, in which, compared with the current oral sustainably released preparations, the tamsulosin hydrochloride contained and have been used for medical purposes, the effectiveness is equivalent or even better to opposing operations like Counter reactions (e.g. postural negative pressure) are reduced, the dose can be increased and, if necessary, no restriction of the Food ingestion exists in the dosage of the preparation. As well there is a need for a method of administering tamsulosin hydrochloride, in which the counter-reactions of tamsulosin with therapy or prevention based on an α-receptor blocking effect, are reduced.

In Given the above circumstances, those that occur here Inventor first diverse studies on a new hydrogel-forming preparation for sustainable release carried out extensively, the has been generated by the applicant's company and it is as a result, it was found that a preparation which have a specific drug release profile under specific dissolution test conditions shows and yields an equivalent or even better potency than has the current preparation and also the backlash of tamsulosin decreased compared to the current preparation can be.

On the basis of this concept, namely that even preparations prepared with other pharmaceutical process technologies have the same or better potency compared to the current preparation and the preparations can be expected to counteract the reactions of tamsulosin according to a theory of in vitro and in vivo correlations are reduced, provided that the preparations have a similar drug release profile under the same dissolution test conditions as the hydrogel-forming preparation mentioned above, the Er occurring here pharmaceutical preparations having a similar drug release profile to the above hydrogel-forming preparation, whereby the present invention has been successfully completed.

Consequently the present invention provides the following:

• 1. a pharmaceutical composition with sustained release, the tamsulosin or a pharmaceutical permissible Salt thereof and a carrier for the contains sustainably released pharmaceutical composition, wherein when performing a test according to Japanese Pharmacopoeia dissolution test method 2 (paddle method: 200 rpm) after the release of tamsulosin approx. 7 hours since the start of the resolution is about 20 to about 85%;
• 2. the pharmaceutical composition for sustainable release according to the above Item 1, wherein the release of tamsulosin after 7 h since Start of the resolution is about 20 to about 75%;
• 3. the pharmaceutical composition for sustained release according to the above Item 1 or 2, wherein the release of tamsulosin after 7 h since the start of the dissolution is about 25 to about 65%;
• 4. the pharmaceutical composition for sustained release according to one of items 1 to 3 above, wherein the release of tamsulosin after 3 h since the start of the dissolution is about 5 to about 45%;
• 5. the pharmaceutical composition after sustained release according to one items 1 to 4 above, wherein the release of tamsulosin after 3 h since the start of the dissolution is about 5 to about 40%;
• 6. the pharmaceutical composition for sustained release according to one of items 1 to 5 above, wherein the release of tamsulosin after 3 h since the start of the dissolution is about 5 to about 35%;
• 7. the pharmaceutical composition for sustained release according to one of items 1 to 6 above, wherein the release of tamsulosin after 12 h since the start of the dissolution is approximately 40% or more;
• 8. the pharmaceutical composition for sustained release according to one of items 1 to 7 above, wherein the release of tamsulosin after 12 h since the start of the dissolution is approximately 50% or more;
• 9. the pharmaceutical composition for sustained release according to one items 1-8 above, wherein the time during which 50% tamsulosin is released have been (T50), is about 3 to about 15 h;
• 10. the pharmaceutical composition for sustained release according to one items 1 to 9 above, wherein T50 is about 4 hours to about 12 hours;
• 11. The pharmaceutical composition for sustained release according to one of items 1 to 10 above, in which the profile of adverse incidents does not change significantly different from that of a placebo;
• 12. The pharmaceutical composition for sustained release according to one of items 1 to 11 above, where it is, when administered Ingestion or after ingestion, no significant Difference in the pharmacokinetic parameters there from the Plasma Tamsulosinkonzentrationen be preserved;
• 13. the pharmaceutical composition for sustained release according to one of items 1 to 12 above, which is a hydrogel-forming preparation for sustainable release;
• 14. The pharmaceutical composition for sustained release according to one of items 1 to 12 above, wherein this is a preparation of an osmotic Pump type;
• 15. The pharmaceutical composition for sustained release according to one of items 1 to 12 above, which is a gel preparation, wherein a variety of rubber species are combined;
• 16. The pharmaceutical composition for sustainable release according to one of items 1 to 12 above, wherein this is a multi-layer tablet which is a drug layer and release control layer (s) comprises which are arranged geometrically;
• 17. the pharmaceutical composition for sustained release according to one of items 1 to 12 above, wherein this is a preparation that held in the stomach where a swelling polymer is used; and
• 18. The pharmaceutical composition for sustained release according to one of items 1 to 12 above, which is a matrix preparation is what is a water soluble Polymer is used.

The term "C _max " means the maximum drug concentration in plasma obtained after the in vivo administration of a unit preparation.

The Term "AUC" means the area under a curve in which the plasma drug concentration versus time is applied, which after the in vivo administration of a Unit preparation is obtained.

The Term "sustainable Release "means that tamsulosin or a pharmaceutically acceptable salt thereof in more sustainable Is released in such a way that the plasma tamsulosin concentrations unite effective salary levels for therapy or prevention of diseases based on an α-receptor blocking effect while about 6 to 8 hrs and even more than not less than 12 hrs.

The Term "steady Condition "means that the plasma tamsulosin concentrations (the salary range) in the range between a minimal effective Concentration for Tamsulosin, which is a concentration (a level) for therapy or disease prevention, and that means concentration (that level) which is lower than the minimum toxic Concentration (the level) in the plasma following maintenance this is the concentration (mirror) range.

The The term "dosage" means the application method for one pharmaceutical preparation with sustainable release, the tamsulosin or a pharmaceutically acceptable Salt of it and a carrier for the sustainable Contains released pharmaceutical compositions to patients based on therapy or prevention of certain diseases an α-receptor blocking effect. For example, the term "administered after a meal" means administration after about 30 minutes since taking the meal. "With no restriction on food intake" means that when administering a preparation that, for example, has no food effect on bioavailability independently exercising and having no meals for the Administration of the preparation there, i.e. like the one that the Preparation after a meal (approx. 30 min after taking the meal) or before a meal (approx. 30 min before eating the meal) becomes. "Administered under a real condition "means that the preparation is administered without food over at least Is digested for 8 hours.

The term "bioequivalent" means that the 90% confidence interval of the ratio of the mean values of a test to the reference value, which relates to AUC and C _max , is in the range from 80 to 125%.

The The term "backlash" means an effect which represents the effect inherent in tamsulosin, that of therapy or disease prevention based on an α-receptor blocking action is applied.

The The term "bioavailability" means speed and amount of unchanged Substance or an effective metabolite found in the systemic Circulation.

The Term "bioequivalents Preparation "means a preparation in which the bioavailability is equivalent.

The Term "therapeutically equivalent Preparation "means a preparation in which its therapeutic effect is equivalent is.

The Term "no significant Difference "means that it is when the influence of meals, the occurrence of backlash etc. under the objects are evaluated for the use of a preparation with sustainable Release should be compared to the tamsulosin or a pharmaceutical permissible Contains salt of it no statistically significant difference or no difference in the restriction in clinical application.

in the Comparison with the current oral preparation with more sustainable Release containing tamsulosin hydrochloride, which is now clinical Determination provided, indicates the sustainably released pharmaceutical Preparation of the present invention is equivalent or even better potency and there are also adverse incidents such as backlashes (e.g. a postural negative pressure) is reduced. There are also excellent ones characteristic features, namely that the dose can be increased and there is no restriction on the digestion of meals gives. Therefore, the sustained release pharmaceutical composition of the present invention as an excellent preparation for sustained release containing tamsulosin hydrochloride oral application useful.

The sustained release pharmaceutical compositions of tamsulosin or its pharmaceutically acceptable salts for oral use according to the present invention are now explained in detail below.

The Release of the drug from the pharmaceutical composition The present invention is characterized in that it a specific resolution profile with a specific resolution test condition results and has. As a result of this characteristic, is capable of sustainably releasable pharmaceutical composition of the present invention tamsulosin or a pharmaceutically acceptable salt to release it in a sustainable manner so that the plasma tamsulosin concentrations within an effective area for therapy or prevention of diseases based on an α-receptor blocking effect which makes the composition effective, to reduce the occurrence of backlashes.

Tamsulosin is (R) (-) - 5- [2 - [[2- (o-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide and is represented by the following structural formula:

It has been known to have tamsulosin or its pharmaceutically acceptable salt have an α-receptor blocking effect and especially its hypochlorite (the tamsulosin hydrochloride) an α-receptor blocking effect in the urethra and having the prostate and usually as a medicine for Improvement urinary Disorders associated with benign prostatic hyperplasia Reduction of prostatic pressure in the urethra Application has arrived. Furthermore, tamsulosin hydrochloride is a very useful Medicinal product in clinical test because it has been clinically confirmed that it is used for Therapy of lower urinary tract symptoms is effective.

Tamsulosin or a pharmaceutically acceptable Salt thereof were first disclosed in JP-A-56-110665. Tamsulosin is used to form pharmaceutically acceptable acid and base addition salts various inorganic and organic acids or bases. such Salts are also included in the present invention. Examples of such salts are salts with inorganic acids such as with hydrochloric, sulfuric and phosphoric acid, salts with organic acids like with formic, apple, citric and succinic acid, salts with alkali metals such as with sodium and potassium, salts with alkaline earth metals such as with calcium and magnesium, etc. In the present invention the most preferred salt is the hydrochloride. The corresponding Salts can with usual Processes are made.

The Dose of tamsulosin or its pharmaceutically acceptable salt can suitably for be determined and determined in each case, the route of administration, the disease symptom and the age and gender of the patients Account should be taken, although there is no particular limitation for it at least insofar as there is a pharmaceutical by the corresponding dose effective amount for therapy or prevention of specific diseases provided. Usually this dose provides an effective amount for therapy or prevention a disease based on an α-receptor blocking effect and it is for example 0.1 to 2 mg, preferably 0.1 to 1.5 mg, more preferred 0.1 to 1.2 mg, and more preferably 0.4 to 0.8 mg. For improvement a urinary Disfunction associated with benign prostatic hyperplasia is the dose 0.1 to 0.2 mg per day in Japan and 0.4 to 0.8 mg per day in Europe and America. Are tamsulosin or the pharmaceutical permissible Salt of it for other indications are used in addition to urinary dysfunction, would be a Doses of more than 0.8 mg up to approx. 2 mg are expected.

Tamsulosin or the pharmaceutically acceptable Salt thereof which are used in the present invention are easy by means of manufacturing processes described in JP-A-56-110665 and are mentioned in JP-A-62-114952, or with similar production processes available. In addition to the above-mentioned patents, the substances are also means Manufacturing process available, the in the international publication WO 2002/68382, the Korean Patent Laid-Open WO 2002-85278, the International Laid-open specification WO 2003/35608 and in the international laid-open specification WO 2003/37850 or WO 2003/37851 are mentioned.

Regarding the dissolution profile for tamsulosin and its pharmaceutically acceptable Salts which are regulated by the present invention there are no particular restrictions as long as a profile is created which is the initial Release of the drug suppressed and shows sustained release of the drug for a long period of time and results, although the following time resolution conversion (%) is preferred. at execution a dissolution test according to Japanese Pharmacopoeia dissolution test method 2 (200 rpm) the dissolution turnover from tamsulosin after 7 h since the start of the dissolution approx. 20% to approx. 85%, preferably 20% to about 75%, more preferably about 25% to about 65 % or even 5% to approx. 45% such as approx. 5% to approx. 40 or approx. 5 % to approx. 35%. When performing a dissolution test according to the Japanese Pharmacopoeia Dissolution Test Procedure 2 (200 rpm) the dissolution turnover of tamsulosin after 12 h since the start of the dissolution not less than approx. 40% and preferably not less than about 50%. When performing the dissolution tests according to Japanese Pharmacopoeia dissolution test method 2 (200 rpm) the time while who released 50% tamsulosin (T50), no less from about 3 hours to not more than about 15 hours, preferably not less from about 4 h to no more than about 12 h. The above amount of salary is either alone or combined by selecting one or fixed several of them. (Preferably one or more Levels from a group of tamsulosin release sales at 7 h, a group of the release turnover of tamsulosin at 3 h and from a group of the release turnover of tamsulosin selected at 12 h, or it is even more preferred that the respective salary amount from the selected time group.)

Becomes Tamsulosin from the preparation with a higher turnover than the above Resolution sales released, there is a risk that counter reactions such as orthostatic Negative pressure occur. On the other hand, the tamsulosin with a released less than the above-mentioned dissolution sales the risk that the effectiveness for one 1 time a day treatment of a urinary Dysfunction associated with benign prostate hyperplasia is not to be expected, because then the effective plasma concentration is undercut.

For the rest through the tamsulosin hydrochloride preparation, which is now a clinical Determination fed a preparation is provided which has such a dissolution profile shows that the dissolution turnover of tamsulosin when performing a dissolution test according to Japanese Pharmacopoeia dissolution test method 2 (200 rpm) not more than 25% (preferably not more than 15 %) after 2 h in a test solution with pH = 1.2 and then in a test solution with pH = 7.2 the dissolution conversion of tamsulosin not less than 70% after 5 h since the start of the resolution is.

Even though various factors both the dissolution and the absorption behavior influence of drugs in the gastrointestinal tract exist in many make a correlation between the dissolution time of the drug in vitro from the preparation and its bioavailability. About such correlations has been reported in many patents and articles, and in general are the release profiles of the drugs from preparations with controlled Release also useful for assessment of their bioavailability for different types of medicines in special preparations. Thus, the dissolution time of medicines in various preparations is one of the most important and fundamental factors to drug release behavior to evaluate in vivo. Compared to conventional preparations, it is the dose per application in sustainably released preparations bigger, where Moreover the property of sustainable release based a specialized drug release mechanism becomes. Therefore, it is a pretty important factor to consider bioequivalence, that the drug release mechanism right under the preparations in a hungry state (before the After a meal) and after the number of meals (after taking the meal) works.

The dissolution test is to assess equivalence (Similarity) a controlled release mechanism among the preparations and to assess bioequivalence useful. It is believed that the in vivo performance after administration within and between lying deviations would be provided that the drug release profiles are among the preparations similar in vitro would.

The maximum concentration in plasma (C _max ) defined in the present invention means the maximum concentration of tamsulosin in plasma when tamsulosin or a pharmaceutically acceptable salt thereof and a carrier for the sustainably released pharmaceutical preparations are administered orally. If 0.4 mg tamsulosin hydrochloride is administered orally for the first time, it is not more than approx. 20 ng / mL. If 0.4 mg of tamsulosin hydrochloride is repeatedly administered via the mouth, it is preferably not more than approximately 20 ng / ml, more preferably approximately 16 ng / ml and even more preferably approximately 12 ng / ml. Furthermore, if 0.8 mg of tamsulosin hydrochloride is repeatedly administered by mouth, it is preferably not more than about 40 ng / mL, more preferably about 32 ng / mL and even more preferably about 24 ng / mL. Furthermore, if 1.2 mg of tamsulosin hydrochloride is repeatedly administered by mouth, it is preferably not more than approx. 60 ng / ml, more preferably approx. 48 ng / ml and even more preferably approx. 36 ng / ml.

Becomes the current preparation, which contains 0.4 mg tamsulosin The maximum concentration is administered orally when a meal is taken about 10 ng / mL in plasma. And with oral administration before ingestion one meal this approx. 17 ng / mL. In this regard, it should be noted that the maximum concentration of tamsulosin in plasma and the absorption rate of the drug plays a role in the expression of the postural negative pressure, etc. by tamsulosin. In In this regard, a remedy is also of use, which in further released from the preparation in an increased sustainable manner becomes.

How above regarding the range of plasma tamsulosin concentrations no special restrictions, provided that the tamsulosin or a pharmaceutical permissible Salt thereof, which act as an active substance, a plasma level maintain which pharmacologically effective to therapy or Disease prevention is when a pharmaceutical composition, the tamsulosin or a pharmaceutically acceptable salt thereof and one carrier for the contains sustainably released pharmaceutical preparation, orally is administered.

At the carrier for the sustainably released pharmaceutical composition for oral use Use with tamsulosin or pharmaceutically acceptable salts there is no particular limitation as long as it is one Carrier, a pharmaceutical preparation or a pharmaceutical process engineering deals with effective plasma tamsulosin concentrations remain effective for therapy or prevention of diseases are. Examples of the carrier (or pharmaceutical Preparation or pharmaceutical process engineering) with which such compositions and components are created (A) a sustainably released hydrogel-forming preparation, with which the preparation is almost completely while in the stomach and small intestine the upper areas of the gastrointestinal tract is gelled, taking this also a drug release ability even in the intestines of the lower part of the gastrointestinal tract, (B) a preparation of an osmotic pump type, (C) a gel preparation, wherein a variety of rubber products are combined, (D) one Preparation from a multi-layer tablet, comprising a geometric arranged drug layer and one or more release control layer (s), (E) a gastric preparation using a swelling polymer, (F) using a matrix preparation of a water soluble Polymers, etc. All compositions or processing techniques for pharmaceutical preparations, the process techniques for pharmaceutical preparations are involved in the present invention.

(A) Hydrogel-forming preparation with sustainable release

The Carrier, the one here for the sustainably released pharmaceutical composition is used, includes an additive through which water enters the interior of the Preparation can penetrate (which also acts as a gelling agent, as a means of funding gelation or as a hydrophilic base and is abbreviated as "hydrophilic base" in the present description), and a polymer substance that forms a hydrogel (a hydrogel-forming Polymer).

As for the "hydrophilic base", there is no particular limitation as long as it is capable of being dissolved before the hydrogel-forming polymer used for the pharmaceutical preparation is gelled. As for this hydrophilic base, the preferred one is that in which the amount of water required to dissolve 1 g of the substrate is not more than 5 mL (at 20 ± 5 ° C), or more preferably not more than 4 mL (at the same temperature) , and the higher the solubility in water, the higher the penetration effect of water into the preparation. Examples of such a hydrophilic base are polymers with a high solubility in water such as polyethylene glycol (PEG: e.g. PEG 400, PEG 1500, PEG 4000, PEG 6000 and PEG 20000 (trade name), (manufactured by NOF), sugar alcohols such as D-sorbitol and xylitol , Polysaccharides such as sugar, anhydrous maltose, D-fructose, dextran (e.g. Dextran 40) and glucose, surface-active agents such as polyoxyethylene hydrogenated castor oil (HCO: e.g. Cremophor RH 40, manufactured by BASF) and HCO-40 and HCO-60 (manufactured by Nikko Chemicals), polyoxyethylene polyoxypropylene glycol (e.g. Puluronic F 68 (manufactured by Asahi Denka)) and higher fatty acid esters by polyoxyethylene sorbitan (Tween: e.g. Tween 80 (manufactured by Kanto Kagaku)), salts such as sodium and magnesium chloride, organic acids such as lemon and Tartaric acid, amino acids such as glycine, β-alanine and lysine hydrochloride, and aminosugars such as meglumine. Particularly preferred examples are PEG 6000, PVP and D-sorbitol e concerns for the pharmaceutical composition, one component or two or more can be used together.

The relationship The hydrophilic basis in the preparation depends on the characteristic Properties (such as solubility and the therapeutic effect) and the amount contained therein the medicine, the solubility the hydrophilic basis, the characteristic properties of the hydrogel-forming polymer, the patient's condition at Administration, etc., and such a ratio is preferred which is capable of preparation is almost complete to be gelled while the preparation is held back in the upper part of the gastrointestinal tract becomes. Although the preparation time remains in the upper range of the Gastrointestinal tract depending fluctuates from the species and also among individuals, it is approximately 2 h in dogs and 4 to 5 h in humans after administration (Br. J. Clin. Pharmac. (1988), 26, 435-443). Therefore, in humans, the preparation preferably almost completely in 4 to 5 hours after Administration can be gelled. Generally the ratio is hydrophilic base about 5 to 80 wt .-% or preferably about 5 to 60 wt .-%, based on the entire preparation. As for the crowd As far as the hydrophilic base is concerned, gelation does not proceed to the inner surface ahead, and the intestinal release is insufficient when the Insufficient amount is. On the other hand, if the hydrophilic base progresses too much is present, the gelation progresses in a short time, but the gels formed disintegrate easily and a rapid release of the Medicament is observed, which enables a sufficiently sustainable Release is not achieved. There is also, because of the large amount of the substrate, the disadvantage that the size of the preparation itself becomes larger.

It is necessary for the hydrogel-forming polymers used herein that they have the appropriate physical properties, including one viscosity in the gelled preparation that can withstand the power capable of contracting the gastrointestinal tract is produced during the digestion of food and is able to move to the intestines of lower area of the gastrointestinal tract to move without the Form of preparation destroyed becomes.

As for the hydrogel-forming polymer used here, the one that has a high viscosity upon gelation is preferred. For example, the viscosity of a 1% aqueous solution thereof at 25 ° C is not less than 1,000 cps, which is particularly preferred. Incidentally, the behavior of the polymeric substance also depends on its molecular weight (weight average molecular weight), and with respect to the polymeric substance which forms a hydrogel applicable to the preparation, a substance having a higher molecular weight is preferred, and that having an average molecular weight of not less than 2,000,000 is also preferred, or the one with an average molecular weight of not less than 4,000,000 is more preferred. Examples of such a polymeric substance are polyethylene oxide (PEO) with a molecular weight of not less than 2,000,000 and, based on trade names, these are, for example, Polyox WSR-303, a trade name (average molecular weight: 7,000,000; viscosity: 7,500 to 10,000 cps (1% aqueous solution at 25 ° C)), Polyox WSR coagulant (average molecular weight: 5,000,000; viscosity: 5,500 to 7,500 cps (same condition)), Polyox WSR-301 (average molecular weight: 4,000,000, viscosity: 1,650 up to 5,000 cps (same condition)), Polyox WSR-N-60K (average molecular weight: 2,000,000; viscosity: 2,000 to 4,000 cps (2% aqueous solution at 25 ° C)) (all manufactured by Union Carbide), hydroxypropylmethyl cellulose ( HPMC) (with trade names such as Metolose 90 SH 100000 (viscosity: 4,100 to 5,600 cps (1% aqueous solution at 20 ° C)), Metolose 90SH 50000 (viscosity; 2,900 to 3,900 cps (same condition)) and Metolose 90 SH 30000 (Viscosity: 25,000 to 35,000 cps (2% aqueous solution at 20 ° C)) (all manufactured by Shinetsu Chemical), carboxymethyl cellulose sodium (CMC-Na) (with trade names such as San Rose F-15 OMC (average molecular weight: 200,000; Viscosity: 1,200 to 1,800 cps (1% aqueous solution at 25 ° C)), San Rose F-1000 MC (average molecular weight: 420,000; viscosity: 8,000 to 12,000 (same condition)) and San Rose F-300 MC (average molecular weight: 300,000; viscosity: 2,500 to 3,000 cps (same condition) (manufactured by Nippon Paper Industries), hydroxyethyl cellulose (HEC) (with trade names such as HEC Daicel SE 850 (average molecular weight: 1,480,000; viscosity: 2,400 to 3,000 cps (1% aqueous Solution at 25 ° C)) and HEC Daicel SE 900 (average molecular weight: 1,560,000; viscosity: 4,000 to 5,000 cps (same condition)) (manufactured by Daicel Chemical Industries) and carboxyvinyl polymer (such as Carbopol 940 (average molecular weight: approx. 2,500,000) (manufactured by BF Goodrich). Preferred is a PEO with an average molecular weight of not less than 2,000,000. Polymes are sustained release over a long period of time not less than 12 hours those with higher molecular weight, which preferably have an average molecular weight of not less than 4,000,000, and those with higher viscosity, which preferably have a viscosity of the 1% aqueous solution of not less than 3,000 cps at 25 ° C, are advantageously listed and to name. With regard to the hydrogel-forming polymer substances as such, only one component or two or more can be used together. A mixture of two or more polymeric substances with a behavior that corresponds to the above mentioned behavior as a whole can also be used advantageously as the hydrogel-forming polymer substance.

Around a release ability of the drug in the intestine in humans, it is necessary that after at least 6 to 8 h or preferably not shorter than 12 h since the administration of part of the gelled preparation in the Intestine remains. To form a hydrogel preparation with such behavior it is preferred that, more generally, in a preparation of not more than 600 mg per tablet, the ratio of hydrogel-forming Polymer substance for total preparation 10 to 95 or preferably 15 to 90 w / w% and its amount per tablet of the preparation is not less than 70 mg per tablet, or preferably not less than 100 mg per tablet, although this depends on the size of the preparation, the Type of polymeric substance, the amount and behavior of the additive for the penetration of water into the medicine and into the tablets etc. fluctuates. is the above amount less, can prepare an erosion in the gastrointestinal tract during not to withstand the long-term trip, including the danger there is one sufficient long-term release is not achieved.

Becomes Polyethylene oxide is used as the hydrogel-forming polymer yellow and / or red iron (III) oxide (ferrioxide) in such a Amount added that does not change the release characteristics of the drug over time.

yellow or red iron (III) oxide can be used either alone or together.

Regarding the ratio of yellow and / or red iron (III) oxide in the preparation no particular restriction, as long as it has such a value that a matrix preparation is stabilized with controlled release and their drug release characteristics not changed by this becomes. Such a relationship for total preparation preferably 1 to 20 and more preferably 3 to 15 w / w%. In the "physical mix in a matrix " yellow and / or red iron (III) oxide, it is preferably 1 to 20 and more preferably 3 to 15 w / w% based on the total preparation. For example, in the red iron (III) oxide, preferably 5 to 20 and more preferably 10 to 15 w / w%, based on the entire preparation. The yellow one Iron (III) oxide is it preferably 1 to 20, and more preferably 3 to 10 w / w%. Become yellow and / or red iron (III) oxide used by means of a "film coating", it is preferably 0.3 to 2 and more preferably 0.5 to 1.5% based on the weight of the Tablet. It is the concentration of yellow or red iron (III) oxide in the film is preferred 5 to 50, and more preferably 10 to 20%.

The the term "physical" used here Mixture in the matrix "means that e.g. Medicament, polyethylene oxide and the above iron (III) oxide be dispersed uniformly so that the drug and the iron (III) oxide are uniformly dispersed in PEO, which is a main substrate of the Release controlling component. The term "film cover" means that e.g. the above iron (III) oxide in a solution of water-soluble Polymer as dissolved or suspended from hydroxypropylmethyl cellulose and as a coating is present as a thin film on separately prepared tablets. Usually it can yellow and / or red iron (III) oxide are present in every surface in the preparation. For example in the film like a film cover, in the grains after granulation or in a matrix (such as near polyethylene oxide) etc. are available.

What the process for the preparation of such a pharmaceutical preparation with sustained release, there is no particular restriction as long it is a process with which a conventional hydrogel-forming preparation can be produced. As examples you can a compression tabletting process, taking medication, hydrophilic base and hydrogel-forming polymer substance together, if necessary mixed with additives such as yellow and / or red iron (III) oxide and compressing, a capsule compression filling process, an extrusion molding process, the corresponding mixtures melted, solidified and can be molded, an injection molding process, etc. specified. It is possible, too, that, after shaping, a cover treatment like a common one Sugar coating method and a film coating process be applied. It is also possible to shape a capsule to fill.

(B) Preparation of the osmotic pump type:

A preparation of the osmotic pump type is a preparation that uses osmotic pressure to generate a driving force for the penetration of liquid into the preparation through a semipermeable membrane, which allows the liquid to diffuse freely, the medication or the osmosis to diffuse freely but not allowed. Therefore, the effect of the osmotic pressure system shows characteristic egg properties in that the release of the drug without pH dependence at a constant rate is sustained over a long period of time even under circumstances with different pH values during passage through the stomach and intestines.

Over a such preparation is reported by Santus and Baker, "Osmotic drug delivery: a review of the patent literature "in Journal of Controlled Release, 35, Pp. 1-21 (1995). The preparation is also available in US 3,845,770, 3, 916, 899, 3, 995, 631, 4, 008, 719, 4, 111, 202, 4, 160, 020, 4,327,725, 4,519,801, 4,578,075, 4,681,583, 5,019,397 and 5,156,850, and the whole Content that is mentioned in these writings is in the present Description added.

The Preparation of the type of an osmotic pressure pump has a two-layer compressed core on which a drug layer containing tamsulosin or pharmaceutically acceptable Salt thereof (preferably the hydrochloride), and a pressure layer, which is covered with a semipermeable membrane through which Water and external liquids, but do not pass medicine, osmagens or osmopolymer, etc. The semipermeable membrane has at least one drug delivery opening Connection of the inner surface preparation with the outside environment equipped. Therefore, the preparation of the osmotic pump type has a mechanism on, in such a way that, after being given by mouth, liquid like water through the semipermeable membrane into the inner surface of the Preparation and, because of the resulting osmotic effect, Tamsulosin in a sustainable manner with constant speed over one released for a long time through the drug delivery opening becomes.

The Contains drug layer Tamsulosin or a pharmaceutically acceptable salt thereof (preferably that Hydrochloride) in the state of a mixture with selected additives.

How explained in detail below will contain the pressure layer an osmotically active component or osmotically active components, it contains but no tamsulosin or a pharmaceutically acceptable salt thereof. The osmotic Pressure component or the osmotic pressure components are representative from an osmotic agent (osmotic agent) and one or more osmopolymer (s) composed. The term "osmopolymer" used here means a polymer with a relatively large molecular weight shows and results in swelling upon absorption of liquid, so as to release tamsulosin through a drug delivery port.

What the semipermeable membrane used here does not exist special limitation as long as they have high permeability for external liquids like water and body fluids for tamsulosin, Osmagens, osmopolymer, etc. but is essentially impermeable. Such a semi-permeable membrane is inherently non-erosive and insoluble in the body.

semipermeable Homopolymers, semipermeable copolymers, etc. can be used to form a semipermeable Membrane used polymer listed and specified. What the material for As for the polymer as such, cellulose type polymers can be used such as cellulose esters, cellulose ethers and cellulose ester ethers become. As for the polymer of a cellulose type, that is used, the degree of substitution (DS) of the anhydroglucose unit is more than 0 and not more than 3. The degree of substitution (DS) stands for an average number of the hydroxyl group originally based on the anhydroglucose unit is present and substituted with a substituent or is transferred to another group. The anhydroglucose unit can be partial or complete with a group such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, Halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, Alkyl sulfamate and with a semipermeable polymer Group may be substituted (the organic radical contains 1 to 12 or preferably 1 to 8 carbon atoms).

Regarding the semipermeable composition, one or more members are used, selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylate, mono-, di- and trialkenylate, , Di- and triaroylate, etc. Representative polymers are cellulose acetate with 1.8 to 2.3 DS and 32 to 39.9% acetyl content, cellulose diacetate with 1 to 2 DS and 21 to 35 acetyl content, cellulose triacetate with 2 to 3 DS and 34 to 44.8% acetyl content, etc. Even more specific polymers of the cellulose type are cellulose propionate with 1.8 DS and 38.5 propionyl content, cellulose acetate propionate with 1.5 to 7 acetyl content and 39 to 42 % Propionyl content, cellulose acetate propionate with 2.5 to 3% acetyl content, 39.2 to 45 average propionyl content and with 2.8 to 5.4 hydroxyl content, cellulose acetate butyrate with 1.8 DS, 13 to 15 acetyl Content and with 34 b is 39% butyryl content or with 2 to 29% acetyl content and 17 to 53% butyryl content and with 0.5 to 4.7% hydroxyl content, cellulose triacylate with 2.6 to 3 DS (such as cellulose trivia lerat, Cellulosetrilamat, Cellulosetripalmitat, cellulose trioctanoate and cellulose tripropionate), cellulose diesters with 2.2 to 2.6 DS (such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate and Cellulosedicaprylat) and mixed Celluloseester (such Celluloseacetatvalerat, cellulose acetate succinate, Cellulosepropionatsuccinat, Celluloseacetatoctanoat, Cellulosevaleratpalmitat, Celluloseacetatheptanoat etc.) , The semipermeable polymers are in US 4,077,407 and such polymers are available by synthesis according to a method mentioned in "Encyclopedia of Polymer Science and Technology", volume 3, pages 325 to 354 (1964), Interscience Publishers, Inc., New York, NY. There are no particular restrictions with regard to the compounding amount of the polymer used, as long as these represent an amount with which the permeability is high for external liquids such as water and body fluids, but essentially not for tamsulosin, osmagens, osmopolymer, etc., although the corresponding amount is preferably 6 to 20 or more preferably 8 to 18 w / w% based on the weight of the two-layer compressed core comprising the medicament and pressure layer.

The semipermeable polymer to form the semipermeable membrane further includes cellulose acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose dimethylamino acetate, semipermeable polyurethane, semipermeable sulfonated polystyrene, or a crosslinked polymer formed by anipermondentation3, 5, 3, 3, 3, 3, 3, 3, 4, 3, 4, 3, 4, 3, 4, 3, 4, and 4, 5, 4, 5, 4, 4, and 4, a crosslinked polymer of aniphenylated, 3,5, anodized, by Aniphenyl, Coated, Anodized, Anodized, Coated by Aniphenyl, Compounded, Anodized, By Aniphenol; , 3,541,006 and 3,546,142, a semipermeable polymer, a semipermeable polystyrene derivative, semipermeable poly (sodium styrene sulfonate) and semipermeable poly (vinylbenzyltrimethylammonium chloride) disclosed in US 3,133,132 , and a semipermeable polymer with a liquid permeability of 10 ^-5 to 10 ^-2 (cc mL / cm h atm) based on the hydrostatic pressure difference or the osmotic pressure difference per atmosphere when passing through a semipermeable wall. Such polymers are mentioned in US 3,845,770, 3,916,899 and 4,160,020 and are also described in the "Handbook of Common Polymers" by Scott and Roff, 1971, CRC Press, Cleveland, Ohio.

The semipermeable membrane can contain a flow regulator. The The term "flow regulating agent" used here means a substance which helps the fluid permeability or the amount of liquid adapt that passes through the semipermeable membrane. Consequently contains a "flow regulator" a substance that has the effect of increasing the flow (hereinafter referred to as as a "flow enhancer"), or a substance, which has the effect of lowering the flow (hereinafter referred to as as a "river subsidence"). The flow enhancer is essentially hydrophilic while the flow depressant is substantially hydrophobic. Examples such flow enhancers are polyhydric alcohols, polyalkylene glycol, Polyalkylene diol and alkylene glycol polyester. Representative flow enhancers conclude Polyethylene glycol 300, 400, 600, 1500, 4000, 6000 etc., low molecular weight Glycol 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) etc., fatty acid esters of 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol etc., alkylene triols such as glycerol, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol etc., and esters such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate, Glycery acetate esters, etc. The preferred flow enhancer conclude Propylene glycol, bifunctional copolymer polyoxyalkylenes or derivatives one of which is a Pluronic (trademark) (manufactured by BASF) are known. The representative Close river sediment Alkyl or alkoxy substituted or alkyl and alkoxy substituted Phthalate such as diethyl phthalate, dimethoxyethyl phthalate and dimethyl phthalate, [Di (2-ethylhexyl) phthalate], Aryl phthalate 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, polymers in powder or particle form, etc. such as polystyrene, Polymethyl methacrylate, polycarbonate and polysulfone, esters such as citrate, esterified with a long chain alkyl group, and inactive and water impermeable fillers such as resins made with a material to form a semi-permeable Cellulose-type membrane are compatible.

The Compounding amount of the "flow regulating agent", which in the semi-permeable Membrane is included about 0.01 to about 20 w / w% or more.

The semipermeable membrane may contain a phthalate type plasticizer such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, C _6-11 straight chain phthalate, diisononyl phthalate, diisodecyl phthalate, etc. to impart plasticity, softness and spreadability to the semipermeable membrane to render the semipermeable or brittle to make it tearproof. Examples of such plasticizers are non-phthalate such as triacetin, dioctyl azelate, oxidized tallate, triisooctyl trimellitate, triisononyl mellitate, sucrose acetate isobutyrate, epoxidized soybean oil, etc.

The Compounding amount of plasticizer in the semi-permeable membrane is about 0.01 to 20 w / w% or more.

The pressure layer used is in the state of a layered contact arrangement to the medicament layer in front. For extruding tamsulosin or a pharmaceutically acceptable salt from an opening the preparation contains the pressure layer an osmopolymer that is absorbed by an aqueous fluid or body fluids is swollen. The term "osmopolymer" used here means a polymer that results interaction with water or aqueous biological fluids swelled up or expanded. The preferred osmopolymer as such is a hydrophilic polymer that is capable of expanding to to give a volume increase of 2 to 50 times. The osmopolymer can either networked or not networked, although it is, in one preferred embodiment, it is advantageous that it is at least slightly networked is so as to form a polymer network structure that so much is enlarged, that it is too big to step out of the preparation. Although the amount of compounding used of the "osmopolymer" of factors such as the characteristic properties, the content etc. of the medicine in the drug layer depends exist for it no special restrictions, provided that a lot is provided with the drug in the drug layer with a desired release rate is released. However, it is preferred that an amount of not less than 30 mg, and more preferably not less than 50 mg is included. The compounding quantity, based on the weight the pressure layer, is 40 to 80 w / w%.

The The "osmopolymer" used contains one Component selected made of poly (alkylene oxide) with a number average molecular weight from 1,000,000 to 15,000,000 represented by e.g. polyethylene oxide, or of poly (alkali carboxymethyl cellulose) with an average number Molecular weight from 500,000 to 3,500,000 (in which the alkali sodium, Is potassium or lithium). Also to be mentioned are osmopolymers containing a hydrogel-forming polymer such as Carbopol (registered trademark), an acidic carboxyl polymer, an acrylic polymer cross-linked with polyallylsucrose, called carboxypolymethylene is known a carboxyvinyl polymer with a molecular weight of 250,000 to 4,000,000, cyanamer (registered Trademark) such as polyacrylamide, a cross-linked, water-swelling anhydrous indene-maleic acid polymer, Good-rite (registered trademark) such as polyacrylic acid a molecular weight of 80,000 to 200,000, acrylate polymer polysaccharide, extensively condensed glucose units, such as Aqua-Keeps (registered Trademark), and diester cross-linked polyglucan, etc. Polymers, which form a hydrogel are disclosed in US 3,865,108, 4,002,173 and 4,207,893 and also in the "Handbook of Common Polymers "by Scott and Roff, Chemical Rubber Co., Cleveland, Ohio.

What relates to the osmagens used herein (also known as an osmotic dissolved Substance or as an osmotically effective agent can), which is both in the drug layer, the tamsulosin or a pharmaceutically acceptable Contains salt thereof as well as in the pressure layer there are no particular restrictions, as long as this has an osmotic gradient through a semipermeable Membrane shows and results. In terms of of Osmagen can one or more members are listed and named, selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, Magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, Lithium sulfate, acidic potassium phosphate, mannitol, glucose, lactose, Sorbitol, an inorganic salt, an organic salt and from carbohydrates, The Osmagen compounding amount used is 15 to 40 w / w%, based on the weight of the pressure layer.

Regarding one Solvent, which are suitable for the preparation of the structural element for the preparation water-soluble or inactive organic solvents to be mentioned that do not have a detrimental effect on the substances used in the system. The solvent broadly covers a component selected from the group consisting of from watery solvents Alcohols, ketones, esters, ethers, aliphatic, halogenated, alicyclic, aromatic and heterocyclic solvents and mixtures thereof.

Representative solvent conclude 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, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, a watery Solvent, containing an inorganic salt such as sodium and calcium chloride, and a mixture thereof such as acetone and water, acetone and methanol, Acetone and ethyl alcohol, methylene chloride and methanol and ethylene dichloride and methanol.

The drug layer used is made up of a pharmaceutical composition, the tamsulosin or a pharmaceutically acceptable salt thereof in a pharmacologically effective amount for therapy or prevention and includes a carrier for the sustainably released pharmaceutical composition. Such a carrier for a sustainably released pharmaceutical composition can contain a hydrophilic polymer. Such a hydrophilic polymer has an effect of releasing tamsulosin or a pharmaceutically acceptable salt thereof at a certain rate. Such a polymer includes poly (alkylene oxide) with 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), and poly (carboxymethyl cellulose) with a number average molecular weight of 40,000 to 400,000, of which the representative poly (alkali carboxymethyl cellulose), poly (sodium carboxymethyl cellulose), poly (potassium carboxymethyl cellulose) and poly (lithium carboxymethyl cellulose). The pharmaceutical composition may include hydroxypropylalkyl cellulose with a number average molecular weight of 9,200 to 125,000, the representative examples of which are hydroxypropylethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl butyl cellulose and hydroxypropyl pentyl cellulose to improve the delivery characteristics of the preparation, and poly (vinyl pyrrolidone) with a number average molecular weight of 75,000 to improve 7,000 the flow properties of the preparation included. Among the polymers as such, the most preferred is poly (ethylene oxide) with a number average molecular weight of 100,000 to 300,000. Although the compounding ratio of the hydrophilic polymer used depends on factors such as the physico-chemical behavior, the content, etc. of the medicament contained therein, it is 40 to 90% by weight, based on the weight of the medicament layer.

Possibly, can a surface active Agent or a disintegrant be incorporated into the medication layer. Regarding the surface active By means of, can those whose HLB value is approximately 10 to 25 are mentioned, such as Polyethylene glycol 400 monostearate, polyoxyethylene 4 sorbitan monolaurate, Polyoxyethylene 20 sorbitan monooleate, Polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 monolaurate, Polyoxyethylene 40 stearate and sodium oleate. Regarding the decay promoting agent, these can from strength, Clay, cellulose, argin and rubber and from cross-linked starch, cellulose and selected from corresponding polymers. Representative can Corn starch, Potato starch, Croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methyl cellulose, Agar, bentonite, carboxymethyl cellulose, alginic acid, guar gum, etc. listed and be called.

On Pans coating method can produce a final treated preparation can be applied, with the outlet opening on the surface the preparation for releasing the drug remains excluded. In a pan coating system can use the composition to form a semipermeable membrane by spraying the semi-permeable membrane is compressed onto the surface of a two-layer Core adherent (by covering) are applied, this being built up from a pressure layer and a medication layer is that tumble in the rotating pan. It is also possible to put on of the above compressed core with a semipermeable Membrane common Procedure according to the state to apply the technology with which the technical Average professionals are familiar. After the application of the semipermeable membrane the semipermeable membrane in an oven with forced ventilation or dried in an oven with controlled temperature and humidity, whereby the solvent or solvents, the for the stalling process used, can be removed from the preparation. The drying conditions used here can be suitably in dependence of the available Devices, environmental conditions, solvents, coating agents, the thickness of the coating etc. selected become.

The sustained release pharmaceutical composition can be prepared by a method known per se. For example, the preparation can be produced using a wet granulation process technology. Regarding the wet granulation process technique, an organic solvent such as a denatured anhydrous alcohol is used as the solution for the granulation, and the drug and a carrier for the sustained released pharmaceutical composition are mixed. Other components may be dissolved in part of the granulation solution as in the above-mentioned solvents, and the wet mixture, which has been prepared separately, is gradually added to the drug together with continuous mixing in a mixer. The granulation solution is then added until a wet mixture is formed. The wet block mixture is passed through a sieve which was previously placed on an oven tray. The mixture is then dried in an oven with forced ventilation at a temperature of about 24 to 35 ° C. for about 18 to about 24 hours. The dried particles are then standardized in terms of their size. Then a lubricant such as magnesium stearate is added to the medicament particles, and the particles are put in a pot in which they disintegrate finely and mixed in the drip mill for about 10 minutes. The composition is pressed into layers in a Manesty (registered trademark) press machine, for example, or in a Korsch LCT press machine. In the two-layer core, the drug-containing layer is pressed, and a wet mixture of one is similar prepared composition for the pressure layer pressed onto the medicinal layer. One or more outlet openings are opened at one end of the medicament layer of the preparation. For a finished preparation, a water-soluble outer coating, which can be either colored (such as an Opadry color coating) or transparent (such as a clear Opadry coating), can be applied if necessary.

At least one exit mouth is formed in the sustainably releasable pharmaceutical preparation. The medicine is released uniformly from the preparation through the outlet mouth in cooperation with the compressed core. The exit orifice can be installed either during the preparation of the preparation or during the dispensing of the medicament by the preparation under the applied aqueous environment. The term "exit orifice", "delivery orifice" or "drug delivery orifice" and other similar terms used herein include terms selected from the group consisting of passageway, opening, mouth and bore. The term also includes an opening formed by a polymer or substance that is eroded, detached, or inserted from the outer wall. The substance or the polymer may also include a pore-forming substance that has liquid elimination capability selected from the group consisting of, for example, penetrating poly (glycolic acid) or poly (lactic acid), gelatinous filaments, water-removing poly (vinyl alcohol), and from an penetrating compound such as inorganic and organic salts, oxides and carbohydrates. The exit orifice (s) is / are formed by installing one or more exit orifices with small diameters in such a size that one or more component (s) selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose , Talose, sodium chloride, potassium chloride, sodium citrate and from mannitol, so that it is possible to control the constant release of the medicine. The outlet mouth can be in any shape such as a circle, horizontal bar, square, ellipse, etc. for the predetermined release of the medicament from the preparation. One or more exit orifices are / are formed in the preparation in a predetermined intermediate space or on one or more surface (s) of the preparation. There are no particular restrictions as to the diameter of the exit orifice, provided that it is possible to control the release of the drug in cooperation with the compressed core, but the diameter is preferably 0.3 to 0.6 mm. A hole-making process that passes through the semipermeable membrane, including mechanical hole-making and laser hole-making processes, can be used to form the exit orifice. An exit mouth as such and a device for forming an exit mouth as such is shown in US 3,916,899 by Theeuwes and Higuchi and in US 4,088,864 by Theeuwes et al. and all of the content set forth in these patents is incorporated into the present specification.

(C) Gel preparation in which a variety of rubber products are combined is.

The used carriers for the pharmaceutical composition with sustainable release a sustained release excipient, a heteropolysaccharide gum and a homopolysaccharide which is used to form a crosslink with the heteropolysaccharide rubber is able if there is an ambient fluid is exposed to an inert diluent selected from e.g. a monosaccharide, disaccharide, polyhydric alcohol and from a mixture thereof, and a pharmaceutically acceptable water-soluble cationic crosslinking agent in order to sustainably release the Medicine about to result at least approx. 24 h if the preparation contains ambient liquids is exposed. In the "ambient liquid" can be an aqueous solution that e.g. For an in vitro dissolution test is used, in addition to body fluids like blood and gastric fluid be included.

How in U.S. 4,949,276, 5,128,143 and 5,135,757 it has been known to comprise a heterodispersing excipient a combination of a homo- and heteropolysaccharide, the synergism shows how a combination of two or more polysaccharide rubber products, a higher one viscosity than each of the individual rubber products and has rapid hydration results and that such a gel is formed faster and harder.

The "Heteropolysaccharide" is used as a water-soluble Polysaccharide defined that contains 2 or more sugar units. Regarding the heteropolysaccharide, there are no particular restrictions as long as it is branched or spiral steric configuration and excellent water absorbency and a high viscosity behavior having. In terms of of the heteropolysaccharide as such are a xanthan gum and Derivatives thereof such as deacylated xanthan gum, a carboxymethyl ether and a propylene glycol ester is preferred. Favorable substances are Heteropolysaccharides with a high molecular weight (> 106) and a xanthan gum.

The "homopolysaccharide" used is defined as a single polysaccharide, which comprises only 1 type of monosaccharide. Regarding this homopolysaccharide, there are no particular restrictions as long as it is for education is capable of crosslinking with the heteropolysaccharide. Regarding the Homopolysaccharide as such becomes a. Galactomannan gum (a polysaccharide, comprehensively called mannose, and only galactose). The preferred substance is a locust bean gum, in which galactose is the mannose in relatively high amount replaced.

Regarding the Combination of "heteropolysaccharide" with "homopolysaccharide" is a combination of Xanthan gum with locust bean gum is particularly preferred. In terms of the compounding ratio from "heteropolysaccharide" to "homopolysaccharide", none exist special restrictions as long an adequate amount is available to obtain the desired Gel strength affects. In terms of of the relationship as such The relationship from heteropolysaccharide gum to galactomannan gum about 3:12 to about 1: 3 and more preferred approx. 1: 1.

The Homopolysaccharide is not limited to galactomannan gum, and the excipient for sustainable release comprises approx. 1 to approx. 99 w / w% heteropolysaccharide gum and approx. 99 to 1 w / w% homopolysaccharide gum. The compounding ratio of the rubber is about 30 to about 60 w / w%, or preferably about 35 to about 50 w / w %, based on the weight of the pharmaceutical composition for sustainable release.

The relationship of tamsulosin or a pharmaceutically acceptable salt thereof to gum is usually approx. 1: 1 to approx. 1: 5 and preferably approx. 1: 1.5 to approx. 1: 4.

At the used water-soluble cationic crosslinking agents have no particular restrictions, as long as this is pharmaceutically permissible and a single or has polyvalent metal cation. What the crosslinking agent as As such, preferred examples thereof are various inorganic ones Salts, e.g. those with an alkali and / or alkaline earth metal, such as sulfate, chloride, borate, bromide, citrate, acetate and lactate. More specific Examples of the crosslinking agent are calcium sulfate, sodium chloride, Potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, Sodium borate, potassium bromide, potassium fluoride, sodium hydrogen carbonate, Calcium chloride, magnesium chloride, sodium citrate, sodium acetate, Calcium lactate, magnesium sulfate and sodium fluoride. With the above polyvalent metal cation is a two-valued one. Calcium sulfate is suitable as the salt or sodium chloride.

The Application amount of the water-soluble cationic crosslinking agent is preferably about 1 to about 20 w / w%, based on the total weight of the sustainably released pharmaceutical composition. Most preferably, the crosslinking agent is approx. 10 w / w%, based on the total weight of the pharmaceutical Composition.

At the inert diluent there are no particular restrictions as long as it is pharmaceutical permissible is. In terms of of the diluent as such, can Sugar, including Mono- and disaccharides, polyhydric alcohols, cellulose derivatives and / or a mixture of the above given as examples become. Can be more specific Sucrose, dextrose, lactose, fine crystalline cellulose, hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, carboxymethyl cellulose, fructose, xylitol, Sorbitol and a mixture thereof are given as examples. Under it is preferred to use a soluble one thinner for the To use preparation such as lactose, dextrose, sucrose and a mix of them.

The above sustained release pharmaceutical composition can be prepared as a pharmaceutically acceptable solid pharmaceutical dosage form for oral use such as a tablet. As for such a sustained release pharmaceutical composition, (1) the heteropolysaccharide gum and the homopolysaccharide capable of crosslinking the heteropolysaccharide gum when exposed to ambient liquid are dried and in a desired ratio together with one mixed pharmaceutically acceptable inert diluent, (2) the mixture is subjected to wet granulation, (3) the grains are dried, (4) the dried grains are pulverized to give an excipient for sustained release with the desired particle size, the resulting excipient for sustainable Release is (5) granulated together with tamsulosin and a pharmaceutically acceptable salt thereof, (6) the resulting grains are dried, then (7) an inert excipient (such as a lubricant) is added, and the mixture is then added, for example (8) Compression shaped to give tablets n. In a further embodiment, a mixture of an excipient for sustained release and of tamsulosin or a pharmaceutically acceptable salt thereof is granulated together with a solution of a hydrophobic substance in an amount, enough to delay their hydration without destroying the rubber. Then an inert excipient (such as a lubricant) is added and the mixture is made into tablets, for example, by compression molding.

wet granulation means that predetermined amounts of heteropolysaccharide gum, Humopolysaccharide gum, cationic crosslinking agent and inert thinner homogeneously mixed, then a humidifier such as water, propylene glycol, Added glycerin or alcohol, the prepared wet agglomerates are dried and the dried ones Agglomerates in a conventional Device are pulverized, thereby making grains with a predetermined Particle size produced become.

At the Lubricants can stearic acid, Magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. called and sodium stearyl fumarate (Edward Mendell Co., Inc., trade name: PruvR) is particularly preferred. Regarding the amount of the lubricant, are about 0.5 to 3 w / w%, based on the total weight of the pharmaceutical Sustainable release composition applied. What that Process for applying the hydrophobic substance with the excipient For sustained release concerns, a method can serve as an example can be specified, with a further granulation together with the grains above is carried out in a solution wherein the hydrophobic substance in an organic solvent solved and / or is dispersed.

Regarding the hydrophobic substance, can Ethyl cellulose, acrylic and / or methacrylic acid polymers or copolymers, hydrogenated vegetable oil, Zein and a pharmaceutically acceptable hydrophobic cellulose substance such as acrylic cellulose mentioned as examples become. The addition amount of this hydrophobic substance based on the total weight of the pharmaceutical composition for sustainable Release preferably about 1 to about 20 w / w%, more preferably about 3 to about 12 W / w% and more preferably about 5 to about 10 w / w%.

On Example of the best combination of components is based on that Xanthan gum as "heteropolysaccharide" and locust bean gum as "homopolysaccharide" in a compounding ratio of approx. 1: 1 in an amount of approx. 35 to approx. 50 w / w%, based on the total weight of the pharmaceutical composition with sustainable Release, and then no more than about 10 w / w calcium sulfate as "water soluble cationic crosslinking agent ", approx. 35 w / w% dextrose as "inert Diluent "and about 5 to about 10 w / w% ethyl cellulose as "hydrophobic Substance "applied become.

(D) Multilayer tablet comprising a geometrically arranged one Drug layer and release control layer

The Carrier, the for the sustained release pharmaceutical composition is used includes a drug-containing layer and release control layer with the following structure:

• a) a first layer (layer 1) through Compressing a mixture that is 5 to 90 w / w (preferably 10 to 85 w / w%) water soluble Polymer contained in the layer and the property of swelling in contact with ambient fluids exhibit;
• b) a second layer (layer 2) comprising a water-soluble Polymer and other auxiliary substances and containing tamsulosin or a pharmaceutically acceptable Salt thereof (preferably the hydrochloride) with the layer on adjoining the first layer, suitable compressibility properties has and is designed to be a physiologically active substance within release a predetermined time; and, if necessary, With
• c) a third layer (layer 3) adhering to layer 2 and a water soluble Polymer that is generally gelled and / or swollen, followed by it crumbles freely, includes and has the function of releasing tamsulosin or a pharmaceutically acceptable Salt thereof (preferably the hydrochloride) from layer 2 Taxes. The "ambient fluids" include one aqueous solution like those one for a dissolution test additionally to body fluids like blood, gastric and intestinal fluids be used.

As in US 4,839,177 and 5,422,123 called, the above pharmaceutical composition for sustained release is characterized in that the medicament-containing layer 2 is arranged as a sandwich between the layer 1 and the layer 3, in which no medicine or this is only optionally contained, whereby the speed and amount of Release of the drug from the pharmaceutical preparation can be controlled in a targeted manner. As also in US 5,780,057 and 6,149,940 called, it is known that in the above pharmaceutical composition for sustained release at least one of the Layer 1 and layer 3 expand rapidly upon contact with body fluids and then layer 2 is expanded or, in other words, the volume of the pharmaceutical composition increases significantly, whereupon the function arises that the pharmaceutical composition remains in the stomach for an extended period of time and most of the active ingredient contained in the upper region of the gastrointestinal tract is released and absorbed in a controlled manner.

The Layer 1 and layer 3 can the same composition and the same functional characteristics or a different composition and different Have characteristics. With the same functional characteristics and Composition of layer 1 and layer 3 can be their Amounts and thicknesses that surround layer 2 as a sandwich can be changed. At least one of layers 1 and 3 acts as a barrier Release of the active ingredient, or it is, in other words, impermeable, from which tamsulosin or a salt thereof (preferably the hydrochloride), that are contained in layer 2, not released or diffused and at least one of the layers has the characteristic property that it is expanding rapidly or, in other words, its volume rises quickly. Optionally, layer 3 also contains the medicine so that it enables will result in a supplementary release of the drug, which is differs from that from layer 2.

The Amount of tamsulosin or the pharmaceutically acceptable salt thereof (preferably of hydrochloride) has already been mentioned and specified.

At the water-soluble Polymer used in Layer 1, Layer 3 and Layer 2 there are no particular restrictions as long as it is pharmaceutical permissible is and a biocompatibility having. Such a water soluble Polymer is in an aqueous liquid gradually solved and / or gradually gelled and / or can quickly or with different Speed can be gelled and then disintegrate if necessary. Specific examples of such a water-soluble polymer are hydroxymethyl cellulose, Hydroxyethyl cellulose, hydroxypropyl methyl cellulose with a molecular weight from 1,000 to 4,000,000, hydroxypropyl cellulose with a molecular weight from 2,000 to 2,000,000, carboxyvinyl polymer, Chitsoan, Mannan, Galactomannan, xanthan, carrageenan, amylase, alginic acid or a salt or derivative thereof, pectin, acrylate, methacrylate, acrylic / methacrylic acid copolymer, polyacid, polyamino Poly (methyl vinyl ether / maleic anhydride) polymer, Polyvinyl alcohol, glucan, scleroglucan, carboxymethyl cellulose and Derivatives thereof, ethyl cellulose, methyl cellulose and conventional water-soluble cellulose derivatives. Hydroxypropylmethyl cellulose with a molecular weight is preferred from 3,000 to 2,000,000. The application amount of layer 1 and Layer 3, based on its weight, is usually 5 to 90 w / w%, preferably 10 to 85 w / w% and more preferably 20 to 80 w / w%. The application amount of water soluble Polymer in layer 2, based on its weight, is usually 5 to 90 and preferably 10 to 85 w / w%.

In order to rapidly increase the volume of the pharmaceutical preparation containing the above water-soluble polymer in the production of layer 1 and layer 3, it is possible to use a water-soluble excipient which promotes the degree of wetting of the layers. Regarding the water-soluble excipient, it is preferred to select it from a group of so-called super-disintegration excipients such as cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropylmethyl cellulose with low or medium molecular weight, cross-linked sodium carboxymethyl cellulose, carboxymethyl starch and salts thereof, from divinylbenzate / potassium Copolymers, etc. The compounding amount of the excipient is 1 to not more than 90 and preferably 5 to 50% by weight of the layer. If necessary, a surfactant (anionic, cationic and non-ionic) can be used to improve the wetting so that the ambient fluids and the tablets are made more compatible, whereby the pharmaceutical composition, in particular the gel-forming layer, can be quickly gelled , Examples of such a substance are sodium lauryl sulfate, sodium ricinolate, sodium tetradecyl sulfonate, sodium dioctyl sulfosuccinate, cetomagrogol, poloxamer, glyceryl monostearate, polysolvate, sorbitan monolaurate, lecithins and other pharmaceutically acceptable surface-active agents. If necessary, it is also possible to use another substance that modifies the hydration. Such a substance is made from hydrophilic diluents such as mannitol, lactose, starch from various sources, sorbitol, xylitol, microcrystalline cellulose and / or from a substance which generally promotes the penetration of water or an aqueous liquid into a pharmaceutical composition a hydrophobic diluent such as from ethyl cellulose, glyceryl monostearate, palmitate, hydrogenated or non-hydrogenated vegetable oil (e.g. from hydrogenated castor oil, wax, mono-, di- and from triglycerides) etc., all of which are selected for the penetration of water or an aqueous liquid into the pharmaceutical Delay preparation. Preferably, it is desirable to choose ethyl cellulose or hydrogenated vegetable oil as the hydrophobic diluent. The amount of hydrophobic diluent in layer 1 and layer 3 is usually 1 to 60 w / w%, preferably 5 to 40 w / w% and more preferably 10 to 30 w / w%, based on their weight.

The pharmaceutical preparation for sustainable release can be a Lubricants such as magnesium stearate, talc, stearic acid, glyceryl monostearate, Polyoxyethylene glycol with a molecular weight of 400 to 7,000,000, hydrogenated castor oil, Glyceryl behenate, mono-, di- and triglycerides etc., fluidizing agents such as colloidal silica or other silicas, Binder, buffer, absorbent and pharmaceutically acceptable others Contain additives.

The Tablets from the pharmaceutical composition for sustainable Release can can be produced, for example, by a method, the corresponding powder and / or particles by means of a known Manufacturing process technology mixed and then compressed. A pharmaceutical composition that contains 2 or 3 layers (such as as a tablet), can be carried out using a tablet method known per se getting produced. The tablet of the present invention can are produced, e.g. a rotary press is used, the empowerment creates "multilayer" tablets. The compression pressure to make the tablets is usually 7 up to 50 kN (kilonewtons). For making tablets in small scale is it also possible that the powder and / or the particles are each using a mortar and pestles are made, and that tablets of 2 or 3 Layers in an oil press tablet machine getting produced. The thickness of each layer of the tablet can be dependent on vary from the amount of active ingredient, although they usually are within a range of preferably 0.2 to 8 and more preferably of 1 to 4 mm. In the pharmaceutical composition (like one Tablet) of the present invention can be the pharmaceutical composition with a coating layer coated from a polymer material with the objective, e.g. to protect the tablet or an initial Delay the release of the active ingredient, which may otherwise occur released too quickly from the pharmaceutical composition. The coating can be one solubility in an acidic solution or a permeability have, so that, after a predetermined time, the tablet releases the active ingredient. Such a coating can with one in itself known methods using an organic or aqueous solution be applied.

The pharmaceutical composition (like a tablet) increases quickly their volume when in contact with liquids and / or gastrointestinal fluids. The volume increase as such can be in a single layer or fixed and limited in several layers in one tablet his. Such a pharmaceutical composition (like a tablet) is characterized in that after 2 h the volume of at least a layer to an extent 1.5 or preferably at least 3 times the initial volume increases. The pharmaceutical composition can be in the form of a Tablet, from small tablets or a gelatin capsule, the small one Includes tablets. It is also possible for at least two small tablets in the same pharmaceutical composition combined. these can e.g. packed in a wafer capsule or in a gelatin capsule his. A pharmaceutical composition includes small tablets, each of these can have a different or the same composition exhibit.

(E) Gastroretentive dosage form using swelling polymers

The for the pharmaceutical composition used for sustainable release carrier comprises a high molecular weight water-soluble polymer that acts on absorption is swollen by water. Such a polymer can either be used alone or used in a combined manner.

On for the pharmaceutical composition used for sustainable release carrier is e.g. in U.S. 6,340,475, 5,972,389, 5,582,837 and 5,007,790 , and in the present description, the entire in content mentioned above descriptions included.

With the "high molecular water soluble Polymer that swells when water is absorbed "does not exist Limitations, as long as it's pharmaceutically acceptable is without limitation in terms of its size when absorbed is swollen with water and releases the medicine in a sustainable manner can. The polymer as such is preferably a polymer with a weight average molecular weight of no less than about 4,500,000, more preferably a polymer with a weight average Molecular weight from about 4,500,000 to about 10,000,000 and special preferably a polymer with a weight average molecular weight from approx.5,000,000 to approx.8,000,000.

Regarding the polymer as such, cellulose polymers and derivatives thereof, polysaccharides and derivatives thereof, polyalkylene oxide and crosslinked polyacrylic acid derivatives thereof are listed and indicated. Here the term "cellulose" stands for a linear polymer of anhydroglucose. A preferred cellulose polymer is an alkyl substituted cellulose polymer that is soluble in the gastrointestinal tract. The preferred alkyl-substituted cellulose derivative is that which is each substituted with a C _1-3 alkyl group. Examples of such a polymer are methyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl and carboxymethyl cellulose. The preferred viscosity includes the case where the viscosity of a 2% aqueous solution at 20 ° C is within a range from about 100 to about 110,000 cps. Another type includes the case where the viscosity of a 1% aqueous solution at 20 ° C is within a range of about 1,000 to about 4,000 cps. The particularly alkyl-substituted cellulose is hydroxyethyl cellulose and hydroxypropyl methyl cellulose. The preferred hydroxyethyl cellulose is currently Natrasol (registered trademark) 250 HX NF.

As the particularly preferred polymer as such becomes a polyalkylene oxide derivative listed and named, and is a more preferred polyalkylene oxide a polyethylene oxide that for is a linear polymer of unsubstituted ethylene oxide. The preferred polyethylene oxide has a weight average Molecular weight in the range of approximately 900,000 to approximately 8,000,000. The preferred viscosity range includes the case where the viscosity a 2% aqueous solution at 20 ° C is in a range from approx. 50 to approx. 2,000,000 cps. The preferred Polyethylene oxide is currently Polyox (registered trademark), and Grade WSR coagulant and Grade WSR 303 can be listed and named become.

additional Examples of such a polymer are both natural and modified (semi-synthetic) polysaccharide rubber species such as dextran, xanthan gum, Gellan gum, Welan gum and Rhamsan gum, with xanthan gum being preferred. With cross-linked polyacrylic acid, the highest Benefit, their property is the same as that for alkyl substituted above Called cellulose and polyalkylene oxide polymers. The preferred cross-linked polyacrylic acid has, in the form of a 1% aqueous solution at 25 ° C, a viscosity in the range from approx.4,000 to approx.40,000 cps. Preferred examples are currently Carbopol (registered trademark) NF grade 971P, 974P and 934P or Water lock (registered trademark), which is a copolymer of Strength, Is acrylate and acrylamide.

The weight ratio of tamsulosin or a pharmaceutically acceptable salt thereof to the "high molecular water soluble Polymer that swelled upon absorption of water "is in the range from approx. 15:85 to approx. 80:20, preferably from approx. 30:70 to approx. 80:20 and more preferably from about 30:70 to about 70:30.

The pharmaceutical composition for sustainable release as pharmaceutically acceptable oral solid dosage form such as tablets, particles or as Particles made that are enclosed in a tablet or capsule can be. A preferred dosage form is currently based on the fact that e.g. 2 or 3 drug-containing polymer particles (pellets) in a No. 0 gelatin capsule be included. The preferred pellet size to include 2 pellets in a No. 0 gelatin capsule is 6.6 to 6.7 in diameter mm (or more common from 6.5 to 7 mm) and a length 9.5 or 10.25 mm (or more common from 9 to 12 mm). The preferred pellet size to include 3 pellets in a No. 0 gelatin capsule is a diameter of 6.6 mm and a length of 7 mm. The preferred pellet size to include 2 pellets in a No. 00 gelatin capsule is a diameter of 7.5 mm and a length of 11.5 mm. The preferred pellet size to include 3 pellets in a No. 00 gelatin capsule is 7.5 mm in diameter and one length of 7.5 mm. A preferred further dosage form is currently one Tablet with a length from 18 to 22 mm, a width from 6.5 to 7.8 mm and with a Height of 6.2 to 7.5 mm, and a preferred combination of length, width and height one tablet is 20 mm long, 6.7 mm wide and 6.4 mm high. This pose bare Examples are given, and the shape and size can be remarkable Extent to be changed.

A granular drug / polymer blend or polymer matrix in which the drug is impregnated can be made by various mixing, pulverizing, and manufacturing techniques with well known methods. For example, direct compression or injection molding or compression molding can be listed and specified using suitable punching tools and dies. A lubricant can be added during compression molding. As the lubricant, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. can be listed and indicated, and magnesium stearate is particularly preferred. The compounding amount of the lubricant based on the total weight of the sustained release composition is 0.25 to 3 and preferably less than 1 w / w%. Hydrogenated vegetable oil and triglycerides of hydrogenated and purified stearic and palmitic acid are preferred as further lubricants, and the corresponding compounding amount is based on the weight of the sustained release pharmaceutical composition, about 1 to 5, or most preferably about 2 w / w%.

What concerns an optimal combination of the above components, become polyethylene oxide with a weight average molecular weight in the range of approx. 2,000,000 to approx. 7,000,000 as "high molecular water soluble Polymer that swelled when water was absorbed "in an amount of approx. 90 to approx. 97 w / w%, based on the total weight of the pharmaceutical Sustainable release composition, and magnesium stearate than the "lubricant" in an amount of less than about 2 w / w%, based on the total weight of the pharmaceutical Composition for sustainable release, compounded. What a combination of e.g. Concerns 2 types of water-soluble polymers, become polyethylene oxide with a weight average molecular weight in the range of approximately 900,000 to approximately 7,000,000 and hydroxypropylmethyl cellulose with a viscosity from approx. 3 to approx. 10,000 cps as a 2% aqueous solution in a compounding ratio of approx. 1: 1 compounded in an amount of approx. 48 w / w%.

(F) Matrix preparation using water-soluble polymers

The Matrix tablet, comprising water-soluble polymers, is a pharmaceutical Preparation for sustainable release, in which the medicine is uniform in water soluble Polymer substrates as dispersed in hydroxypropylmethyl cellulose is.

The Matrix preparation is, for example, in the international published application No. 93/16686, and all of the content described in the above Description is included by reference in the present Description added.

Becomes Hydroxypropylmethyl cellulose, which is a water-soluble polymer, hydrates, when it comes into contact with water, a hydrogel layer forms on the surface the tablet. Will the gel layer that contains the medicine and itself on the surface the tablet forms, gradually dissolved and eroded, the drug released. The present tablet has the characteristic Property on that the drug in a sustainable manner by repetition of contact with water, formation of a gel layer that the drug contains and by dissolution and erosion of the gel layer released.

The sustainably released pharmaceutical preparation has the characteristic Property on that excipients for sustainable release, the water soluble Polymers comprise, together together, further inert diluents and a physiologically active ingredient are dispersed. at the water-soluble Substrates are not particularly limited as long as they are gradual gelled and / or eroded and / or dissolved and / or decomposed, if they have ambient fluids are exposed. Examples of such a water-soluble substrate are hydroxypropylmethyl cellulose, Hydroxymethyl cellulose, hydroxyethyl cellulose with a molecular weight from 1,000 to 4,000,000, hydroxypropyl cellulose with a molecular weight from 2,000 to 2,000,000, carboxyvinyl polymer, chitosan, mannan, Galactomannan, xanthan, carrageenan, amylase, alginic acid and Salts and derivatives thereof, pectin, acrylate, methacrylate, acrylic / methacrylic acid copolymers, polyacid, polyamino Poly (methyl vinyl ether / maleic anhydride) polymers, Polyvinyl alcohol, glucan, scleroglucan, carboxymethyl cellulose and Derivatives thereof, ethyl cellulose, methyl cellulose and conventional water-soluble cellulose derivatives. Hydroxypropylmethyl cellulose with a molecular weight is preferred from 1,000 to 2,000,000 or carboxyvinyl polymer, wherein the 0.5% aqueous solution (25 ° C) one viscosity from 3,000 to 45,000 cps. Hydroxypropylmethyl cellulose is even more preferred with a molecular weight of 10,000 to 1,000,000 or a carboxyvinyl polymer, where the viscosity a 0.5% aqueous solution (25 ° C) 4,000 up to 40,000 cps. The amount of water soluble Polymer per preparation unit is 5 to 95 w / w%, preferably 10 to 90 w / w% and more preferably 30 to 85 w / w%.

Various types of excipients for pharmaceuticals are suitably used for the pharmaceutical composition, after which the pharmaceutical composition is prepared. Such excipients for pharmaceuticals are not particularly limited as long as they are pharmaceutically acceptable and can be used as an additive for pharmaceuticals. For example, diluents, binders, disintegrants, acidic agents, foaming agents, artificial sweeteners, perfumes, lubricants, colorants, etc. can be used. The diluent is selected from a group of the following substances: mannitol, lactose, starch from various sources, sorbitol, xylitol, from microcrystalline cellulose and / or a water-soluble diluent which generally promotes the penetration of water or an aqueous liquid into the pharmaceutical preparation , Examples of the binder are hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, Me ethyl cellulose and acacia gum. Examples of the disintegration aid are corn starch, starch, calcium carmellose, sodium carmellose and low-substituted hydroxypropyl cellulose. Examples of the acidic agent are citric, tartaric and malic acid. Examples of the foaming agent are sodium bicarbonate, etc. Examples of the artificial sweetener are saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.

Examples of the perfume are lemons, lemons, orange and menthol. Examples of the lubricant are Magnesium stearate, calcium stearate, sucrose fatty acid ester, Polyethylene glycol, talc and stearic acid. What such a pharmaceutical Excipients can 1 excipient or 2 or more excipients used together become.

The Tablet comprising the pharmaceutical composition can be produced using a method known per se. Such Tablet can be made using a tableting process become that in very common Manner and is known to those of ordinary skill in the art. Usually is the tablet compression force for performing the method in one Range from 3 to 20 kN (kilonewtons). The tablets are small scale manufactured, it is also possible that, according to one Method specified and described in more detail in the examples each powder and / or grain using a mortar and Pistills is made and prepared, followed by the tablets in an oil press tableting machine getting produced.

The A method of the present invention for the administration of tamsulosin or a pharmaceutically acceptable Salt of what counter-reactions with therapy or prevention of an α-receptor blocking effect associated, reduced, can be done with a procedure that is mentioned in the above detailed description of the invention and is indicated which a pharmaceutical composition with sustainable release concerns.

The present invention will now be further enhanced by the following examples, Test examples and test examples explained, although the present Invention is not limited to these examples.

Example A (hydrogel-forming Preparation with sustainable release)

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 1.6 parts of tamsulosin hydrochloride which was pulverized beforehand in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron) was suspended (partially dissolved), to make a spray liquid. PEG 6000 (56.16 parts) and 300 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were put in a fluid bed granulator (Flow Coater, manufactured by Furointo), and the above spray liquid was made under the conditions of an inlet -Air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40s sprayed to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (1.8 parts) was added to 361.6 parts of the dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 181.7 mg in a rotary tablet machine (HAT P-22, manufactured by Hata Tekkosho). Tappets 8.5 mm in diameter were used and 400 kgf / tappet compression pressure was applied to give a sustained release formulation (tablets) of the present invention.

Example A-2

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 1.6 parts of tamsulosin hydrochloride, which was pulverized beforehand in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron), was suspended (partially dissolved) to produce a spray liquid. Then, 76.16 parts of PEG 6000 and 400 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were put in a fluid bed granulator (Flow Coater, manufactured by Furointo) and the above spray liquid under the conditions of an inlet air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40 s to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (2.4 parts) was added to 481.6 parts of dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 242 mg in a rotary tablet machine (HT P-22, manufactured by Hata Tekkosho). Tappets 9 mm in diameter were used and a compression pressure of 400 kgf / tappet was applied to provide a sustained release formulation (tablets) of the present invention.

Example A-3

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 1.6 parts of tamsulosin hydrochloride, which was pulverized beforehand in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron), was suspended (partially dissolved) to produce a spray liquid. Then, 96.16 parts of PEG 6000 and 500 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were put in a fluid bed granulator (Flow Coater, manufactured by Furointo), and the above spray liquid under the conditions of an inlet air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40 s to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (3 parts) was added to 601.6 parts of dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 302.3 mg in a rotary tablet machine (HT P-22, manufactured by Hata Tekkosho). Tappets of 9.5 mm diameter were used and a compression pressure of 400 kgf / tappet was used to give a sustained release formulation (tablets) of the present invention.

Example A-4

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 1.0 part of tamsulosin hydrochloride, which was pulverized in advance in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron), was suspended (partially dissolved) to produce a spray liquid. Then 76.16 parts of PEG 6000 and 400 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were placed in a fluid bed granulator (Flow Coater, manufactured by Furointo), and the above spray liquid under the conditions of an inlet air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40 s to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (2.4 parts) was added to 481.0 parts of dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 241.7 mg in a rotary tablet machine (HAT P-22) by Hata Tekkosho). Tappets 9 mm in diameter were used and a compression pressure of 400 kgf / tappet was used to give a sustained release formulation (tablets) of the present invention.

Example A-5

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 2.0 parts of tamsulosin hydrochloride, which was pulverized beforehand in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron), was suspended (partially dissolved) to produce a spray liquid. Then 76.16 parts of PEG 6000 and 400 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were placed in a fluid bed granulator (Flow Coater, manufactured by Furointo), and the above spray liquid under the conditions of an inlet air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40 s to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (2.4 parts) was added to 482.0 parts of dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 242.2 mg in a rotary tablet machine (HAT P-22) by Hata Tekkosho). Tappets 9 mm in diameter were used and a compression pressure of 400 kgf / tappet was used to give a sustained release formulation (tablets) of the present invention.

Example A-6

PEG 6000 (3.84 parts) were dissolved in 10.56 parts of water using a magnetic stirrer. While stirring with the magnetic stirrer, 0.5 part of tamsulosin hydrochloride, which was pulverized beforehand in a hammer mill (Sample Mill AP-S, with a 1 mm sieve manufactured by Hosokawa Micron), was suspended (partially dissolved) to produce a spray liquid. Then 76.16 parts of PEG 6000 and 400 parts of PEO (product name: Polyox ^™ WSR-303, Dow Chemical) were placed in a fluid bed granulator (Flow Coater, manufactured by Furointo) and sprayed the above spray liquid under the conditions of an inlet air temperature of 25 ° C, a spray amount of 5 g / min and a spray / drying cycle of 20 s / 40 s to produce particles. The particles were then dried at an inlet air temperature of 40 ° C for 30 minutes. Magnesium stearate (2.4 parts) was added to 480.5 parts of dried particles, the whole was mixed and the mixture was compressed to make the tablets with an average weight of 241.5 mg in a rotary tablet machine (HAT P-22) by Hata Tekkosho). Tappets 9 mm in diameter were used and a compression pressure of 400 kgf / tappet was used to give a sustained release formulation (tablets) of the present invention.

Test example A1 (dissolution test)

The Drug release characteristics of each of the preparations of the Examples A1 to A5 were carried out using method II, dissolution test, Japanese pharmacopoeia (paddle method) rated. Distilled water (900 mL) was used as the test medium and it was, without a sinker, the test at a paddle rotation speed of 200 rpm. Samples were taken at each time and tamsulosin hydrochloride in the sample solution determined quantitatively by means of HPLC with a UV spectrophotometer (225 nm). The results are shown in Table 1.

[Table 1]

at Use of polyethylene oxide as a hydrogel-forming substrate and PEG as a hydrophilic basis has been a sustainable release the medicine for Tamsulosin hydrochloride found. The release of the drug could by the amount of exposure to polyethylene oxide and PEG to be controlled.

How in experimental examples that later are indicated in clinical studies with Example A-2 (or A-4, 5, 6), the result was that the effectiveness was equivalent or even better than with the current preparation, and the Backlashes were reduced compared to the current preparation. Accordingly, is used in preparations that are similar Pharmacokinetic parameters show how when administered orally obtained in Example A-2 is expected to be effective at the same dose equivalent or even better compared to the current preparation and the occurrence of adverse incidents is reduced becomes. It is also expected that the dose will increase or that limitations regarding the Meals are eliminated.

Example B (Osmotic Pump Type Preparation)

step 1: preparation of a mixed powder for building up a medicament layer, which contains the active ingredient

A mixed powder containing 0.80 mg of tamsulosin hydrochloride was prepared with the following compositions and used to make a two-layer complicated core. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Polyethylene oxide (Polyox ^TM WSR N80) 100 mg Hydroxypropylmethyl cellulose (HPMC 2910) 6 mg magnesium stearate 1.00 mg All in all 115.00 mg

The Medicament and the various additives were made according to the above compositions weighed out and in a mortar mixed well with a pestle until a uniform mixture was obtained.

Step 2: Preparation of a compression layer A mixed powder having the following compositions was prepared and used to produce a two-layer compressed core. Polyethylene oxide (Polyox ^TM WSR coagulant) 60 mg NaCl 30 mg Hydroxypropylmethyl cellulose (HPMC 2910) 4 mg Red iron (III) chloride 1 mg magnesium stearate 0.5 mg Overall 95,5mg

The various additives were made according to the above compositions weighed out and in a mortar mixed well with a pestle until a uniform mixture was obtained.

step 3: Manufacture of a two-layer compressed core comprising a medication and a pressure layer

The two-layer compressed core was made in an oil press tableting machine. A pestle from 8.0 mm diameter · 9.6 R was applied. The mixed powder for the pressure layer is placed in a mortar, whereupon the mixed powder for the drug layer is layered on top of it, and it became the whole thing compressed to give a two-layer compressed core containing 0.8 mg tamsulosin hydrochloride.

step 4: Production of a semipermeable membrane and a membrane coating

PEG 400 and cellulose acetate (94: 6 (w / w%)) were mixed solvent dissolved in dichloromethane and methanol (9: 1 (w / w%)). The coating solution contains approx. 4 solids in the Application. This coating solution was as a coating on the three-layer compressed core produced above Application of an enrobing machine ventilation type (High Coater HCT-30, manufactured by Furointo Sankyo] sprayed until the amount of the coating component 10 w / w% of the weight of the two-layer compressed core was.

step 5: Hole formation

The with a semipermeable membrane as such was coated tablet a hole on the side of the drug layer using an injection needle (27G) with a diameter of 0.4 mm. Preparations of the examples B-2 to B-13 shown in Tables 2 and 3 were made in the same way as above.

[Table 2]

Table 3

Test example B (dissolution test)

test example B-1: The release properties of the preparations of Examples B-1 through B-13 were according to the procedure of Test Example A and the results are shown in Table 4 specified. Besides, was the delay time until the release the release of the drug from the release profile of the drug and the value at which the delay time was 0 h, which results in the release amount after triggering the drug release results, which is given in Table 5.

[Table 4]

[Table 5]

In Each of them showed the preparations of the osmotic pump type a delay time (time zone in which there is no release of the drug 2 h to trigger the release of the drug. To release the drug release showed a sustained drug release profile, whereby the amount of medication released at 3 h after the delay time 14 to 33%, at 7 hours of which 32 to 78% and at 12 hours of which 55% or more in all Preparations were fraudulent and therefore they were pharmaceutical compositions for sustained release with similar drug release profiles as obtained in Example A-2. As a result of that assumed that similar pharmacokinetic parameters such as that of the A-2 preparation when administered can be obtained with the same dose, and it is therefore expected that compared to the current preparation, equivalent to the potency or better and reduces the incidence of adverse events becomes. It is also expected that the dose will be increased or the restrictions be eliminated when taking meals.

Example C (gel preparation, where a variety of rubber species are combined)

Example C-1

On Powder comprising the following various compositional units, was obtained by weighing 5 parts of carob bean gum (Sansho; San-Ace M175), 5 parts xanthan gum (Nitta Gelatin, VS 900), 7 Parts of dextrose (Wako Pure Chemical) and 1 part of calcium sulfate (Kanto Kagaku) prepared, followed by the whole thing in a mortar a pestle was mixed well until a uniformity of Mixture was made. In the prepared mixed powder gradually drop 2 mL (1 mL, 2 times) of pure water, after which the Mix well with a pestle and mixed to granulate. The grains produced were through a 16 mesh sieve (0.59 μm) sieved and dried at a constant temperature of 40 ° C for 12 h to give granulated powder A.

Tamsulosin hydrochloride and lactose were added to the granulated powder A, and a 10% solution of ethyl cellulose dissolved in methanol (100 mg / mL) was gradually added dropwise, and the whole was stirred well with a pestle and mixed to give a granulated one To give powder B. The granulated powder B was dried at a constant temperature of 40 ° C for 12 hours. The dried granulated powder B was put in a mortar and compressed in an oil press tabletting machine with a pestle of 8.0 mm in diameter × 8.0 R with a tablet compression pressure of 1,000 kg / pestle to give tablets with an average weight of To produce 202.00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Carob Bean Gum (Sansho, San-Ace M175) 50.00 mg Xanthan gum (Nitta Gelatin, VS 900) 50.00 mg dextrose 70.00 mg calcium sulphate 10.00 mg ethylcellulose 14.00 mg All in all 202.00 mg

Example C-2

To the granulated powder A was tamsulosin hydrochloride and lactose was given and a 10% solution of ethyl cellulose dissolved in methanol (100 mg / mL), added dropwise in stages, whereupon the whole thing with a Mix the pestle well and mixed to give a granular powder C.

The granulated powder C was dried at a constant temperature of 40 ° C for 12 hours. The dried granulated powder C was put in a mortar and compressed in an oil press tabletting machine with a pestle of 8.0 mm diameter × 8.0 R with a compression pressure of 1,000 kg / pestle to give tablets with an average weight of 396, To give 00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Carob Bean Gum (Sansho-San-Ace M175) 100.00 mg Xanthan gum (Nitta Gelatin, VS 900) 100.00 mg dextrose 140.00 mg calcium sulphate 20.00 mg ethylcellulose 28.00 mg All in all 396,00mg

Example C-3

Tamsulosin hydrochloride and lactose were added to the granulated powder A, and a 10% solution of ethyl cellulose dissolved in methanol (100 mg / mL) was gradually added dropwise, and the whole was stirred well with a pestle and mixed to give a granulated one To give powder D. The granulated powder D was dried at a constant temperature of 40 ° C for 12 hours. The dried granulated powder D was placed in a mortar and compressed in an oil press tabletting machine with a pestle of 8.0 mm diameter × 8.0 R with a compression pressure of 1,000 kg / pestle to give tablets with an average weight of 590, To give 00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Carob Bean Gum (Sansho, San-Ace M175) 150.00 mg Xanthan gum (Nitta Gelatin, Vs 900) 150.00 mg dextrose 210.00 mg calcium sulphate 30.00 mg ethylcellulose 42.00 mg Overall 590.00 mg

Example C (dissolution test)

test example C-1: According to the procedure from Test Example A, the release properties of the preparations of Examples C-1 through C-3, and the results are in Table 6 specified.

[Table 6]

As Result of the use of gels in which a variety of gum species sustainable drug release was achieved. The release of tamsulosin from these preparations can be caused by the exposure amount of locust bean gum and xanthan gum to be controlled. The release of the drug after 7 h since the release of the resolution was about 54 to about 88%. As a result, it is believed that similar pharmacokinetic parameters such as those of the preparation of A-2 Administration can be obtained with the same dose, and therefore to expect that, compared to the current preparation, the effectiveness is equivalent or better and the occurrence of disadvantageous incidents is reduced. It is also expected that the dose will be increased or the restrictions on meals are eliminated.

Example D (multilayer Tablet preparation comprising a geometrically arranged medicament layer and Releasing control layers)

Example D-1: Preparation a 3-layer tablet containing tamsulosin hydrochloride

step 1A: Preparation of a mixed powder that builds up layer 2 which contains the active ingredient

A mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared and used for the preparation of the layer 2, which is an intermediate layer for the 3-layer tablet. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg mannitol 10.00 mg Hydroxypropylmethyl cellulose (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 All in all 100.00 mg

The Powder comprising the above composition units was made by Weigh in the necessary amounts of active ingredient, mannitol, microcrystalline Cellulose, hydroxypropylmethyl cellulose (HPMC 90SH-15000), polyvinylpyrrolidone, Magnesium stearate and prepared from colloidal silica, followed by the whole in a mortar was mixed with a pestle until a uniform mixture was obtained.

step 1B: Production of particles that layer 1 (layer 1, that contains no medication) build up that is used to control the drug

Particles comprising the following compositional units were made and used to make layer 1, which is the top layer for the 3-layer tablet. HPMC (90SH-15000) 80.96 mg Hydrogenated castor oil 13.71 mg Yellow iron (III) oxide 0.25 mg ethylcellulose 5.08 mg All in all 100.00 mg

At the Manufacturing processes were the necessary amounts of Hyctroxypropylmethylcellulose (HPMC 90SH-15000), hydrogenated castor oil and yellow iron (III) oxide weighed in and well in a mortar mixed with a pestle until a uniform mixture is obtained has been. The particles were prepared so that the homogeneous powder mixture with 10 w / v alcoholic solution of an ethyl cellulose base, the homogeneously wetted agglomerates at 40 ° C dried and passed through a sieve.

step 1C: Production of particles that layer 3 (layer 3, that contains no medication) build that applied to control the release of the drug becomes

Particles comprising the following compositional units were made and used to make layer 3, which is the bottom layer for the 3-layer tablet. HPMC (905H-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg All in all 150.00 mg

The Particles for Layer 3 is used, which is the lowest layer of the 3-layer tablet, according to the in Process called Example D-1 (Step 1B).

step 1D: Production of a 3-layer tablet (compression molding)

A 3-layer tablet was produced in an oil press tablet machine. On tappet 8.0 mm diameter x 9.6 R was used and the compression pressure was 1,000 kg / plunger created. The particles for Layer 3 mentioned in point 1C was placed in a mortar and slightly beveled, around their top surface flatten. A mixed powder containing the active ingredient Layer 2 mentioned in point 1A was filled and slightly beveled, around their surface flatten. Furthermore, the particles were those mentioned in point 1B Layer 1 in a mortar applied to it and compressed using the 3-layer tablet an average weight of 350.00 mg and 0.80 mg tamsulosin hydrochloride manufacture. Layer 1 and Layer 3 can also be put in the mortar brought in in reverse order and then compressed.

Examples D-2 to D-13. Production of 3-layer tablets containing tamsulosin hydrochloride

step 2A: Preparation of a mixed powder, from which the layer 2 is built that contains the active ingredient

On mixed powder used for the production of layer 2, the the middle layer of the 3-layer tablet with 0.80 mg tamsulosin hydrochloride represents, according to the in Process called Example D-1 (Stage 1A). Each of the Preparations of Examples D-2 to D-16 is in Tables 7 and 8 specified.

[Table 7]

[Table 8]

step 2B: Production of particles to build up layer 1 (the layer 1 contains no drug) used to control the release of the drug becomes

The Particles used to make layer 1, the represents a layer for controlling the release of the medicament, were according to the in Process called Example D-1 (Step 1B). Each of the Preparations of Examples D-2 to D-13 are in Tables 9 and 10 specified.

[Table 9]

[Table 10]

step 2C: Production of particles to build layer 3 (the layer 3 contains no drug) used to control the release of the drug becomes

The Particles that are used to produce layer 3, the represents a layer for controlling the release of the medicament, were according to the in Process called Example D-1 (Step 1B). Any preparation Examples D-2 to D-13 are given in Tables 11 and 12.

[Table 11]

[Table 12]

step 2D: Production of a 3-layer tablet (compression molding)

The 3-layer tablet containing 0.80 mg tamsulosin hydrochloride according to the in Process called Example D-1 (Stage 1D).

Example D-14: Preparation a 3-layer tablet containing tamsulosin hydrochloride

step 3A: Preparation of a mixed powder to build up the layer 2, which contains the active ingredient

A mixed powder containing 1.20 mg of tamsulosin hydrochloride, which is used for the production of layer 2, which represents a middle layer for the 3-layer tablet, was produced by the process mentioned in Example D-1 (stage 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 All in all 150.00 mg

step 3B: Production of particles for building up layer 1 (the layer 1 contains no drug) used to control the release of the drug becomes.

The particles used to make Layer 1, which comprises the following compositional units and which is a layer for controlling the release of the drug, were prepared by the method mentioned in Example D-1 (Step 1B). HPMC (90SH-15000) 80.96 mg Hydrogenated castor oil 13.71 mg Yellow iron (III) oxide 0.25 mg ethylcellulose 5.08 mg All in all 100.00 mg

step 3C: Production of particles for building up layer 3 (the layer 3 contains no drug) used to control the release of the drug becomes

The particles used to make layer 3, which comprises the following compositional units and which is a layer for controlling the release of the medicament, were produced by the method mentioned in Example D-1 (stage 1B). HPMC (90SH-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg All in all 150.00 mg

step 3D: Production of the 3-layer tablet (compression molding)

The 3-layer tablet with an average weight of 400.00 mg and with 1.20 mg tamsulosin hydrochloride according to the in Process called Example D-1 (Stage 1D).

Example D-15: Preparation a 3-layer tablet containing tamsulosin hydrochloride

step 4A: Preparation of a mixed powder to build up the layer 2, which contains the active ingredient

A mixed powder containing 1.60 mg of tamsulosin hydrochloride, which is used to prepare Layer 2, which is a middle layer for the 3-layer tablet, was prepared by the method mentioned 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 131.10 mg magnesium stearate 2.00 mg Colloidal silica 2.50 mg All in all 200.00 mg

step 4B: Production of particles for building up layer 1 (the layer 1 contains no drug) used to control the release of the drug becomes

The particles used to prepare Layer 1, which comprises the following compositional units and which is a layer for controlling the release of the drug, were prepared by the method mentioned in Example D-1 (Step 1B). HPMC (90SH-15000) 80.96 mg Hydrogenated castor oil 13.71 mg Yellow iron (III) oxide 0.25 mg ethylcellulose 5.08 mg All in all 100.00 mg

step 4C: Production of particles for building up layer 3 (the layer 3 contains no drug) used to control the release of the drug becomes

The particles which are used to produce layer 3, which comprises the following composition units and is a layer for controlling the release of the medicament, were produced by the process mentioned in Example D-1 (stage B1). HPMC (90SH-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg All in all 150.00 mg

step 4D: Production of the 3-layer tablet (compression molding)

The 3-layer tablet with an average weight of 450.00 mg and with 1.60 mg tamsulosin hydrochloride according to the in Process called Example D-1 (Stage 1D).

Examples D-16 to D-17: Production of 3-layer tablets containing tamsulosin hydrochloride

step 5A: Preparation of a mixed powder to build up the layer 2, which contains the active ingredient

A mixed powder containing 0.80 mg of tamsulosin hydrochloride and used to make Layer 2, which is the middle layer for the 3-layer tablet, was prepared by the procedure outlined 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 All in all 100.00 mg

step 5B: Production of particles for building up layer 1 (the layer 1 contains no medicine) used to release the medicine

The particles used to prepare Layer 1, which comprises the following compositional units and which is a layer for controlling the release of the drug, were prepared by the method mentioned 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 (III) oxide 0.13 mg ethylcellulose 2.54 mg All in all 50,00mg

step 5C: Production of particles for building up layer 3 (the layer 3 contains no drug) used to control the release of the drug becomes

The particles used to make layer 3, which comprises the following compositional units and which is a layer for controlling the release of the medicament, were produced by the method mentioned in Example D-1 (stage 1B). HPMC (90SH-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg All in all 150.00 mg

step 5D: Production of the 3-layer tablet (compression molding)

The 3-layer tablet was placed in an oil press tablet machine manufactured. In Example D-16, a ram of 7.0 mm diameter x 8.4 R was used applied while in Example 17 a pestle of 9.5 mm diameter · 11.4 R was used, with tablet printing in both examples of 1,000 kg / pestle has been. The particles of layer 3 mentioned in point 5C were in a mortar filled and slightly beveled, so the top surface became flat. A mixed powder that contains the active ingredient in the Point 5A so included, was filled on it and slightly beveled, around the top surface flatten. Furthermore, the particles were those mentioned in point 5B Layer 1 on top of it in a mortar given and compressed to the 3-layer tablet with an average weight of 300.00 mg and with 0.80 mg tamsulosin hydrochloride.

Example D-18: Preparation a 3-layer tablet containing tamsulosin hydrochloride

step 6A: Preparation of a mixed powder to build up the layer 2, which contains the active ingredient

A mixed powder containing 0.80 mg of tamsulosin hydrochloride and used to make Layer 2, which is a middle layer for the 3-layer tablet, was prepared by the procedure outlined 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 Overall 100,00mg

step 6B: Production of particles for building up layer 1 (the layer 1 contains no drug) used to control the release of the drug becomes

The particles used to make Layer 1, which comprises the following compositional units and which is a layer for controlling the release of the drug, were prepared by the method mentioned in Example D-1 (Step 1B). HPMC (90SH-15000) 80,96mg Hydrogenated castor oil 13.71 mg Yellow iron (III) oxide 0.25 mg ethylcellulose 5.08 mg All in all 100.00 mg

step 6C: Production of particles for building up layer 3 (the layer 3 contains no drug) used to control the release of the drug becomes

The particles used to make layer 3, which comprises the following compositional units and which is a layer for controlling the release of the medicament, were produced by the method mentioned in Example D-1 (stage 1B). HPMC (90SH-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg All in all 150.00 mg

step 6D: Production of the 3-layer tablet (compression molding)

The 3-layer tablet with a diameter of 8.0 mm was placed in an oil press tablet machine prepared with a tableting pressure of 1000 kg / pestle has been. The particles of layer 3 mentioned in point 6C were in a mortar filled and slightly beveled, so the top surface became flat, whereupon it with a convex pestle of the same diameter lightly pressed has been. A mixed powder containing the active ingredient of in point 6A, layer 2, was filled and with a pestle 8.0 mm diameter x 9.6 R slightly beveled. Furthermore, the particles of the layer mentioned in point 6B 1 in a mortar applied to it and with a pestle of 8.00 mm diameter · 9.6 R compressed to the 3-layer tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride. Layer 1 and Layer 3 can also be put in the mortar given in reverse order and then compressed.

Example D-19: Preparation a 2-layer tablet containing tamsulosin hydrochloride

step 7A: preparation of a mixed powder for building up the layer, which contains the active ingredient

A mixed powder used to make the layer containing 0.80 mg of tamsulosin hydrochloride was prepared by the procedure outlined 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 All in all 100.00 mg

step 7B: Production of particles for building up the layer (the layer contains no medicine) used to release the medicine

The particles, which comprise the following composition units and constitute a layer for controlling the release of the medicament, were produced by the method mentioned in Example D-1 (stage 1B). HPMC (90SH-15000) 121.45 mg Hydrogenated castor oil 20.56 mg Yellow iron (III) oxide 0.38 mg ethylcellulose 7.61 mg Overall 150.00 mg

step 7D: Production of the 2-layer tablet (compression molding)

The 2-layer tablet was produced in an oil press tablet machine. On tappet 8.0 mm diameter x 9.6 R was applied and a tableting pressure of 1000 kg / pestle was applied. The particles of the layer mentioned in point 7B were placed in a mortar and slightly beveled, so the top surface is flat has been. A mixed powder that contains the physiologically active ingredient the layer mentioned in point 7A was filled on it and compressed to the 2-layer tablet with an average weight of 250.00 mg and 0.80 mg tamsulosin hydrochloride manufacture.

Test example D (dissolution test)

test example D-1: According to the procedure of Test Example A were the release properties of the preparations of Examples D-1 through D-8 evaluated, and the corresponding results are given in Tables 13 and 14.

(Results and considerations)

[Table 13]

[Table 14]

at Placing a layer containing the drug between two release control layers, that do not contain any medicine, as a sandwich to obtain a multilayer Tablet sustained release of the drug was achieved. The release of the drug from the present preparations can by the molecular weight of HPMC used for the release control layers is used by the thickness of the release control layers, the addition of ethyl cellulose to the release control layers, the HPMC content and its molecular weight in the drug-containing layer, the Thickness of the drug-containing layer, the geometric shape of the drug-containing Layer and by the diameter size of the multilayer tablet to be controlled. Moreover was the release of the drug in all preparations after 7 h since triggering the dissolution 38 to 70%, and these preparations are therefore sustainable releasable pharmaceutical composition with similar Drug release profiles as obtained in Example A-2. Accordingly, it is believed that similar pharmacokinetic Parameters such as those of the preparation from A-2 when administered the same dose, which is why it can be expected that compared to the current preparation, the potency is equivalent or better and reduces the occurrence of backlashes becomes. It is also expected that the dose can be increased or the restrictions be eliminated when taking meals.

Example E. Gastroretentive Dosage form in which swelling polymers are used

Example E-1

On Powder comprising various types of composition units, was obtained by weighing tamsulosin hydrochloride, polyethylene oxide and Magnesium stearate is made, followed by the whole thing in a mortar a pestle completely was mixed until uniform.

The mixed powder prepared was placed in a mortar and compressed in an oil press tabletting machine with a pestle of 7.0 mm diameter x 8.4 R with a compression pressure of 1000 kg / pestle to give tablets with an average weight of 276.0 mg to manufacture. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Polyethylene oxide (Polyox ^TM WSR N60K) 266.00 mg magnesium stearate 2.00 mg All in all 276.00 mg

Example E-2

A mixed powder containing tamsulosin hydrochloride and polyethylene oxide and comprising the following composition units was compressed with a pestle of 6.0 mm in diameter · 6.0 R according to the procedure mentioned in Example E-1 to prepare tablets with an average weight of 143, 00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg magnesium stearate 2.00 mg Overall 143.00 mg

Example E-3

On mixed powder containing tamsulosin hydrochloride and polyethylene oxide and comprising the following composition units, was with a pestle of 7.0 mm x 8.4 R according to the in Example E-1 is compressed to tablets with a method To produce an average weight of 276.00 mg.

Example E-4

A mixed powder containing tamsulosin hydrochloride and 2 types of polyethylene oxides with different molecular weights (Polyox ^™ WST 303 and Polyox ^™ WSR 1105) and comprising the following composition units was made with a pestle of 7.0 mm diameter x 8.4 R according to the in Example 1 compressed to produce tablets with an average weight of 276.00 mg. Tamsulosin Hydrdochlorid 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 Overall 276.00 mg

Example E-5

A mixed powder containing tamsulosin hydrochloride, which is compounded with polyethylene oxide and hydroxypropylmethyl cellulose (TC5E) and comprises the following composition units, was compressed with a pestle of 7.00 mm in diameter · 8.4 R in accordance with the procedure mentioned in Example E-1 to make tablets with an average weight of 276.00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg Hydroxypropylmethyl cellulose (TC5E) 133.00 mg magnesium stearate 2.00 mg All in all 276.00 mg

Example E-6

A mixed powder containing tamsulosin hydrochloride, which is compounded with polyethylene oxide and hydroxypropylmethyl cellulose (90SH-10000) and comprising the following composition units, was made with a pestle of 7.0 mm in diameter · 8.4 R in accordance with that mentioned in Example E-1 Process compressed to produce tablets with an average weight of 276.00 mg. Tamsulosin hydrochloride 0.80 mg lactose 7.20 mg Polyethylene oxide (Polyox ^TM WSR 303) 133.00 mg Hydroxypropylmethyl cellulose (90SH-10000) 133.00 mg magnesium stearate 2.00 mg All in all 276,00mg

Test example E (dissolution test)

test example E-1: The release properties of the preparations of Examples E-1 through E-6 were according to the procedure of Test Example A, and the results are in Table 15 specified.

[Table 15]

As Result of making an intragastric (in the stomach) restrained Preparation using a swelling polymer became one sustained release of the drug achieved. The release of the drug from the present preparations can by molecular weight and the application of the amount of polyethylene oxide and the combination a variety of water-soluble Polymers can be controlled. The release of the drug after 7 h since triggering the dissolution was 43 to 66% in all preparations. Therefore, these posed Preparations of sustainably releasable pharmaceutical compositions with similar ones Drug release profiles as obtained in Example A-2. Accordingly, it is believed that similar pharmacokinetic Parameters such as those of the preparation from A-2 when administered can be obtained with the same dose, and it is therefore expected that that, compared to the current preparation, the potency is equivalent or better and reduces the occurrence of backlashes becomes. It is also expected that the dose will be increased can or the restrictions are eliminated when taking meals.

Example F: (matrix preparation, wherein water soluble Polymers are used)

Example F-1: Production a hydroxypropylmethyl cellulose (HJPMC) matrix tablet, the Contains tamsulosin hydrochloride

step 1A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg of tamsulosin hydrochloride comprising the following composition units was prepared. Tamsulosin hydrochloride 0.80 mg lactose 149.20 mg Hydroxypropylmethyl cellulose (60SH-10000) 200.00 mg All in all 350.00 mg

The Powder comprising the above composition units was made by Weighing in the necessary amounts of the active ingredient, of mannitol and manufactured by hydroxypropylmethyl cellulose (HPMC 60SH-10000), what the whole thing in a mortar was mixed well with a pestle until uniform.

step 1B: Production of an HPMC matrix (compression molding)

A HPMC matrix tablet was in an oil press tablet machine manufactured. A pestle of 9.5 mm diameter 11.4R was applied and a compression pressure was applied of 500 kg / pestle created. A mixed powder containing the one mentioned in point 1A Active ingredient was added and compressed to the matrix tablet with an average weight of 350.00 mg and 0.80 mg tamsulosin hydrochloride manufacture.

Example F-2: Manufacturing an HPMC matrix tablet containing tamsulosin hydrochloride

step 2A. Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg tamsulosin hydrochloride and comprising the following composition units was prepared according to the procedure mentioned in Example F-1 (Step 1A). Tamsulosin hydrochloride 0.80 mg lactose 149.20 mg HPMC (90 SH-400) 200.00 mg All in all 350.00 mg

step 2B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride according to the procedure described in Example F-1 (step 1B) produced process.

Example F-3: Production an HPMC matrix tablet containing tamsulosin hydrochloride

step 3A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg tamsulosin hydrochloride and comprising the following composition units was prepared according to the procedure mentioned in Example F-1 (Step 1A). Tamsulosin hydrochloride 0.80 mg lactose 149.20 mg HPMC (90SH-100000) 200.00 mg All in all 350.00 mg

step 3B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride according to the procedure described in Example F-1 (step 1B) produced process.

Example F-4: Preparation an HPMC matrix tablet containing tamsulosin hydrochloride

step 4A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg of tamsulosin hydrochloride comprising the following composition units was prepared according to the procedure mentioned in Example F-1 (Step 1A). Tamsulosin hydrochloride 0.80 mg lactose 49.20 mg HPMC (90SH-15000) 350.00 mg All in all 400.00 mg

step 4B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 400.00 mg and with 0.80 mg tamsulosin hydrochloride according to the procedure described in Example F-1 (step 1B) produced process.

Example F-5: Production an HPMC matrix tablet containing tamsulosin hydrochloride

step 5A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared according to the procedure mentioned in Example F-1 (Step 1-A). Tamsulosin hydrochloride 0.80 mg lactose 249.20 mg HPMC (60SH-10000) 100.00 mg All in all 350.00 mg

step 5B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride according to the procedure described in Example F-1 (step 1B) produced process.

Example F-6: Preparation an HPMC matrix tablet containing tamsulosin hydrochloride

step 6A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 mg of tamsulosin hydrochloride and comprising the following composition units was prepared according to the procedure in Example F-1 (Step 1A). Tamsulosin hydrochloride 0.80 mg lactose 199.20 mg HPMC (60SH-10000) 150.00 mg All in all 350.00 mg

step 6B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride according to that in Example F-1 (step 1B) produced process.

Example F-7: Production an HPMC matrix tablet containing tamsulosin hydrochloride

step 7A: Preparation of a mixed powder containing the active ingredient contains

A mixed powder containing 0.80 tamsulosin hydrochloride and comprising the following composition units was prepared according to the procedure mentioned in Example F-1 (Step 1A). Tamsulosin hydrochloride 0.80 mg lactose 49.20 mg HPMC (60SH-10000) 300.00 mg All in all 350.00 mg

step 6B: Production of the HPMC matrix tablet (compression molding)

The Matrix tablet with an average weight of 350.00 mg and with 0.80 mg tamsulosin hydrochloride was compared with that in Example F-1 (Step 1B) called process.

Test example F (dissolution test)

test example F-1: The release properties of the preparations of Examples F-1 through F-7 were according to the procedure of Test Example A, and the results are in Table 16 specified.

[Table 16]

As Result of using hydroxypropylmethyl cellulose (HPMC) as water soluble Polymer sustained release of the drug was achieved. The Release of the drug was 7 hours after triggering the dissolution 38 to 85% in all preparations, and was almost the same as that Drug release in test example A. The present preparations are accordingly sustained release pharmaceutical compositions with the special drug release profile of the present invention. Furthermore the rate of release of the drug by molecular weight and control the amount of HPMC.

experimental example 1: Comparison of the current preparation with the present invention preparation in single administration

The current preparation (Flomax (registered trademark)) or the preparation of Example A-2 was orally administered to healthy male volunteers before a meal (under a real condition) at a dose of 0.4 mg once a day. After administration, blood samples were collected periodically, plasma tamsulosin concentrations were determined, and the ratio (C _24h / C _max ) of plasma tamsulosin concentration after 24 h after administration (C _24h ) to the maximum plasma tamsulosin concentration (C _max ) calculated and given in Table 17.

[Table 17]

When the current preparation was administered, the average value of C _24h / C _{max was} 0.161, whereas when the preparation of the present invention was administered, this value was 0.709.

Many incidents of postural negative pressure, which is often found when an a-receptor blocking agent is administered, are believed to occur temporarily as a result of a rapid increase in plasma concentrations in the initial phase after administration. As a result, increasing the C _24h / C _max while keeping plasma concentrations constant is useful not only for reducing the occurrence of backlashes but also for sustained effectiveness, and it is believed that the preparation meets the above condition fulfilled, can be administered with high doses. The C _24h / C _max value of the A-2 preparation in a single administration is significantly larger than that of the current preparation (p 0.1), and there is a reduction in the occurrence of counter reactions as compared with the current preparation as well to expect sustainable effectiveness.

As a result, has now been shown to control plasma tamsulosin concentrates release control within a preferred range of tamsulosin from the preparation is useful.

experimental example 2: Comparison of the current preparation with the present inventive preparations with repeated administration

Before taking a meal (real condition) or after taking a meal, the current preparation (Omnic / Flomax (registered trademarks)) or the preparation from Example A-2 were given by mouth to healthy male volunteers with a dose of 0.4 mg administered repeatedly once a day for at least 5 days. For the current preparation, blood samples were collected periodically after administration on day 7 for the "before a meal" condition or on day 6 for the "after a meal" condition. For the administration of the A-2 preparation before and after taking a meal, the blood samples were collected periodically after the administration on day 5. The plasma tamsulosin concentrations were then determined. The maximum plasma tamsulosin (C _max) and the plasma tamsulosin 24 hours after administration (C _24h) were determined and the ratio of C ₂₄ to C _max (C ₂₄ / C _max) are calculated, and the results are in Table 18 specified.

[Table 18]

Regarding C _max , a significant increase before eating a meal in the current preparation compared to the value after eating the meal (p <0.01) was observed, whereas in the case of the A-2 preparation, no significant influence was observed from the meal has been. Furthermore, in the current preparation before taking a meal, the ratio of C _24h / C _max decreased significantly compared to that after taking the meal (p <0.01), while in the case of the A-2 preparation there was no significant difference regardless of conditions affected by meals. In addition, the C _24h / C _max value in the current preparation under a food intake condition was small compared to the value in the A-2 preparation. It can be concluded from the above result that the A-2 preparation is not influenced by food or its consumption and that, compared with the current preparation, the tolerance is improved, the frequency of the occurrence of counter reactions is reduced and , in addition, sustainable effectiveness can be expected. Accordingly, it has now been proven that the release of the medicament from the preparation is hardly influenced by meals and this inclusion is useful in the planning of the preparation of the tamsulosin preparation.

experimental example 3: Adverse incident profiles in the clinical test in phase III

at the clinical examination of female patients aged 18 to 70, where symptoms of overactive Bladder (urinary Frequency, Urgency or urinary Forced) 3 months or more The preparations of the present invention have continued (Examples A-4, -5 and -6) q orally once daily with doses of 0.25 mg to 1.5 mg administered per day for 6 weeks. As a result, were the profiles of adverse events in the group to which 1.5 mg tamsulosin hydrochloride was considered sustainable released preparation of the present invention administered were not significantly different from those profiles the group to which placebo was administered. As a result, it is documented that when planning a tamsulosin preparation, which enables high-dose administration, without the frequency an expression of backlash increases, the inclusion of controlled release the drug from the preparations is useful.

experimental example 4: Adverse incident profiles in the clinical test in phase III

placebo was given orally to male Administered to patients with lower uropathy symptoms for 2 weeks, and after that the current preparation or the preparation Example A-2 orally at a dose of 0.4 mg once daily 12 Administered for weeks. The test was carried out by means of a double blind test, and it became the expression of backlashes.

As a result of the comparison of the group to which the A-2 preparation was administered with the group to which the current preparation was administered, the profiles of adverse events in the group to which the A-2 preparation was administered were improved Comparison with that of the group to which the current preparation was administered, and in particular the effect on abnormal ejaculation and postural negative pressure was remarkable. As a result, it has been demonstrated that the control of the release of Tamsulosin from the preparation is useful for suppressing the frequency of manifestation of backlash.

in the Comparison with the current orally administered sustained release Preparation, the tamsulosin hydrochloride contains which has been brought to the clinical definition shows the lasting released pharmaceutical composition of the present invention an equivalent or even better potency, and it also becomes disadvantageous incidents like counter reactions (e.g. a postural negative pressure). The preparation is also useful as an excellent sustainably released preparation for oral application with which the dose can be increased and there are no restrictions taking a meal there.

1 shows the release characteristics of the drug from each preparation of Example A.

2 shows the release characteristics of the medicament from each preparation of Example B.

3 shows the release characteristics of the drug from each preparation of Example C.

4 shows the release characteristics of the drug from each preparation of Example D.

5 shows the release characteristics of the medicament from each preparation of Example E.

6 shows the release characteristics of the drug from each preparation of Example F.

Claims (18)

Pharmaceutical composition with sustainable Release that tamsulosin or a pharmaceutically acceptable salt of it and a carrier for the contains sustainably released pharmaceutical composition, wherein at execution a test according to Japanese Pharmacopoeia dissolution test procedure 2 (Paddle method: 200 rpm) after the release of tamsulosin 7 h since the start of the resolution is about 20 to about 85%. Pharmaceutical composition with sustainable Release according to claim 1, wherein the tamsulosin release after 7 h since the start of the dissolution is about 20 to about 75%. Pharmaceutical composition with sustainable Release according to claim 1 or 2, wherein the tamsulosin release after 7 hours from the start the dissolution is about 25 to about 65%. Pharmaceutical composition with sustainable Release according to a of claims 1 to 3, wherein the tamsulosin release after 3 hours from the start the dissolution is about 5 to about 45%. Pharmaceutical composition with sustainable Release according to a of claims 1 to 4, wherein the tamsulosin release after 3 hours from the start the dissolution is about 5 to about 40%. Pharmaceutical composition with sustainable Release according to a of claims 1 to 5, wherein the tamsulosin release after 3 hours from the start the dissolution is about 5 to about 35%. Pharmaceutical composition with sustainable Release according to a of claims 1 to 6, wherein the tamsulosin release after 12 hours from the start the dissolution is about 40% or more. Pharmaceutical composition with sustainable Release according to a of claims 1 to 7, wherein the tamsulosin release after 12 hours from the start the dissolution is about 50% or more. Pharmaceutical composition with sustainable Release according to a of claims 1 to 8, where the time during 50% tamsulosin has been released (T50), approx. 3 h to approx. Is 15 h. Pharmaceutical composition with sustainable Release according to a of claims 1 to 9, wherein T50 is about 4 hours to about 12 hours. Pharmaceutical composition with sustainable Release according to a of claims 1 to 10, in which their profile of adverse incidents is not differs significantly compared to a placebo. Pharmaceutical composition with sustainable Release according to a of claims 1 to 11, wherein it, when administered before taking a food or after taking food, no significant difference in the pharmacokinetic parameters that result from plasma tamsulosin concentrations be preserved. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, wherein this is a hydrogel-forming preparation for sustainable Release is. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, which is a preparation of an osmotic pump type is. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, wherein this is a gel preparation, wherein a variety of rubber species is combined. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, wherein this is a multi-layer tablet, the one Drug layer and Release control layer (s) comprises the geometrically arranged are. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, which is a preparation that is retained in the stomach using a swelling polymer. Pharmaceutical composition with sustainable Release according to a of claims 1 to 12, which is a matrix preparation, being a water-soluble Polymer is used.