KR20080007252A - Therapeutic combination in case of benign prostate hyperplasia - Google Patents

Abstract

The invention relates to a novel method for treating the symptoms of benign prostate hyperplasia. According to said method, the following substances are used simultaneously: (1) an alpha-1 adrenoceptor antagonist in a controlled releasing formulation or a 5-alpha reductase inhibitor, and (2) a cGMP PDE 5 inhibitor in a controlled releasing formulation or a cGMP PDE 5 inhibitor having a long half-life.

Description

Treatment combinations for benign prostatic hyperplasia {Therapeutic Combination in case of Benign Prostate Hyperplasia}

The present invention relates to a novel method for the treatment of symptoms associated with benign prostatic hyperplasia. This method comprises (1) an α-1 adrenergic receptor antagonist in the form of a controlled-release preparation, or a 5-α reductase inhibitor, and (2) a cGMP PDE 5 inhibitor in the form of a controlled-release preparation, or cGMP PDE with a long half-life. 5 concurrent use of inhibitors.

Α-1 and α-1A adrenergic receptor antagonists with maximal selectivity are currently used in medical therapy for benign prostatic hyperplasia (BPH). Their effect is based on relaxing the smooth muscle of the prostate to improve symptoms of dysfunction of the urethra due to the enlarged prostate. Examples of corresponding compounds are tamsulosin, alfuzosin, doxazosin and terrazosin. However, the extent of improvement of BPH symptoms is limited, and possible methods of further increasing the maximum flow rate of urine and further reducing residual urine volume are being investigated.

In addition, therapies using 5-a reductase inhibitors such as finasteride or dutasteride are possible. This therapy inhibits the reduction of testosterone to dihydrotestosterone. The result after long-term therapy is a decrease in prostate volume and an improvement in BPH symptoms. This therapy is likewise of limited degree of improvement, and it is desirable to increase the effect. In addition, side effects occur, for example, for male sexual function, during therapy with 5-a reductase inhibitors.

It has also been proposed to use PDE 5 inhibitors for the treatment of benign prostatic hyperplasia symptoms [Forssmann et al., US application 2003/0199517 A1]. However, according to the description of section 0027, page 3 of this application, the inhibitor is administered orally ("usual galenic preparations such as tablets, coated tablets, capsules ..."). This type of therapy has the problem that the efficacy is not adequate, the duration of action is too short, and the tolerance is poor.

Also in some cases combinations of these drug groups have been described. Thus, a combination of selective α-adrenergic receptor antagonists and cGMP PDE inhibitors has been described for the treatment of erectile dysfunction (Wyllie, US 2003/0040514 A1). However, this combination is not used for the treatment of erectile dysfunction. The main reason for this is evident in that the combination is considered contraindicated due to tolerability disadvantages. Accordingly, the US Drug Product List ("Physicians' Desk Reference") sets forth the following contraindications for Levitra® tablet (vardenafil) products: "Co-administration of alpha-blockers and Levitra. May cause high blood pressure, so Levitra is contraindicated in patients taking alpha-blockers. " In addition, US application 2003/0040514 A1 discloses "when needed as opposed to taking for long periods of time" (paragraph 0023 of page 2), preferably a "fast acting" combination (page 2 To paragraph 0024). The combination proposed here is not suitable for the treatment of other disorders such as benign prostatic hyperplasia.

Summary of the Invention

In accordance with the present invention, α-1 adrenergic receptor antagonists, or 5-α reductase inhibitors in the form of controlled-release preparations; And combinations of cGMP PDE 5 inhibitors in the form of controlled-release preparations, or cGMP PDE 5 inhibitors with long half-lives, have been found to result in improved therapeutic effects in the treatment of benign prostatic hyperplasia. These preparations have markedly improved efficacy for bladder urination disorders associated with benign prostatic hyperplasia, such as improved maximum urine flow, less residual urine, reduced need for nighttime urination, less bladder irritation or urination. Has the advantage of impulse. In addition, improved tolerability to therapy may be achieved by keeping the dosage of each of the combination subjects less than for each monotherapy. This replaces the current theory that the combinations according to the invention are contraindicated in formulations prepared according to the invention. In addition, 5-α reductase inhibitors for male sexual function using a combination of a 5-α reductase inhibitor and a cGMP PDE 5 inhibitor in the form of a controlled-release preparation or a cGMP PDE 5 inhibitor with a long half-life according to the invention. Can reduce the adverse effects of.

In addition, selective α-1 adrenergic receptor antagonists in the form of controlled-release preparations; Combinations of the three components of the 5-α reductase inhibitor and the PDE 5 inhibitor are possible, for example, a combination of tamsulosin, finasteride in the form of a controlled-release preparation, and vardenafil in the form of a controlled-release preparation. .

The compounds may be combined without limitation, for example via a combination pack, wherein the pack comprises a pharmaceutical formulation of each substance, wherein the pharmaceutical formulations are on the same date on the pack, package leaflet, or label. Include instructions to take. In this regard, each pharmaceutical formulation may be taken at about the same time or at different times during the day.

However, pharmaceutical formulations comprising a fixed combination, ie all drug substances to be combined, are preferred. Possible examples are tablets, hard gelatin or soft gelatin capsules.

Dual sustained release pharmaceutical formulations are used to combine α-1 adrenergic receptor antagonists with short half-life PDE 5 inhibitors, for example vardenafil or sildenafil. These formulations represent a combination of a controlled-release α-1 adrenergic receptor antagonist portion and a controlled-release PDE 5 inhibitor portion. Examples suitable for this purpose are capsules comprising two types of pellets, minitablets or tablets, ie pellets for the controlled-release of α-1 adrenergic receptor antagonists and pellets for the controlled-release of PDE 5 inhibitors. Another possibility is a sustained release formulation consisting of two or more different active ingredient layers. One of these layers is for the control-release of the α-1 adrenergic receptor antagonist and the other is for the control-release of the PDE 5 inhibitor. Osmotic-release tablets are also possible. This tablet comprises two combination objects in the active ingredient layer. Optionally, osmotic active swellable layers free of active ingredient are also possible. The resulting monolayer or bilayer tablets are coated with a coating which consists of a water-insoluble but permeable coating, for example cellulose acetate and is provided with one or more pores on the active ingredient-containing side which release the active ingredient.

A single sustained release pharmaceutical formulation is used to combine the α-1 adrenergic receptor antagonist with a long half-life PDE 5 inhibitor, eg tadalafil, or a 5-α reductase inhibitor with a short half-life PDE 5 inhibitor, eg Combine with vardenafil or sildenafil. In the first case, the pharmaceutical formulation releases the α-1 adrenergic receptor antagonist in controlled form and comprises tadalafil in the form of a fast-release formulation. In the second case, the pharmaceutical formulation releases the PDE 5 inhibitor in controlled form and includes a 5-α reductase inhibitor in the form of a fast-release formulation. Examples of single sustained release pharmaceutical formulations are capsules comprising controlled-release combination subjects in the form of pellets, minitablets or tablets and fast-release combination subjects in the form of powders, compacts, tablets or pellets. In addition, sustained release tablets consisting of two or more different active ingredient layers are possible. One layer comprises a controlled-release combination object. Its release is controlled, for example, by incorporation into an insoluble matrix or an eroding matrix. The other active ingredient layer of the tablet comprises a non-controlled-release combination subject in the form of a conventional fast-release formulation. Another possibility is sustained release tablets with a monolayer structure. This tablet comprises a combination of α-1 adrenergic receptor antagonist in the form of diffusion pellets with a long half-life PDE 5 inhibitor, or 5-α reductase inhibitor. Alternatively, the tablet comprises a combination of a short half-life PDE 5 inhibitor in the form of a diffusion pellet and a 5-α reductase inhibitor. In addition to this, osmotic-release tablets are possible. This tablet comprises, for example, a monolayer with a triple layer structure, a bilayer with a non-controlled-release combination, a bilayer with a controlled-release combination object and an osmotic reactive swelling layer free of active ingredients. . The resulting triple layer tablets are coated with a water-insoluble but permeable coating, for example cellulose acetate, with a coating provided on the active ingredient-containing side with one or more pores that release the active ingredient.

Very particular preference is given to tablets or capsules comprising two combination subjects in the form of fast-release preparations in combining a 5-a reductase inhibitor with a long half-life PDE 5 inhibitor, for example tadalafil. Tablets may be made from powder mixtures or granules already comprising the two combination subjects. Alternatively, granules or powders, each containing only one of the combination objects, may be mixed together and then compacted. It is also possible to prepare bilayer tablets in which the active ingredient is contained separately in two layers. Similarly, in the preparation of capsules, separate powders, granules, pellets or tablets, or powders, granules, pellets or tablets already comprising the two combination subjects can be used. Also possible are soft gelatin capsule formulations having two combination subjects. This formulation comprises a suspension or solution for two combinations of oils or water-miscible vehicles, for example polyethylene glycol.

α-1 and α-1A adrenergic receptor antagonists are known and are generically named in the present invention as α-1 adrenergic receptor antagonists. Tamsulosin, alfuzosin, doxazosin and terrazosin are particularly preferred. These compounds can be used as bases or salts, each of which varies in hydration level and modification. Preferred dosages and formulations are 0.2-0.8 mg tamsulosin HCl, 5-20 mg alfuzosin HCl, 1-16 mg doxazosin mesylate and 2-20 mg terazosin HCl.

5-α reductase inhibitors are known. Finasteride and dutasteride are particularly preferred. Preferred dosages are 1-10 mg finasteride and 0.2-1 mg dutasteride.

cGMP PDE 5 inhibitors are known. Vardenafil, sildenafil and tadalafil are particularly preferred. These compounds can be used as bases or salts, each of which varies in hydration level and modification. A cGMP PDE 5 inhibitor with a long half-life means that its half-life exceeds 8 hours. A cGMP PDE 5 inhibitor with a short half life means that its half life is 8 hours or less. A preferred cGMP PDE 5 inhibitor with a long half-life is tadalafil. Dosage and formulation are particularly preferably 5-30 mg of vardenafil hydrochloride trihydrate (calculated as vardenafil), 25-150 mg of sildenafil citrate (calculated as sildenafil) and 5-30 mg of tadalafil. .

The present invention delivers α-1 adrenergic receptor antagonist in a controlled manner with an 80% average release rate of greater than 45 minutes and PDE 5 inhibitor in a controlled manner with an 80% average release rate of greater than 45 minutes. It relates to a pharmaceutical formulation. the α-1 adrenergic receptor antagonist is delivered in a controlled manner with an 80% average release rate of 2 to 16 hours and the PDE 5 inhibitor is delivered in a controlled manner with an 80% average release rate of 2 to 16 hours Pharmaceutical formulations are particularly preferred.

In addition, the invention relates to pharmaceutical formulations comprising a modulated α-1 adrenergic receptor antagonist in a controlled manner with an 80% average release rate of greater than 45 minutes, and a PDE 5 inhibitor with a long half-life. Particular preference is given to pharmaceutical formulations comprising an α-1 adrenergic receptor antagonist in a controlled manner with an 80% average release rate of 2 to 16 hours, and a PDE 5 inhibitor with a long half-life.

The invention also relates to a pharmaceutical formulation comprising a 5-α reductase inhibitor and delivering the PDE 5 inhibitor in a controlled manner with an 80% average release rate of greater than 45 minutes. Particular preference is given to pharmaceutical formulations comprising a 5-α reductase inhibitor and delivering the PDE 5 inhibitor in a controlled manner with an 80% average release rate of 2 to 16 hours.

The present invention also relates to pharmaceutical formulations comprising 5-α reductase inhibitors and PDE 5 inhibitors with long half-lives.

In addition, the present invention delivers the α-1 adrenergic receptor antagonist in a controlled manner with an 80% average release rate of greater than 45 minutes and the PDE 5 inhibitor in a controlled manner with an 80% average release rate of greater than 45 minutes. And a pharmaceutical formulation comprising 5-α reductase inhibitor. the α-1 adrenergic receptor antagonist is delivered in a controlled manner with an 80% average release rate of 2 to 16 hours and the PDE 5 inhibitor is delivered in a controlled manner with an 80% average release rate of 2 to 16 hours Particular preference is given to pharmaceutical formulations comprising a 5-α reductase inhibitor.

The invention also provides pharmaceutical formulations comprising a modulated α-1 adrenergic receptor antagonist with an 80% average release rate of greater than 45 minutes, a PDE 5 inhibitor with a long half-life, and a 5-α reductase inhibitor. It is about. Pharmaceutical formulations that deliver an α-1 adrenergic receptor antagonist in a controlled manner with an 80% average release rate of 2 to 16 hours and which have a long half-life, and a 5-α reductase inhibitor desirable.

To determine the average release rate according to the definition of the present invention, the pharmaceutical formulation of the present invention is tested in USP (US Pharmacopoeia) "Device 2". The test medium used is 900 ml of phosphate buffer, pH 6.8, with 0.1% sodium lauryl sulfate added. The rotation speed of the stirrer is 75 revolutions per minute. The sample is passed through an 8 μm filter and its active ingredient content is determined. The amount of dissolved active ingredient determined in this way is converted to the weight percent of the amount of active ingredient used.

The pharmaceutical formulations described above are, for example, in the form of capsules. It may consist, for example, of glycerol, gelatin and colorants, of hypromellose, pullulan, or of other known materials and may include the following:

Α-1 adrenergic receptor antagonist in the form of a controlled-release preparation

PDE 5 inhibitors in the form of controlled-release preparations

PDE 5 inhibitors with long half-lives, eg in the form of fast-release preparations

5-α reductase inhibitors, eg in the form of fast-release preparations

Diffuse-controlled pellets are particularly suitable for formulating α-1 adrenergic receptor antagonists and PDE 5 inhibitors in controlled-release form for subsequent packing into capsules. Diffusion-controlled pellets with α-1 adrenergic receptor antagonists or PDE 5 inhibitors, for example, may contain neutral pellets consisting of sucrose or microcrystalline cellulose, active ingredients, conventional binders, acids and, if necessary, additional conventional It is prepared by coating with a mixture of excipients and then with a diffusion coating which may include a plasticizer. Preferably the binder used is hydroxypropylmethylcellulose or polyvinylpyrrolidone. Likewise, other natural, synthetic or semisynthetic polymers can be used, such as methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyacrylic acid, polyvinyl alcohol or gelatin. Particularly suitable diffusion coatings are ethylcellulose and are commercially available as aqueous dispersions, for example under the name Aquacoat® or Surelease®. However, other materials such as poly [(methacrylic acid) (ethyl acrylate)] (1: 1) or other acrylates (Eudragit®), cellulose acetate or cellulose acetate butyrate can be used. It may be. Examples of suitable plasticizers include phthalic acid derivatives (eg dimethyl phthalate, diethyl phthalate, dibutyl phthalate), citric acid derivatives (eg triethyl citrate, tributyl citrate, acetyl triethyl citrate), other esters (eg di Ethyl sebacate, triacetin), fatty acids and derivatives (glycerol monostearate, acetylated fatty acid glycerides, castor oil and other natural oils, migliol oils), polyols (glycerol, 1,2-propanediol, various chain lengths Polyethylene glycol). In addition, the type and amount of plasticizer is adjusted to achieve the above defined release and the required pellet stability according to the invention. In addition, the release as defined above is controlled by adjusting the pore size and / or thickness thereof of the diffusion coating. Pore formers that can be used to control pore size are optionally soluble polymers such as polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose or salts thereof, methylcellulose, dextrin, Maltodextrin, cyclodextrin, dextran or other soluble compounds such as salts (sodium chloride, potassium chloride, ammonium chloride, etc.), urea, sugars (glucose, sucrose, fructose, lactose, etc.), sugar alcohols (mannitol, sorbitol, Lactitol and the like). In this case, the proportion of pore formers in the amount of coating is from 0 to 50% (w / w) (w = weight). In the case of pellets it is particularly important to use a fixed weight ratio of active ingredient-coated pellets to diffusion membrane and a fixed ratio of diffusion coating to plasticizer amount. Some of the plasticizers used may be evaporated during coating and subsequent heat treatment. When changing the constraints, the amount of diffusion coating applied must be varied. Thus, for example, when reducing the desired release rate, increasing the amount of pore former, or decreasing the proportion of plasticizer for a particular plasticizer, a larger amount needs to be applied. If increasing the desired release rate, decreasing the amount of pore former, or increasing the proportion of plasticizer for a particular plasticizer, a smaller amount needs to be applied. Diffusion pellets can be prepared, for example, by suspending or dissolving the active ingredient in water and thickening with a concentrated hydroxypropylmethylcellulose solution. The suspension or solution obtained in this way is absorbed onto the neutral pellets by a spraying process in a fluid bed system. The pellet is then coated with a diffusion membrane, preferably by spraying on an aqueous ethylcellulose dispersion or an organic ethylcellulose solution comprising a suitable physiologically acceptable plasticizer, in a fluid bed system. The pellet is then heat treated at a temperature of 50 to 125 ° C, preferably 60 to 110 ° C. In this regard, higher heat treatment temperatures tend to be sufficient to apply less amounts of coating to achieve release according to the invention, and the resulting pellets are physically more stable upon storage. The thickness of the diffusion membrane, the type of plasticizer, the amount of plasticizer and the pellet size are selected such that the 80% release rate of the α-1 adrenergic receptor antagonist and PDE 5 inhibitor is greater than 45 minutes, preferably 2 to 16 hours. For example, an amount of pellets corresponding to the daily dose of 0.4 mg tamsulosin HCL and 10 mg vardenafil HCl trihydrate is packed into hard gelatin capsules. In addition to the neutral pellet coatings described above, other pellet preparation methods are also possible, such as wet extrusion and rounding, rotor granulation, fluidized bed aggregation or thermal extrusion. Alternatively, it is also possible to produce minitablets with a diameter of 1 to 4 mm. The active ingredient-containing pellet or minitablet is then coated with a diffusion membrane as described above.

In another embodiment of the pharmaceutical formulation according to the invention, tablets comprising the active ingredient in a matrix of water-swellable polymers are suitable for formulating α-1 adrenergic receptor antagonists and PDE 5 inhibitors in controlled-release preparations. These tablets are sized such that there is room for one or more tablets inside the capsule. The tablets can be packed into capsules in uncoated form or precoated with a coating, for example an insoluble coating in gastric juice.

A tablet comprising a PDE 5 inhibitor or α-1 adrenergic receptor antagonist in a matrix of the water-swellable polymer and for later packing into a capsule is prepared as follows. Such so-called matrix preparations advantageously comprise 0.1 to 70% by weight, preferably 0.2 to 60% by weight of active ingredient. The proportional amount of the water-swellable polymer matrix is advantageously 10 to 95% by weight, preferably 20 to 60% by weight. Particular preference is given to pharmaceutical preparations according to the invention in the form of erosive tablets. These tablets include conventional excipients and carriers, and tableting excipients as well as defined amounts of water-swellable hydrogel-forming polymers, wherein the polymers are at least 15 cps, preferably at least 50 cps (as a 2% concentration aqueous solution at 20 ° C.). Measured). Examples of conventional excipients and carriers are lactose, microcrystalline cellulose, mannitol or calcium phosphate. Common tableting aids are, for example, magnesium stearate, talc or colloidal silicon dioxide (Aerosil®). They are advantageously present in amounts of 0.5 to 3% by weight for magnesium stearate and advantageously in amounts of 0.1 to 1% by weight for colloidal silicon dioxide. Preferred water-soluble hydrogel-forming polymers include hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, carboxymethylcellulose, alginate, galactomannas, polyacrylic acid, polymethacrylic acid, or Copolymers of methacrylic acid and methyl methacrylate, guar, agar, pectin, tragacanth, gum arabic, xanthan or mixtures of these materials. Particular preference is given to using HPMC. In this case, the erosive tablet according to the invention preferably has a hydroxypropylmethylcellulose type having a viscosity (measured as a 2% concentration aqueous solution at 20 ° C.) of at least 15 cps, preferably at least 50 cps, based on the mass of the tablet. 10 weight% or more is included. Pharmaceutical formulations comprising the active ingredient in a matrix of water-swellable polymers are prepared by mixing the active ingredient, the polymer and suitable excipients and carriers (as described above) and conventional tableting aids (as described above) and directly tableting do. In addition, the active ingredient, the water-swellable polymer and a suitable carrier can be granulated in the fluidized bed. In this case, the amount and viscosity of the water-swellable polymer are selected so that the resulting tablet has an average release rate of the α-1 adrenergic receptor antagonist or PDE 5 inhibitor as described above. Dry granules are screened, mixed with a lubricant such as, for example, magnesium stearate and tableted. Then, if desired, the tablets are coated. For later packing into capsules, erosive tablets with a diameter of 3 mm to 7 mm are preferred.

PDE 5 inhibitors, or 5-α reductase inhibitors with long half-lives can be introduced into capsules as powders, granules, pellets or tablets. Conventional rapid-release preparations are suitable for this purpose.

In other embodiments of the pharmaceutical formulation, the combination subjects are in a bilayer tablet. Bilayer tablets consist of two controlled-release layers, one controlled-release layer and one quick-release layer, or two quick-release layers. These layers may be as follows:

On the one hand, a controlled-release layer for α-1 adrenergic receptor antagonist or a fast-release layer for 5-α reductase inhibitor, and

On the other hand, a controlled-release layer for a PDE 5 inhibitor or a fast-release layer for a PDE 5 inhibitor with a long half-life.

Each controlled-release layer is prepared based on the principles described above for matrix formulations for later packing into capsules. To prepare each rapid-release layer, the active ingredient is mixed with suitable excipients and carriers (as described above) and conventional tableting aids (as described above) and directly tableted. In addition, the active ingredient and a suitable carrier can be granulated in a fluidized bed, mixed granulator or roll compactor. Dry granules are screened, mixed with a lubricant such as, for example, magnesium stearate and tableted. Especially suitable for tableting is a double layer press provided with two filling and compression stations. Then, if desired, the tablets are coated. In order to ensure that the initial release rate of one of the combination subjects is not too fast, the bilayer tablet may be provided with a third layer free of active ingredient.

In a further embodiment of the pharmaceutical formulation, the combination subject is present as a monolayer tablet. This tablet includes the following:

On the one hand, short half-life PDE 5 inhibitors or α-1 adrenergic receptor antagonists in the form of controlled-release preparations, and

On the other hand, a 5-α reductase inhibitor in the form of a fast-release formulation (for a combination of short half-life PDE 5 inhibitors) or a PDE 5 inhibitor with a long half-life (α-1A adrenergic receptor antagonist) Occation).

The diffusion-controlled pellets described above are particularly suitable as controlled-release preparations for later incorporation into monolayer tablets. The pellets are mixed with the active ingredient and additional excipients, carriers and tableting aids to be combined in the form of fast-release preparations and compressed into single layer tablets. It is also possible to granulate the fast-release excipients and then coat the tablets.

A further embodiment of the pharmaceutical formulation of the present invention is an osmotic drug release system. Such osmotic drug release systems are known in principle in the art and are described, for example, in Richard W. Baker, "Osmotic Drug Delivery: A Review of the Patent Literature", Journal of Controlled Release 35 (1995) 1-21. Are covered in detail. Pharmaceutical formulations that are osmotic drug release systems preferably consist of:

a) a core comprising the active ingredient and optionally a hydrophilic polymeric swelling agent and optionally a water soluble material (induces osmotic action), and

b) a shell through which water and components of the active ingredient-containing core can permeate

c) a hole for delivering the components present in the core through the shell b) to the surrounding body fluid.

Such specific osmotic drug release systems are described in principle in the art, for example in DE-A-2 328 409 or US-A-3 85 770. For materials for the shell, reference may be made to EP-A-0 277 092, US-A-3 916 899 and US-A-3 977 404, mentioned herein.

For suitable hydrophilic polymer swelling agents, reference may be made, for example, to the polymer swelling agents mentioned in EP-A-0 277 092 and WO 96/40080. Ethylene oxide homopolymers (polyethylene glycols), and vinylpyrrolidone-vinyl acetate copolymers, for example, known under the name polyox and having a molecular weight of 100,000 to 8,000,000 and varying degrees of polymerization, and US-A- Further water-swellable polymers mentioned in 3 865 108, US-A-4 002 173 and US-A-4 207 893 can be used. Water-soluble substances for inducing osmotic action are in principle all water-soluble substances which are permitted to be used in pharmacy, for example, in the pharmacopoeia or as described in "Hager's Handbuch der Pharmazeutischen Praxis, 1990-1995, Springer Verlag" and Remington's Pharmaceutical Sciences as water soluble excipient]. Specific water soluble materials include salts of inorganic or organic acids or nonionic organic materials with high water solubility, for example carbohydrates such as sugars. Creating pores in the shell of a tablet is known per se in the art and is described, for example, in US Pat. Nos. 3,485,770 and 3,916,99. The release rate is controlled by the type and amount of the semipermeable material forming the shell, the type and amount of the present or suitable hydrophilic polymer swelling agent, and the type and amount of the water-soluble material suitable for present or inducing osmotic action. Combination subjects of the invention can be introduced into the osmotic drug release system in a variety of ways. For controlled delivery of the two active ingredients, these ingredients are mixed with excipients and compressed together into one active ingredient layer. When only one combination subject performs controlled release, the subject may be introduced separately into the coated shell of the tablet or the active ingredient which does not perform controlled release is compressed into a separate active ingredient layer, The component is pumped out of the drug release system prior to the combination subject performing the controlled release.

Example  One

12.5 g of tamsulosin HCl were dissolved in a mixture of 47.5 g of water and 427.5 g of methanol with 12.5 g of hypromellose. This solution was sprayed onto 2500 g of neutral pellets consisting of microcrystalline cellulose with an average particle diameter of 125 μm in a fluid bed system. 2500 g of pellets coated in this way were sprayed into a fluid bed system having a dispersion consisting of 1167 g of poly (ethyl acrylate-methyl methacrylate) 30% dispersion, 350 g of talc and 1260 g of water. The pellet coated with the diffusion membrane was then dried at 40 ° C.

741 g of micronized vardenafil hydrochloride trihydrate and 625 g of crushed tartaric acid were suspended or dissolved in a solution of 156 g hypromellose and 6250 g of water. This suspension was sprayed onto 2500 g of neutral pellets made of sucrose in a fluid bed system. The pellets coated in this way were sprayed onto a fluidized bed with a dispersion consisting of 1473 g of poly (ethyl acrylate-methyl methacrylate) 30% dispersion, 442 g of talc and 1593 g of water. The pellet coated with this diffusion membrane was then dried at 40 ° C.

103.4 mg of diffusion-regulated tamsulosin pellets and 157 mg of diffusion-controlled vardenafil pellets were packed into hard gelatin two-piece capsules.

Example  2

Triple layer tablets were prepared as follows: For layer 1, 75.4 kg of hypromellose, 5 kg of ethylcellulose and 15 kg of hydrogenated castor oil were mixed and granulated using a solution consisting of 3.2 kg of povidone K30 and 28.8 kg of ethanol. It was done. The dried granules were then mixed with 0.5 kg of colloidal silicon dioxide and 1 kg of magnesium stearate. For layer 2, 5 kg of alfuzosin hydrochloride, 15 kg of hypromellose and 75 kg of microcrystalline cellulose were granulated in a fluidized bed with a solution of 3 kg of povidone K30 and 97 kg of water. The granules were dried and then mixed with 0.5 kg of colloidal silicon dioxide and 1.5 g of magnesium stearate. For layer 3, 23.7 kg vardenafil hydrochloride trihydrate, 130 kg hypromellose and 3.1 kg microcrystalline cellulose were mixed and dry-granulated on a roll. The granules were then mixed with 0.8 kg of colloidal silicon dioxide and 2.4 kg of magnesium stearate. Three granules were placed in the filling hopper of the triple layer tablet press in such a way that layer 2 became the middle tablet layer. Circular triple layer tablets with a diameter of 8 mm, a mass of layer 1 of 100 mg, a mass of layer 2 of 100 mg, and a mass of layer 3 of 160 mg were compressed.

Example  3

Tablets of the following composition were prepared: finasteride 5 mg, tadalafil 10 mg, lactose monohydrate 50 mg, microcrystalline cellulose 47.625 mg, sodium dodecyl sulfate 0.625 mg, croscarmellose sodium 7.5 mg, hyprolos 3 mg, magnesium stearate 1.25 mg. The preparation was performed in a fluidized bed granulator with an aqueous solution of sodium dodecyl sulphate and hyprolosin in an amount corresponding to a batch of 16 million tablets, finasteride, tadalafil, lactose monohydrate, microcrystalline cellulose, and half amount croscarmellose. Los sodium was performed by granulating. The dried granules were then mixed with magnesium stearate and compressed into rotary tablets of 7 mm diameter and 125 mg mass in a rotary press. The tablets were coated with a coating consisting of 2.391 g of hypromellose, 0.797 mg of macrogol 3, 0.653 mg of titanium dioxide and 0.144 mg of yellow iron oxide.

Example  4

In a first batch, 70.225 g of sildenafil citrate, 35.075 kg of microcrystalline cellulose and 37.5 kg of hypromellose were granulated in a fluid bed granulator with a solution of 5.7 kg of hypromellose in 136.8 kg of water. The dried granules were then mixed with 1.5 kg of magnesium stearate and compressed into round tablets of 7 mm diameter and 150 mg mass. In a second batch, 5 kg finasteride, 60 kg lactose monohydrate, 47.625 kg microcrystalline cellulose and 3.75 kg sodium croscarmellose, with a solution of 0.625 kg sodium dodecyl sulfate and 100 kg hyprolose in 100 kg water Granulated in a fluid bed granulator. The dried granules were then mixed with 3.75 kg of croscarmellose sodium and 1.25 g of magnesium stearate. The mixture was compressed into round tablets 7 mm in diameter and 125 mg in mass. In each case, one tablet of the first batch and one tablet of the second batch were encapsulated in a hard gelatin capsule of size 00.

Claims (21)

Agents for the treatment of benign prostatic hyperplasia comprising at least one α-1 adrenergic receptor antagonist in the form of a controlled-release preparation and at least one PDE 5 inhibitor in the form of a controlled-release preparation, or at least one PDE 5 inhibitor having a long half-life Formulation or combination pack. The pharmaceutical formulation of claim 1 comprising a controlled-release formulation of tamsulosin, alfuzosin, doxazosin or terrazosin and a controlled-release formulation of vardenafil or sildenafil. The pharmaceutical formulation of claim 1, comprising a controlled-release formulation of tamsulosin, alfuzosin, doxazosin or terrazosin, and tadalafil. A pharmaceutical formulation or combination pack for treating benign prostatic hyperplasia comprising at least one 5-α reductase inhibitor and at least one PDE 5 inhibitor in the form of a controlled-release formulation, or at least one PDE 5 inhibitor with a long half-life. The pharmaceutical formulation of claim 4 comprising finasteride or dutasteride and a controlled-release formulation of vardenafil or sildenafil. The pharmaceutical formulation of claim 4 comprising finasteride or dutasteride and tadalafil. One or more α-1 adrenergic receptor antagonists in the form of controlled-release preparations and one or more PDE 5 inhibitors in the form of controlled-release preparations; Or at least one 5-α reductase inhibitor and at least one PDE 5 inhibitor with a long half-life, comprising: a pharmaceutical formulation or combination pack for treating benign prostatic hyperplasia. The method of claim 1, wherein the α-1 adrenergic receptor antagonist is in the form of pellets, granules or tablet (s) coated with a diffusion-modulating membrane, and in the form of pellets, granules or tablet (s) coated with a diffusion-modulating membrane. Pharmaceutical formulation, characterized in that the capsule containing a PDE 5 inhibitor. 2. A pharmaceutical formulation according to claim 1, characterized in that a capsule comprises α-1 adrenergic receptor antagonist as a matrix tablet in which the active ingredient is controlled-release, and a PDE 5 inhibitor as a matrix tablet in which the active ingredient is controlled-release. . 2. A bilayer tablet according to claim 1, characterized in that it comprises one layer with an α-1 adrenergic receptor antagonist in the form of a controlled release matrix formulation and a layer with a PDE 5 inhibitor in the form of a controlled release matrix formulation. Pharmaceutical formulation. 2. A capsule according to claim 1, characterized in that it comprises a capsule comprising an α-1 adrenergic receptor antagonist in the form of pellets, granules or tablet (s) coated with a diffusion-modulating membrane, and a PDE 5 inhibitor with a long half-life. Pharmaceutical preparations. 2. A pharmaceutical formulation according to claim 1, wherein the active ingredient exhibits a capsule comprising α-1 adrenergic receptor antagonist as a matrix tablet to be controlled-release, and a PDE 5 inhibitor with a long half-life. 2. A pharmaceutical formulation according to claim 1, characterized in that it comprises a bilayer tablet comprising one layer with an α-1 adrenergic receptor antagonist in the form of a controlled release matrix formulation and a layer with a PDE 5 inhibitor having a long half-life. . 2. A layer according to claim 1, having one layer with an α-1 adrenergic receptor antagonist in the form of pellets, granules or tablet (s) coated with a diffusion-modulating membrane, and one layer with a PDE 5 inhibitor with a long half-life. Pharmaceutical formulation, characterized in that it represents a monolayer tablet comprising a. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation exhibits an osmotic drug release system comprising an α-1 adrenergic receptor antagonist and a PDE 5 inhibitor. The pharmaceutical formulation of claim 2, wherein the capsule comprises a 5-α reductase inhibitor and a PDE 5 inhibitor in the form of pellets, granules or tablet (s) coated with a diffusion-modulating membrane. The pharmaceutical formulation according to claim 2, wherein the capsule comprises a 5-α reductase inhibitor and a PDE 5 inhibitor as a matrix tablet in which the active ingredient is controlled-released. 3. A pharmaceutical formulation according to claim 2, wherein the pharmaceutical formulation is represented as comprising a bilayer tablet comprising one layer with a 5-α reductase inhibitor and one layer with a PDE 5 inhibitor in the form of a controlled-release matrix formulation. The monolayer according to claim 2 comprising one layer with PDE 5 inhibitor in the form of pellets, granules or tablet (s) coated with a diffusion-controlled membrane, and one layer with 5-α reductase inhibitor. Pharmaceutical formulations characterized in that they represent tablets. The pharmaceutical formulation according to claim 2, wherein the pharmaceutical formulation exhibits an osmotic drug release system comprising a 5-α reductase inhibitor and a PDE 5 inhibitor. The pharmaceutical formulation of claim 2 comprising a long half-life PDE 5 inhibitor, and a 5-α reductase inhibitor.