Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• This invention relates to a novel method of treating the symptoms of benign prostatic hyperplasia.
• BPH benign prostatic hyperplasia
• Outflow obstruction in the urethra is symptomatically improved by an enlarged prostate.
• Examples of such compounds are tamsulosin, alfuzosin, doxazosin and
• 5- ⁇ reductase inhibitors such as finasteride or dutasteride. This inhibits the reduction of testosterone to dihydrotestosterone. As a result, after prolonged therapy, the prostate volume is reduced and the symptoms of BPH improved. Even with this therapy, the extent of the improvements is limited and it is desirable to increase the effect. Furthermore, occur under the therapy with 5- ⁇ reductase inhibitors side effects, such as an impairment of male sexual function.
• PDE 5 inhibitors to treat symptoms of benign prostatic hyperplasia has also been proposed (Forssmann et al., US Application 2003/0199517 Al). However, as described in section 0027 on page 3 of the application, their oral administration is carried out in "conventional pharmaceutical preparations such as tablets, coated tablets, capsules ." This form of therapy has in addition to insufficient efficacy and too short duration of action the problem of moderate Compatibility.
• a triple combination of selective ⁇ -1 adrenoceptor antagonist in controlled-release formulation, 5- ⁇ reductase inhibitors and PDE 5 inhibitor is also possible,
• tamsulosin in controlled release formulation, finasteride and vardenafil in controlled release formulation is also possible.
• the combination of said compounds can be carried out freely, for example by a combination pack containing drug forms of the respective substances and on the package, the package insert or a label contains an instruction to take the drug forms on the same day.
• the individual dosage forms can be taken approximately at the same time or at different times in the course of a day.
• fixed combinations ie dosage forms containing all the drugs to be combined.
• These may be, for example, tablets, hard gelatin or soft gelatine capsules.
• ⁇ -1 adrenoceptor antagonist for example vardenafil or sildenafil
• two-sidedly retarded drug forms are used. These are a combination of controlled release ⁇ -1 adrenoceptor antagonist portion with a controlled release PDE 5 - inhibitor - proportion.
• This is for example capsules containing two types of pellets, minitablets or tablets, namely those that the ⁇ - Adrenoceptor antagonists and those that release the PDE 5 inhibitor in a controlled manner.
• slow-release tablets which consist of at least two different active ingredient layers. One of them releases the ⁇ -1 adrenoceptor antagonist controlled, another the PDE 5 inhibitor.
• osmotic-releasing tablets are also possible. These contain both combination partners in the active substance layer.
• an osmotically active, drug-free swelling layer is also possible.
• the resulting one- or two-layer tablet is coated with a water-insoluble, but permeable lacquer, for example of cellulose acetate, and provided on the active substance-containing side with at least one hole for drug release.
• ⁇ -1 adrenoceptor antagonists for example tadalafil
• a 5- ⁇ reductase inhibitor for example vardenafil or sildenafil
• unilaterally sustained dosage forms are used.
• the dosage form releases the ⁇ -1 adrenoceptor antagonist in controlled form and contains the tadalafil in a rapidly releasing form.
• the dosage form releases the PDE 5 inhibitor in a controlled manner and contains the 5- ⁇ reductase inhibitor in a rapidly releasing form.
• Single-sidedly retarded dosage forms are, for example, capsules which contain the controlled release partner in the form of pellets, minitablets or tablets and which can be rapidly released. _
• slow-release tablets which consist of at least two different active ingredient layers.
• Another active ingredient layer of the tablet contains the uncontrollably released combination partner in the usual fast-release form.
• Another possibility is single-layered sustained-release tablets. These contain the ⁇ -1 adrenoceptor antagonist in the form of diffusion pellets and the PDE 5 inhibitor - long half-life or 5- ⁇ reductase inhibitor to be combined. Alternatively, they contain the PDE 5 inhibitor short half-life in the form of diffusion pellets and the 5- ⁇ reductase inhibitor to be combined.
• osmotically releasing tablets are possible. These are, for example, constructed in three layers and contain a first layer with the uncontrollably release combination partner, a second layer with the combination partner to be released in a controlled manner and an osmotically active, active substance-free swelling layer.
• the resulting three-layer tablet is coated with a water-insoluble, but permeable lacquer, for example of cellulose acetate, and provided on the active substance-containing side with at least one hole for drug release.
• tablets or capsules which contain both combination partners in rapidly releasing form are particularly preferred.
• the tablets can be made from a granulate or a powder mixture which already contains both combination partners.
• granules or powders can be mixed and then pressed together, each containing only one of the combination partners.
• the production of a two-layer tablet in which the active ingredients contained separately in the two layers.
• separate powders, granules, pellets or tablets can be used or such powders, granules, pellets or tablets that already contain both combination partners.
• Soft gelatin capsule formulations with both combination partners are also possible. These contain a suspension or solution of both combination partners in an oil or water-miscible vehicle such as polyethylene glycol.
• ⁇ -1 and ⁇ -IA adrenoceptor antagonists are known and are summarized in the context of this invention by the term ⁇ -1 adrenoceptor antagonist.
• Particularly preferred are tamsulosin, alfuzosin, doxazosin and terazosin.
• the compounds can be used as base or salt and these in each case in different Hydratease and modification.
• the preferred doses and forms are 0.2-0.8 mg tamsulosin HCl, 5-20 mg alfuzosin HCl, 1-16 mg doxazosin mesilate, and 2-20 mg terazosin HCl.
• 5- ⁇ reductase inhibitors are known. Particularly preferred is finasteride and dutasteride. The preferred doses are 1-10 mg finasteride and 0.2-1 mg dutasteride.
• cGMP PDE 5 inhibitors are known. Particularly preferred are vardenafil, sildenafil and tadalafil. The compounds can be used as base or salt and these in each case in different Hydratease and modification.
• CGMP PDE 5 inhibitors with a long half-life are to be understood as those whose half-life is more than 8 hours.
• CGMP PDE 5 inhibitors with a short half-life should be understood as those whose half-life is equal to or less than 8 hours.
• a preferred cGMP PDE 5 inhibitor with long half-life is tadalafil.
• vardenafil hydrochloride trihydrate 5 - 30 mg (calculated as vardenafil)
• sildenafil citrate 25 - 150 mg (calculated as sildenafil)
• tadalafil 5 - 30 mg The most preferred doses and forms are: vardenafil hydrochloride trihydrate 5 - 30 mg (calculated as vardenafil), sildenafil citrate 25 - 150 mg (calculated as sildenafil) and tadalafil 5 - 30 mg.
• the invention relates to a pharmaceutical formulation which controls an ⁇ -1 adrenoceptor antagonist with an average release rate of 80% in more than 45 minutes and a PDE 5 inhibitor controlled with an average release rate of 80% in longer than
• compositions containing an ⁇ -1 are particularly preferred.
• Adrenoceptor antagonists controlled with a mean release rate between 80% in
• the invention further relates to a pharmaceutical formulation containing an ⁇ -1 adrenoceptor antagonist controlled with an average release rate of 80% in more than 45 minutes and a long half-life PDE 5 inhibitor.
• Particularly preferred are drug formulations containing an ⁇ -1 adrenoceptor antagonist controlled with an average release rate between 80% in 2 hours and 80% in 16 hours and a long half-life PDE 5 inhibitor.
• the invention further provides a pharmaceutical formulation containing a 5- ⁇ reductase inhibitor and delivering a PDE 5 inhibitor controlled at a mean release rate of 80% in more than 45 minutes.
• Particularly preferred are drug formulations containing a 5- ⁇ reductase inhibitor and deliver a PDE 5 inhibitor controlled with an average release rate between 80% in 2 hours and 80% in 16 hours.
• the invention also provides a pharmaceutical formulation containing a 5- ⁇ reductase inhibitor and a long half-life PDE 5 inhibitor.
• the invention further relates to a pharmaceutical formulation containing an ⁇ -1 adrenoceptor
• Antagonist controls at a mean release rate of 80% in more than 45 minutes and delivers a PDE 5 inhibitor controlled at a mean release rate of 80% in more than 45 minutes and contains a 5- ⁇ reductase inhibitor.
• PDE 5 inhibitor controlled at a mean release rate of 80% in more than 45 minutes and contains a 5- ⁇ reductase inhibitor.
• Drug formulations that control an ⁇ -1 adrenoceptor antagonist with an average release rate between 80% in 2 hours and 80% in 16 hours and a PDE 5
• the invention further relates to a pharmaceutical formulation which controls an ⁇ -1 adrenoceptor antagonist with an average release rate of 80% in more than 45 minutes and a PDE 5 - long half-life inhibitor and a 5- ⁇ reductase inhibitor.
• Particularly preferred are drug formulations which deliver an ⁇ -1 adrenoceptor antagonist controlled with an average release rate between 80% in 2 hours and 80% in 16 hours and a PDE 5 - long half-life inhibitor and a 5 ⁇ reductase inhibitor included.
• the pharmaceutical formulations of the present invention are tested in USP "Apparatus 2" (The United States Pharmacopeia) 900 ml of pH 6.8 phosphate buffer with 0.1% sodium lauryl sulfate are used as the test medium The speed of rotation of the stirrer is 75 revolutions per minute Samples are passed through an 8 ⁇ m filter and their active ingredient content is determined, the amount of active substance determined in this way being converted into percent by weight of the active substance used.
• compositions described above are present, for example, in a capsule.
• This consists for example of glycerol, gelatin and dyes, hypromellose, pullulan or other known materials and may contain:
• the ⁇ -1 adrenoceptor antagonist and the PDE 5 - inhibitor in controlled release form for subsequent filling in a capsule are particularly suitable diffusion-controlled pellets.
• the binders used are preferably hydroxypropylmethylcellulose or polyvinylpyrrolidone.
• methylcellulose hydroxypropylcellulose, sodium carboxymethylcellulose, polyacrylic acids, polyvinyl alcohols or gelatin
• Particularly suitable as a diffusion coating is ethylcellulose, as it is commercially available, for example, as an aqueous dispersion under the name Aquacoat® or Surelease®.
• ethylcellulose as it is commercially available, for example, as an aqueous dispersion under the name Aquacoat® or Surelease®.
• other materials such as poly [(methacrylic acid) (ethyl acrylate)] (1: 1) or other acrylates (Eudragit®), cellulose acetate or cellulose acetate butyrate may also be used.
• Suitable plasticizers are, for example, phthalic acid derivatives (for example dimethyl phthalate, diethyl phthalate, dibutyl phthalate), citric acid derivatives (eg triethyl citrate, tributyl citrate, acetyl triethyl citrate), other esters (eg diethyl sebacate, triacetin), fatty acids and derivatives (glycerol monostearate, acetylated fatty acid glycerides, castor oil and other native oils , Miglyol), polyols (glycerol, 1,2-propanediol, polyethylene glycol of different chain length).
• phthalic acid derivatives for example dimethyl phthalate, diethyl phthalate, dibutyl phthalate
• citric acid derivatives eg triethyl citrate, tributyl citrate, acetyl triethyl citrate
• other esters eg diethyl se
• the type and amount of the plasticizer are adjusted so that the above-defined inventive release and the required stability of the pellets are achieved.
• the adjustment of the above-defined release is further effected by controlling the pore size of the diffusion coating and / or its thickness.
• Soluble polymers such as polyethylene glycols, polyvinylpyrolidones, hydroxypropylmethylcelluloses, carboxymethylcelluloses or their salts, methylcelluloses, dextrins, maltodextrins, cyclodextrins, dextranes or other soluble compounds, such as, for example, salts (sodium chloride, potassium chloride, Ammonium chloride, etc.), urea, sugars (glucose, sucrose, fructose, lactose, etc.), sugar alcohols (mannitol, sorbitol, lactitol, etc.).
• G mass
• Parts of the plasticizer used can evaporate during painting and tempering.
• a change in the coating amount of diffusion coating is required. Such is for example a higher coating amount is required if the desired rate of release is reduced, the amount of pore former is increased, or in certain plasticizers the level of plasticizer is reduced.
• the 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 thus obtained is applied to neutral pellets in a fluidized-bed plant in a spraying process. This is followed by the coating of the pellets with a diffusion membrane, preferably in a fluidized-bed plant, by spraying, for example, an aqueous dispersion of ethylcellulose or organic ethylcellulose, which contains a suitable, physiologically compatible plasticizer.
• the pellets are then tempered at temperatures of 50 to 125 ° C, preferably 60 to 110 0 C. In this case, higher tempering temperatures lead to lower coating application quantities being sufficient to achieve the release according to the invention and the resulting pellets being physically more stable during storage.
• the thickness of the diffusion membrane, type of plasticizer, amount of plasticizer and pellet size are chosen such that a rate of release of the ⁇ -1 adrenoceptor antagonist and PDE 5 inhibitor of 80% results in more than 45 minutes, preferably between 80% in 2 hours to 16 hours.
• the amount of pellets corresponding to a daily dose of, for example, 0.4 mg tamsulosin HCL and 10 mg Vardenaf ⁇ l HCl trihydrate is filled into a hard gelatine capsule.
• pellet production In addition to the described coating of neutral pellets, other methods of pellet production are feasible, such as moisture extrusion and rounding, rotor granulation, fluidized-bed agglomeration or thermal extrusion. Alternatively, minitablets with a diameter of 1 - 4 mm can be produced. Subsequently, the active ingredient-containing pellets or minitablets are coated with a diffusion membrane as described.
• ⁇ -1 adrenoceptor antagonist and the PDE 5 - inhibitor in controlled release form for subsequent filling in a capsule are in another embodiment of the drug formulation according to the invention tablets containing the active ingredient in a matrix of a water-swellable polymer.
• the size of these tablets is such that one or more tablets fit inside the capsule.
• the tablets may be filled in uncoated form into the capsule or previously coated with a varnish, for example a gastric juice-insoluble varnish.
• Tablets for subsequent filling in a capsule containing the ⁇ -1 adrenoceptor antagonist or PDE 5 inhibitor in a matrix of a water-swellable polymer are prepared as follows. These so-called matrix formulations suitably contain from 0.1 to ,
• compositions according to the invention in the form of erosion tablets are particularly preferred. These tablets are characterized in that they contain, in addition to customary auxiliaries and excipients and tabletting excipients, a certain amount of water-swellable hydrogel-forming polymers, these polymers having a viscosity of at least 15, preferably at least 50 cps (measured as 2% aqueous solution at 20 0 C).
• Typical excipients and carriers are, for example, lactose, microcrystalline cellulose, mannitol or calcium phosphates.
• Typical Tablettierzsmittel are for example magnesium stearate, talc or fumed silica (Aerosil ® ).
• magnesium stearate these are expediently present in an amount of from 0.5 to 3% by weight, in the case of highly dispersed silicon dioxide, advantageously in an amount of from 0.1 to 1% by weight.
• Preferred water-soluble, hydrogel-forming polymers are hydroxypropylcelluloses, hydroxypropylmethylcelluloses (HPMC), methylcelluloses, carboxymethylcellulose, alginates, galactomannans, polyacrylic acids, polymethacrylic acids or copolymers of methacrylic acid and methyl methacrylate, guar, agar, pectin, tragacanth, gum arabic, xanthan or mixtures of these substances used. Particularly preferred is the use of HPMC.
• the erosion tablets according to the invention should preferably contain at least 10 wt .-% of a hydroxypropylmethylcellulosetypses based on the mass of a tablet whose viscosity (measured as 2% aqueous solution at 20 0 C) is at least 15, preferably at least 50 cps.
• the drug formulation comprising the active ingredient in a matrix of a water-swellable polymer is prepared by mixing the active ingredient, the polymer and suitable excipients and excipients (as described above) and conventional tabletting aids (as described above) and tableting directly. It is also possible to granulate the active substance, the water-swellable polymer and suitable carriers in the fluidized bed.
• the amount and viscosity of the water-swellable polymer is chosen so that tablets with the above-described average release rates of the ⁇ -1 adrenoceptor antagonist or PDE 5 - inhibitor result.
• the dry granules are sieved, mixed with a lubricant, such as magnesium stearate, and tableted. If necessary, the tablet is still painted.
• Erosionstabletten are preferred with a diameter of 3 mm to 7 mm.
• the PDE 5 long half-life inhibitor or the 5- ⁇ reductase inhibitor may be incorporated into the capsule as a powder, granule, pellet or tablet.
• customary fast-release formulations are suitable.
• the combination partners are present in a bilayer tablet. It consists of two controlled release layers, one controlled and one rapidly releasing layer or two rapidly releasing layers. These can be:
• each controlled release layer is based on the principles set forth above for the matrix formulation for subsequent filling into a capsule.
• the active compound is mixed with suitable auxiliaries and excipients (as described above) and customary tabletting aids (as described above) and directly tabletted.
• suitable auxiliaries and excipients as described above
• customary tabletting aids as described above
• the dry granules are sieved, mixed with a lubricant, such as magnesium stearate, and tableted.
• a lubricant such as magnesium stearate
• the combination partners are present in a single-layer tablet. This contains:
• a PDE 5 inhibitor with a long half-life for combination with an ⁇ -1 A adrenoceptor antagonist
• a 5- ⁇ reductase inhibitor for combination PDE 5 - short half-life inhibitor
• Suitable controlled-release formulations for subsequent incorporation into a single-layer tablet are, in particular, the above-described diffusion-controlled pellets. These are mixed with the active ingredient to be combined in a rapidly releasing form and further hips, excipients and tabletting aids and pressed into a single-layer tablet. Granulation of the fast-release adjuvant and subsequent coating of the tablet are also possible.
• the pharmaceutical formulation of the present invention is an osmotic drug delivery system.
• osmotic drug delivery systems are generally known in the art and are e.g. reviewed in detail in Richard W. Baker, "Osmotic Drug Delivery: A Review of the Patent Literature,” Journal of Controlled Release 35 (1995) 1-21.
• the drug formulation as an osmotic drug delivery system is preferably composed
• a core which contains the active substances, optionally a hydrophilic polymeric swelling agent and optionally a water-soluble substance for inducing osmosis, and
• hydrophilic polymeric swelling agents reference may be made, for example, to the polymeric swelling agents mentioned in EP-A-0 277 092 and WO 96/40080.
• ethylene oxide homopolymers polyethylene glycol
• Polyox having various degrees of polymerization, known for example by the name Polyox, having molecular weights of between 100,000 and 8,000,000
• vinylpyrrolidone-vinyl acetate copolymers and others in US Pat. No. 3,865,108, US Pat 002 173 and US-A-4207 893 mentioned water-swellable polymers can be used.
• Water-soluble substances for the induction of osmosis are, in principle, all water-soluble substances whose use is unobjectionable in pharmacy, as mentioned in the Pharmacopoen or in "Hager's Handbook of Pharmaceutical Practice, 1990-1995, Springer Verlag” and Remington's Pharmaceutical Sciences as water-soluble excipients are.
• Special water-soluble substances are salts of inorganic or organic acids or nonionic organic substances with high water solubility such as carbohydrates such as sugar etc.
• the preparation of an opening in the shell of the tablet is known per se in the prior art and described, for example, in US Pat. Nos. 3,485,770 and 3,916,899.
• the release rate is adjusted by the nature and amount of the semipermeable material forming the shell, by the nature and amount of the optional hydrophilic polymeric swelling agent and any water-soluble substance which is present to induce osmosis.
• the combination partners of the present invention may be incorporated into an osmotic drug delivery system in a variety of ways. For controlled release of both active ingredients, these are mixed with the excipients and compressed to a common drug layer. If only one combination partner is to be released in a controlled manner, it can either be introduced separately into the coating shell of the tablet or the active substance not to be released in a controlled manner is pressed into a separate active substance layer which is first pumped free of the drug release system before the combination partner to be released in a controlled manner.
• 12.5 g of tamsulosin HCl is dissolved together with 12.5 g of hypromellose in a mixture of 47.5% water and 427.5 g of methanol.
• This solution is sprayed onto 2 500 g of neutral pellets of microcrystalline cellulose having a mean particle diameter of 125 ⁇ m in a fluidized bed system.
• 2 500 g of the thus coated pellets are sprayed in a fluidized bed system with a dispersion consisting of the following constituents: 1167 g of poly (ethyl acrylate-methyl methacrylate) - dispersion 30%, 350 g of talc and 1260 g of water.
• the coated with this diffusion membrane pellets are post-dried at 40 0 C.
• a three-layer tablet is prepared as follows: For layer 1, 75.4 kg of hypromellose, 5 kg of ethylcellulose and 15 kg of hydrogenated castor oil are mixed and granulated with a solution consisting of 3.2 kg of povidone K 30 and 28.8 kg of ethanol. The dried granules are mixed with 0.5 kg highly dispersed Sicliciumdioxid and 1 kg magnesium stearate. For layer 2, 5 kg of alfuzosin hydrochloride, 15 kg of hypromellose and 75 kg of microcrystalline cellulose in the fluidized bed are granulated with a solution of 3 kg of povidone K 30 and 97 kg of water.
• the granules are dried and mixed with 0.5 kg of highly dispersed Sicliciumdioxid and 1.5 kg of magnesium stearate.
• layer 3 23.7 kg of vardenafil hydrochloride trihydrate, 130 kg of hypromellose and 3.1 kg of microcrystalline cellulose are mixed and granulated dry on a roller.
• the granules are mixed with 0.8 kg of highly dispersed Sicliciumdioxid and 2.4 kg of magnesium stearate.
• the three granules are placed in the hopper of a three-layer tablet press such that layer 2 represents the middle tablet layer. It For example, round three - layer tablets of 8 mm diameter are pressed, layer 1 having a mass of 100 mg, layer 2 of 100 mg and layer 3 of 160 mg.
• the dried granules are mixed with magnesium stearate and pressed on a rotary press into round tablets of 7 mm diameter and 125 mg mass.
• the tablets are coated with a lacquer consisting of: 2.391 mg hypromellose, 0.797 mg Macrogol 3350, 0.653 mg titanium dioxide and 0.144 mg iron oxide yellow.

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