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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics
• • 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

Definitions

• the present invention relates to compositions for nasal application of cGMP-PDE inhibitors, in particular of PDE5 inhibitors, which contain a small amount of a local anesthetic in addition to the cGMP PDE inhibitor.
• Cyclic guanosine-3 ', 5'-monophosphate phosphodiesterase inhibitors abbreviated cGMP PDE inhibitors
• cGMP PDE inhibitors have a known spectrum of action (cf., for example, EP-A-0 463 756, WO 99/24433).
• cGMP -PDE inhibitors in particular PDE5 inhibitors, are suitable for the treatment of male erectile dysfunction (cf. Rajfer et al., New England J. Med. 326 (1992), 90; Murray, Drug News & Perspectives 6 (1993), 150).
• WO 94/28902 then described the use of certain cGMP-PDE inhibitors for the treatment of male erectile dysfunction, one of which (sildenafil citrate, Viagra ® ) is now approved as an orally administrable medication for this indication.
• a disadvantage of oral administration is the delayed onset of action, which in particular in this indication is at the expense of the spontaneity desired by the patient.
• first-pass effects or food effects can impair the effectiveness of the orally administered drug.
• benzyl alcohol is also known as a preservative or as a solubility enhancer and is described in these functions in EP-A-0 967 214 and WO 00/00199 as one of several auxiliaries which can also be used for the formulations mentioned therein ,
• benzyl alcohol is unable to reduce or avoid the disadvantages described above which occur in the nasal application of cGMP PDE inhibitors.
• WO 99/15177 describes liquid-crystalline nicotine preparations to which a local anesthetic is added in order to avoid adverse effects of the nicotine, which are caused by its local irritant effect.
• the local anesthetic works by blocking peripheral pain receptors. It should be noted that cGMP PDE inhibitors do not, or only to a small extent, produce such a local irritant effect when administered nasally.
• GB-A-2 315 673 proposed the intranasal application of local anesthetics such as lidocaine in addition to a 5-HTID agonist for the treatment of migraines.
• local anesthetics such as lidocaine
• this proposal is based on the vasodilating effect of local anesthetics, which leads to an accelerated absorption of the 5-HT1D agonist and thus to a faster onset of action.
• composition which comprises at least one cGMP PDE inhibitor and at least one local anesthetic, the local anesthetic not being benzyl alcohol.
• cGMP-PDEs Cyclic guanosine 3 ', 5'- monophosphate metabolizing phosphodiesterases
• cGMP PDE inhibitors are therefore, according to the present invention, compounds which contain one or more of these cGMP- According to the invention, preference is given to compositions which, in addition to one or several local anesthetics comprise one or more inhibitors of phosphodiesterase 5.
• a PDE 5 inhibitor should be understood to mean a compound which primarily inhibits PDE 5.
• Preferred according to the invention are compositions which, in addition to one or more local anesthetics, comprise one or more phosphodiesterase 5 inhibitors which inhibit the PDE5 with an IC 50 value of less than 100 nM, preferably less than 30 nM and a selectivity compared to the PDE5 PDE 1 by a factor of 50, preferably 100, and compared to PDE 4 by a factor of 300, preferably 1000.
• the IC 50 values can be determined, for example, in accordance with the procedure described in WO 99/24433. The relevant content of WO 99/24433 is expressly referred to here. The determination of the above IC 50 values is, however, fundamentally familiar to the person skilled in the art and can also be carried out in other ways.
• R 2 H optionally substituted Ci-C6 cycloalkyl-C ⁇ -alkyl, C ⁇ -C 3 with C 3 - perfluoroalkyl or C 3 -C 6 cycloalkyl; R 3 optionally substituted with C 3 -C 6 cycloalkyl -CC 6 alkyl; C] -C 6 - perfluoroalkyl; C 3 -C 5 cycloalkyl; Is C 3 -C 6 alkenyl or C 3 -C 6 alkynyl;
• R 4 optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6 or CO 2 R 7 d- C 4 alkyl; C 2 - optionally substituted with CN, CONR 5 R 6 or CO 2 R 7 -
• R 5 and R 6 are each independently H or - alkyl or, together with the nitrogen atom to which they are attached, a pyrrolidinyl, piperidino, morpholino, 4-N (R n ) -
• R 7 is H or CrC 4 alkyl
• R 8 is optionally substituted with NR 5 R 6 -CC 3 alkyl
• R 9 and R 10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N (R 12 ) -piperazinyl group, this group optionally having dC 4 alkyl, d- CrAlkoxy, NR 13 R 14 or CONR 13 R 14 is substituted;
• R 1 are hydrogen, -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo-C ⁇ -6 alkyl, C3-8 - cycloalkyl, C3-8 cycloalkyl-C ⁇ -3 - alkyl, aryl-C 1-3 alkyl, where aryl is phenyl or with one to three substituents from the group consisting of
• R represents an optionally substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan and pyridine, or an optionally substituted bicyclic ring
• R 3 represents hydrogen or C ⁇ - - alkyl
• R 1 and R 3 together represent a 3- or 4-membered alkyl or alkenyl chain part of a 5- or 6-membered ring,
• compositions which, as cGMP PDE inhibitor, are a compound selected from the group consisting of 1- ⁇ [3- (6,7-dihydro-imethyl-7-oxo-3-propyl-1H-pyrazolo [4 , 3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl ⁇ -4-methylpiperazine (sildenafil) or (6R, 12aR) -2,3,6,7,12,12a- hexahydro-2 -methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ',: 6, l] pyrido [3,4-b] indole-l, 4-dione or its pharmaceutically acceptable salts, isomers and / or hydrates such as the corresponding hydrochloride, hydrochloride trihydrate, citrate or mesylate.
• the compounds of formula (I) can be prepared, for example,
• Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms.
• Alkynyl generally represents a straight-chain or branched hydrocarbon radical with 2 to 6 carbon atoms and one or more, preferably with one or two triple bonds.
• Alkynyl generally represents a straight-chain or branched hydrocarbon radical with 2 to 6 carbon atoms and one or more, preferably with one or two triple bonds.
• Acyl generally represents straight-chain or branched lower alkyl having 1 to 6 carbon atoms, which is bonded via a carbonyl group. Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
• Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms which is bonded via an oxygen atom.
• alkoxy and alkyloxy are used synonymously.
• Alkoxyalkyl generally represents an alkyl radical with up to 6 carbon atoms which is substituted by an alkoxy radical with up to 6 carbon atoms.
• Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Examples include the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
• Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
• heterocycle generally represents a saturated, unsaturated or aromatic 3- to 6-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the series S, N and / or O and which in the case of a nitrogen atom can also be bound via this.
• Examples are: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, tetra hydropyranyl, Tetrahydroiuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl , Thiazolyl, furyl, oxazolyl, pyrazolyl, Triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl.
• heteroaryl stands for an aromatic heterocyclic radical.
• Physiologically acceptable salts are preferred in the context of the present invention.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or
• Be sulfonic acids For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid and sugar acids such as glucuronic acid.
• the compounds of formulas (I) and (U) can exist in isomeric forms. According to the present invention, this means stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by racemate resolution or chromatographic separation.
• Double bonds can exist in the eis or trans configuration (Z or E form).
• Local anesthetics which can be used according to the invention are known per se and are listed, for example, in Remington's Pharmaceutical Sciences 1990, pp. 1048-1056. Local anesthetics are compounds that reversibly increase the excitability of sensory
• Preferred local anesthetics according to the present invention are compounds of the formula (III) embedded image in which
• R 1-6 for OC - represents alkyl, optionally bearing a radical from the group consisting of NH (C 1-6 alkyl), N (C ⁇ -6 alkyl) 2 or a saturated 5- or six-membered heterocycle which contains at least contains and is bonded via a nitrogen atom and optionally has one or two further heteroatoms from the group consisting of N, O, S and optionally carries one to three further C t - 6 alkyl radicals, or
• Het stands for (CH 2 ) ⁇ _ 6 -Het, where Het stands for a saturated 5-membered or six-membered heterocycle which contains at least one nitrogen atom and is bonded thereto, and optionally one or two further heteroatoms from the group consisting of N, O, S, and optionally carries one to three further C 6 alkyl radicals;
• R 3 for H, halogen or OC ! -6 - alkyl
• R 1 represents H or OH
• R 2 stands for C 1-6 alkyl-N (-C ⁇ -6- alkyl) 2 , where the bridging alkyl chain can optionally carry one or more d-6-alkyl radicals, or for a saturated 5- or 6-membered heterocycle, which at least contains a nitrogen atom and optionally carries one or two further heteroatoms from the group consisting of N, O, S, and optionally carries one to three further C 1-6 alkyl radicals,
• R J is C ⁇ -6 alkyl, halogen or COOC 1-6 alkyl
• R 1 represents H, NH 2 , NH-nC 4 H 9 , OnC 3 H 7 , OnC 4 H 9 or CH 2 OPh;
• R 2 for OC 2 H 5 , OnC 4 H 9 , O- (CH2) 2 N (C 2 H 5 ) 2, O (CH 2 ) 2 N (CH 3 ) 2, or a radical from the group consisting out
• R J is H, CI, OnC 3 H 7 or OnC 4 H 9 ;
• R 1 represents H or OH
• n 1 or 2; and benoxinate and physiologically acceptable salts and / or hydrates thereof.
• the following can particularly preferably be used as local anesthetics: benzocaine, butambene, piperocaine, piperocaine hydrochloride, procaine, procaine hydrochloride, chloroprocaine, chloroprocaine hydrochloride, oxybuprocaine,
• benzocaine, lidocaine, tetracaine, benoxinate, polidocanol or their pharmaceutically acceptable salts can preferably be used as local anesthetics.
• Lidocaine hydrochloride or lidocaine methanesulfonate are particularly preferred according to the invention.
• the benzyl alcohol sometimes referred to as the local anesthetic is not covered by the subject matter of the present invention, since it has not proven to be suitable for overcoming the disadvantages described above and additionally led to local irritation on the nasal mucosa.
• lidocaine is contained in the compositions according to the invention in a concentration of less than 4% (m / v), preferably from 0.5 to 3.0% (m / v), which corresponds to an administered volume of 100 ⁇ l corresponds to a single dose of less than 4 mg, preferably 0.5-3 mg.
• concentration of lidocaine in the commercial product Xylocaine ® 4% which contains 200 mg lidocaine per 5 ml volume for surface anesthesia in the throat, ear and throat area (Rote Liste 1999, Editio Cantor, Aulendorf).
• oxybuprocaine (benoxinate) in the compositions according to the invention is in a concentration of less than 1% (m / v) (corresponding to a single dose of 0.5 mg / 50 ⁇ l), preferably 0.1-0.8% (m / v) included.
• a single dose of up to 105 mg benoxinate per 70 kg body weight is recommended for surface anesthesia in rhinology (specialist information service ⁇ ovesine ® Wander 1%, 1998, cited in: Drugdex Drug Evaluations, Micromedex 2001, Engelwood, Colorado, USA).
• tetracaine is contained in the compositions according to the invention in a concentration of less than 0.5 mg per single dose, preferably to less than 0.25 mg per single dose.
• tetracin is recommended for nasal mucosal anesthesia (Reynolds 1990, cited in: Drugdex Drug Evaluations, Micromedex 2001, Engelwood, Colorado, USA).
• compositions according to the invention can be used as a solution, suspension, emulsion or
• Powder for atomization can be formulated to be sprayed into the nose, sucked in, dripped or applied to the nasal mucus wall.
• Formulations in the form of a solution, suspension, for example a nanoparticle suspension, or emulsion can be used as a drip preparation, for example from a nasal dropper bottle or a pipette, pump spray or compressed gas pack (for example one
• Aerosol or an atomizing device can be administered, which is calibrated be able to deliver a specified amount of the active ingredient (s).
• Powder preparations can, for example, be sprayed into the nose from a capsule provided with small holes with the aid of an air flow generated, for example, by a rubber ball. All forms of preparation can represent multi-dose containers or divided single-dose containers.
• the Pfeiffer unit can and bidose system, the Valois monospray, bidose and monopowder system or the Becton-Dickinson Accuspray® system. Glass or plastic bottles with commercially available pump dosing spray heads are also suitable.
• Nanoparticle suspensions can be obtained by grinding powdered constituents of the compositions according to the invention or by finely divided precipitation from solutions of constituents of the formulations according to the invention and generally have improved solubility properties.
• compositions according to the invention When formulated in liquid form, the compositions according to the invention contain solvents and, if appropriate, one or more auxiliaries, such as, for example, buffers or substances for pH adjustment, viscosity-increasing substances, preservatives, surfactants, solubilizers, isotonizing agents, antioxidants and flavorings.
• auxiliaries such as, for example, buffers or substances for pH adjustment, viscosity-increasing substances, preservatives, surfactants, solubilizers, isotonizing agents, antioxidants and flavorings.
• water, glycerol, polyethylene glycol, propylene glycol or medium-strength triglycerides can be used as solvents.
• liquid formulations of the compositions according to the invention are preferably adjusted to a pH in the range from 2 to 9, preferably 3 to 8, in order to avoid irritation in the nose and to optimize the absorption of the cGMP PDE inhibitor.
• this can be done by adding lactic acid (lactate), acetate, phosphate or citrate buffers or by adding methanesulfonic acid, hydrochloric acid, sulfuric acid, toluene. sulfonic acid, gluconic acid, glucuronic acid, lactobionic acid, nitric acid, sodium hydroxide, potassium hydroxide, sodium carbonate or trometamol can be achieved.
• Viscosity-increasing auxiliaries are, for example, polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose,
• concentration of viscosity-increasing auxiliaries in the compositions according to the invention can be selected depending on the substance used and the desired viscosity of the composition according to the invention.
• compositions according to the invention can contain one or more preservatives such as, for example, benzalkonium chloride, sorbic acid or its salts or benzoic acid or its salts, parabens such as methyl paraben or
• the concentration of the preservative in the compositions according to the invention can be chosen depending on the substance used and the desired application. Typically, a preservative, if used, is present in the compositions of the invention in a concentration of up to 2%.
• polysorbates polyethylene glycol, polyoxyethylene derivatives of fatty acid half-esters of sorbitol anhydrides such as Tweeen 80, polyoxyl 40 stearate, polyoxyethylene 50 stearate, bile salts, octoxynol, polyoxyethylated castor oil, polyoxystearate, poloxamers, phospholipid, phospholipid , Caffeine, vaniline, urea, nicotinamide,
• Cyclodextrins or cyclodextrin ethers can be used. According to the invention nonionic, anionic or cationic additives of the above category can be used.
• concentration of the surfactants and / or solubihsators in the compositions according to the invention can be selected depending on the substance used and the desired application. Typically, a surfactant and / or solubilizer, if used, is present in the compositions of the invention in a concentration from 0.001% (m / v) to about 5% (m / v).
• the compositions according to the invention can also contain one or more isotonizing agents.
• sodium chloride, calcium chloride, glycerin, mannitol or glucose can be used for this.
• concentration of the isotonizing agents in the compositions according to the invention can be selected depending on the substance used and the desired application.
• an isotonizing agent, if used, is present in the compositions of the invention at a concentration of from 0.001% (m / v) to about 5% (m / v).
• compositions according to the invention can also contain one or more antioxidants. According to the present invention, the compositions according to the invention can also contain one or more antioxidants. According to the present invention
• sodium metabisulfite, sodium bisulfite, ascorbic acid and its salts, butylated hydroxytoluene, butylated hydroxyanisole, metal chelators such as ethylenediaminetetraacetic acid, butylated hydroxyanisole, propyl gallate, ascorbyl palmitate or tocopherol can be used for this purpose.
• concentration of the antioxidants in the compositions according to the invention can be selected depending on the substance used and the desired application. Typically, an antioxidant, if used, is present in the compositions of the invention in a concentration from 0.001% (m / v) to about 5% (m / v).
• the compositions according to the invention can also contain one or more flavorings.
• saccharin sodium, aspartame, acesulfame potassium or menthol can be used for this purpose.
• concentration of the flavors in the compositions according to the invention can be chosen depending on the substance used and the desired application.
• a flavoring, if used, is present in the compositions of the invention in a concentration from 0.001% (mv) to about 5% (m / v).
• compositions according to the invention in powder form also contain carriers such as, for example, glucose, sucrose, mannitol, crystalline cellulose or lactose.
• compositions according to the invention in powder form can furthermore contain substances for prolonging the contact time with the nasal mucosa, for example polymers such as carbomer, chitosan or cellulose ether.
• substances for prolonging the contact time with the nasal mucosa for example polymers such as carbomer, chitosan or cellulose ether.
• compositions can be chosen depending on the substance used and the desired application. Typically, such an adjuvant, if used, is present in the compositions of the invention in a concentration from 0.001% (m v) to about 5% (m v).
• compositions according to the invention can also contain moisturizers in order to prevent or reduce drying out of the mucosal membrane and thus to avoid irritation thereof.
• moisturizers for example, according to the present invention, sorbitol, propylene glycol or glycerin can be used for this.
• concentration of the wetting agents in the compositions according to the invention can be dependent the substance used and the desired application.
• a wetting agent, if used, is present in the compositions of the invention at a concentration of from 0.001% (m / v) to about 5% (m / v).
• Soluble formulations can be prepared in a simple manner by dissolving the ingredients in the chosen solvent, then filtering the solution, filling it in the containers provided under aseptic conditions and, if necessary, heat sterilizing it.
• compositions according to the invention may be advantageous to formulate as a powder.
• Particles are not sufficiently absorbed.
• Purified water means purified water in the sense of the European Pharmacopoeia (Ph. Eur.), which is known to the person skilled in the art. It is demineralized water of standardized quality. example 1
• a powder formulation is made from the following ingredients:
• Lidocaine hydrochloride micronizes 10.0 kg
• the ingredients are mixed homogeneously in an intensive mixer and filled in amounts of e 20 mg in single-dose powder insufflators.
• a solution is made up of the following components:

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