DE20321445U1 - Otorhinological dispenser - Google Patents

Abstract

Otorhinological delivery device comprising at least one pharmaceutically active agent, characterized in that the device comprises:
A core comprising at least the one pharmaceutically active agent, wherein the core consists of an elastomeric composition selected from the group consisting of poly (dimethylsiloxane), a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si Atoms of the siloxane units are bonded, a siloxane-based elastomer comprising poly (alkylene oxide) groups, and mixtures thereof, is prepared, and
A membrane surrounding the core, wherein the membrane is made of a same or different core composition from the core.

Description

OTORHINOLOGISCHE DISPENSER

AREA OF INVENTION

The The invention relates to a otorhinological delivery device which at least one pharmaceutically active agent.

BACKGROUND THE INVENTION

The publications and other materials used herein to illustrate the background of the invention, and more particularly to the practical cases for providing further details, are to be incorporated by reference. In particular, the patents US 6,056,976 and US 6,299,894 as well as the applications in progress with the serial numbers US 09 / 701,547 filed on 30.11.2000 (equivalent: WO 00/00550) and PCT / FI02 / 00692 are to be included by reference.

The Concept of treatment of sudden Deafness, Meniere's disease and tinnitus, of which it is assumed that they have the same etiology, with the middle ear through the round-window membrane for perfusion applied corticosteroids was considered future Treatment method presented. The sudden deafness has an annual Occurrence of 2: 10,000 and Menier's disease an estimated annual Occurrence of 1: 5000, however, are due to the chronic nature this condition the prevalence numbers much higher. In Germany require about 20,000 patients (of 80 million inhabitants) each year Treatment for Tinnitus, these numbers include only the severe cases.

Several Publications disclose various devices in the ear of patients, the sudden Deafness, Meniere's disease, tinnitus or other ear disorders (such as e.g. endolymphatic hydrops, endolymphatic hypertension, perilymphatic hypertension, perilymphatic hydrops, perilymphatic Fistulas, intracochlear fistulas, dizziness or vertigo, with hairy cell or ganglion cell damage or dysfunction related hearing loss) suffer, can be placed. Such devices allow the delivery of therapeutic agents to different ear tissues in a controlled manner. For example has developed a variety of structures that are able therapeutic agents to the external auditory canal of the outer ear or to tissue structures of the inner ear. The same situation exists with tissue materials, which lead into the inner ear (e.g., the round-window membrane).

Inner ear tissue structures, the for These types of treatment are suitable include the cochlea, the Endolymphatic sinus / endolymphatic duct or endolymphatic duct and the atrial labyrinth. Access to these and other inner ear tissue regions is typically achieved through a variety of structures, including, but not limited on, the Round Window Membrane, the Oval Window / Stirrup Foot Plate, the Annular Ligament and the otic capsule / temporal bone the middle ear, here as a physiological air-containing tissue zone is defined behind the eardrum and in front of the inner ear, for delivery therapeutic agent can be used. A peculiarity of the ear and the nose compared to subcutaneous placement of delivery devices is that there are no body fluids which induce and support the release of the active agent and it to the target organ.

corticosteroids become ordinary used to treat these diseases. The devices mentioned can in the round-window niche ("round window niche ") or another inner ear cavity to be placed.

US Patent No. 6,120,484 discloses an otologic implant for delivery of a medicament comprising a gauze tampon ("wick") inserted through an opening in a membrane One end of the gauze tampon (distal end) is in contact with the treatment site and the other end (FIG. The gauze tampon transports the drug from the proximal end to the distal end by capillary action, for example, the gauze tampon is made of polyvinyl acetate, a material capable of wicking the medicament through capillary action. The implant may further comprise a tubular member for supporting the gauze tampon, said tube being made of, for example, silicone The document does not mention how the release rate of the drug can be regulated.

on the other hand presents the patent application WO 00/33775 a device for controlled Delivery of a therapeutic agent to an inner ear cavity. The device is placed so that at least part of it in the round-window niche lies. The released therapeutic agents come in contact with the round window niche and thereby reach the inner ear. The device consists essentially of a carrier medium, which is combined with said agent. The carrier medium can be biodegradable material and at least one synthetic material Origin. Said material may be polymeric materials, which are networked and in contact with water in body temperature sources, be. The application discloses various methods for Release of the drug, e.g. Diffusion, solvent drag ("solvent drag "), electrodiffusion, Osmosis, active / passive transport or a combination thereof. This document discloses that the active ingredient is the deepest positioned in the device is released the slowest becomes. The rate of release of the drug is so with its relative position within the device together, i. she hangs with the distance to the outer surface of the Device together.

It is also known from the literature that implants in the nose can be used for the controlled delivery of pharmaceutical agents. An example of such implants is given in US Patent RE35,408, which presents a metal nasal drug delivery device comprising end parts in the form of relatively thin tabs. Silastic ^® ). The active pharmaceutical ingredient is contained in surface depressions or pockets or in the coating of the surface.

TASKS AND SUMMARY OF THE INVENTION

The The object of this invention is to provide a otorhinological delivery device provide a constant release of one or more enables pharmaceutically active agents in a manner the no or only minimal inconvenience or complaints ("Discomfort") in the patient caused.

The In particular, the object of this invention is a dispenser for nasal or to provide otological applications that have predetermined, allows constant release rates of the active ingredients. Another object of the invention is a dispenser to provide in a safe and reproducible manner can be produced, with the hygiene during their manufacturing process reliable can be controlled. The invention aims to provide a dispenser, which is safe and easy to introduce in their final position and to use.

PRECISE DESCRIPTION THE INVENTION

The Invention is in the claims disclosed in the appendix.

The otorhinological delivery device containing at least one pharmaceutical active ingredient according to the invention is characterized in that the device has a Core comprising the said pharmaceutically active ingredient comprising, said core of an elastomeric composition is made, selected from the group consisting of poly (dimethylsiloxane), a siloxane-based elastomer, the 3,3,3-trifluoropropyl groups attached to the Si atoms of the siloxane units a siloxane-based elastomer comprising poly (alkylene oxide) groups, and mixtures thereof.

Therefore The invention relates to a dispenser, which essentially of an elastomeric composition and at least one active Active ingredient exists. In this application, the term "elastomeric composition" is intended to refer to a single Elastomer, for a blend of at least two elastomers intertwined are or in any other form of a mixture and said Term can also be used for a composition comprising components other than elastomers, stand, such as Fillers. A difference in terms the device disclosed in WO 00/33775 is that Release rate in the invention by the properties of the core and optionally by the properties of the membrane is controlled.

According to one embodiment of the invention, said apparatus further comprises a membrane, which surrounds the said core and which consists of the same or a different one Elastomer composition is prepared, wherein said elastomer composition one of the above is listed.

A inventive device allows In this way, a constant release of one or more pharmaceutical effective means in a way that does not or minimal in the patient Inconvenience or discomfort and the above does not have mentioned disadvantages.

It It is to be noted that the physiological conditions in ear and nose are different from the conditions e.g. in the Uterus. Indeed there are e.g. no body fluids in the ear, but a vacuum. Air is the only medium in the ear emotional. A specialist would therefore not immediately be able to establish that the The elastomer compositions listed above are known per se are for otorhinological applications are suitable.

Of the Core and the optional membrane of the device according to the invention are therefore essentially of the same or a different elastomer composition manufactured, which will be described further below.

The Elastomeric composition used in the membrane as described below allows predetermined, constant release rates of active agents. The first object of the invention is therefore by the choice of elastomeric composition solved. Second, the core is essentially of an elastomeric composition, i. the core is an elastomer matrix in which the active ingredients are dispersed are. Therefore, even if the membrane surrounding the nucleus were damaged, the active agents not in a complete released in an uncontrolled manner.

The Release rates of the active ingredients can by the membrane alone or through the membrane together with the nucleus to be controlled. It is also possible that the release rate mainly is controlled by the core and that the membrane is only the final control causes the release rate. The lifetime of a device according to the invention may be treated for the illness or disorder being treated should be adjusted. It can typically be, for example, from 3 to 6 months are enough.

The Production of dispensers according to the invention will be described below discussed, although it is well known in the art. The form and Size of the device with regard to the cavity, in which the device is to be placed, can by the skilled person chosen quite freely become. It is also obvious that the devices according to the invention both in humans and in animals can be used.

The Parts of the device according to the invention can also be used in any number and in any form, as hereinafter in the form of various embodiments of the invention discussed will be.

The inventive device may also comprise more than one therapeutically active agent. According to one embodiment the invention, the core consists of a part which at least one therapeutically active agent. According to another embodiment the invention, the core consists of at least two parts, wherein each part comprises at least one therapeutically active agent. The elastomeric compositions of said parts are according to the desired ge Release rates are chosen and may be the same or equal in each part to be different. According to one embodiment, in which the core consists of two or more parts, the Share either side by side in such a way that part of one Kerns at least partially surrounds another part of the core, positioned become. Any structure combination is naturally possible and is within the scope of the invention.

According to one another embodiment invention, the membrane consists of at least two layers, each layer having a certain thickness. The thickness of the Layers can be the same or different and those in each layer used compositions also be the same or different. The each above Part of the core surrounding membranes can also be identical or different in relation either its elastomer composition or the structure of the membrane (a or more layers). The combination of different membrane layers either in thickness or material or both allows another way to control the Release rates of the active agents.

According to one embodiment, the device according to the invention further comprises a space that separates at least two of said at least two parts of the core and / or at least one separation membrane that separates at least two of said at least two parts of the core, wherein the separation membranes essentially consists of an elastomeric composition. For example, it is possible to produce a device according to the invention which produces a core consisting of three parts A, B and C, parts A and B being separated by a space and parts B and C by a membrane. A device in which the parts A and B are arranged side by side without a space for a membrane therebetween, and in which the parts B and C are separated by a membrane or a device in which the parts A and B are separated by a membrane, the is comprised of a first elastomeric composition, are separate, and parts B and C are separated by a membrane consisting of a second elastomeric composition other than the first elastomeric composition, is also within the scope of the invention, as well as any other any combination.

According to one another embodiment In accordance with the invention, the separation membranes are permeable or impermeable across from at least one of the therapeutically active agents. It is of course possible to use a membrane the opposite permeable to a first active ingredient, but towards one second active ingredient impermeable is to use.

• – einer Elastomerzusammensetzung, umfassend Poly(dimethylsiloxan),
• – einer Elastomerzusammensetzung, umfassend ein Siloxan-basiertes Elastomer, umfassend 3,3,3-Trifluorpropylgruppen, die an die Si-Atome der Siloxaneinheiten gebunden sind,
• – einer Elastomerzusammensetzung, umfassend Poly(alkylenoxid)gruppen und
• - einer Kombination von mindestens zweien davon.

In the present invention, the above-mentioned elastomer compositions, namely, the elastomer compositions of the core, the membrane and the possible separation membrane are the same or different and selected from the group consisting of

• An elastomeric composition comprising poly (dimethylsiloxane),
• An elastomer composition comprising a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si atoms of the siloxane units,
• An elastomeric composition comprising poly (alkylene oxide) groups and
• - a combination of at least two of them.

According to one embodiment from 1 to about 50% of the substituents attached to the Bonded Si atoms of the siloxane units of the elastomer composition which are a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups, which are bonded to the Si atoms of the siloxane units, 3,3,3-trifluoropropyl.

According to one another embodiment the invention are the said poly (alkylene oxide) groups of the elastomer composition, the poly (alkylene oxide) groups comprise as alkoxy-terminated grafts or blocks, those with the polysiloxane units through silicon-carbon bonds or as a mixture of these forms.

According to one another embodiment of the invention are the poly (alkylene oxide) groups poly (ethylene oxide) groups.

The The above-mentioned elastomer compositions are described below in further details discussed. It is also obvious that other elastomeric compositions as the above disclosed in the device according to the invention in addition to that disclosed in claim 1, e.g. biodegradable elastomers, can be used.

According to one another embodiment of the invention are for In the case of more than one therapeutically effective agent, the release rates the at least two therapeutically active agents are identical or different. The device may also have other therapeutically effective Contain substances suitably with a given active agents are associated.

Of the One skilled in the art will readily be able to provide the desired release rates to determine the therapeutically active agent. Examples for choice the elastomer composition depending on the therapeutic active agent are e.g. in the previous patents and patent applications of the applicant as given in the description and are intended hereby be incorporated by reference.

Any Combination of the above embodiments is possible and is within the scope of the invention and a person skilled in the art to be able to do that for to find a special purpose most suitable combination.

The preparation of the device according to the invention will be apparent to those skilled in the art. In fact, the device can be produced, for example, by extrusion or compression molding or shaping. The device may also have any desired shape and size. For example, it can be shaped so that it fits into the existing indentations of nose or ear, or it may be shaped as a hook or rod with an enlargement at one end. By way of example, it can be mentioned that a nasal delivery device is typically 1 to 3 cm long and has a diameter of 0.5 to 5 mm. The shape and size of the device will be apparent to one skilled in the art when he / she has decided on the final position of the device.

elastomer compositions

One the for the use according to the invention the device suitable elastomers, especially for use in the membrane of the device, is a siloxane-based elastomer, the 3,3,3-trifluoropropyl groups attached to the Si atoms of the siloxane units are included.

Of the Term "siloxane-based Elastomer "should be understood that it elastomers consisting of poly (disubstituted Siloxanes), wherein the substituents are mainly lower alkyl, preferably Alkyl groups having 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl is substituted or unsubstituted can be. A widely used and preferred polymer This type is poly (dimethylsiloxane) (PDMS).

Verbindung I According to the invention, a certain number of the substituents which are bonded to the Si atoms of the siloxane units in the elastomer should be 3,3,3-trifluoropropyl groups. Such an elastomer can be obtained in various ways. In one embodiment, the elastomer may be based on a single crosslinked siloxane-based polymer, such as a poly (dialkylsiloxane), with some number of the alkyl groups on the Si atoms being replaced by 3,3,3-trifluoropropyl groups. A preferred example of such polymers is poly (3,3,3-trifluoropropylmethylsiloxane), the structure of which as compound I is shown below.

Compound I

One Polymer of this type, in which about 50% of the methyl substituents Si atoms are replaced by 3,3,3-trifluoropropyl groups commercially available. The term "about 50% "means that the degree of 3,3,3-trifluoropropyl substitution is actually below about 50%, because the polymer has a certain amount (about 0.15 of the substituents) on crosslinkable groups, e.g. Vinyl or vinyl-terminated Groups, must contain. Similar Polymers with a low degree of substitution of 3,3,3-trifluoropropyl groups can be easily getting produced.

Of the retarding effect of 3,3,3-trifluoropropyl groups on permeation the active agent through an elastomeric membrane depends on the number of these groups from. Furthermore, the effect is highly dependent on the active one used Dependent on funds. If the elastomer is made from only a single polymer, then it is necessary to use polymers with different numbers of 3,3,3-trifluoropropyl groups for different to produce and use active agents.

According to another embodiment, which is particularly preferred when suitable elastomers are needed for several different active agents, a mixture comprising a) a non-fluoro-substituted siloxane-based polymer and b) a fluorine-substituted siloxane-based polymer is crosslinked, said polymer 3,3,3-trifluoropropyl groups bonded to the Si atoms of the siloxane units. The first ingredient of the blend, the non-fluorine-substituted polymer, may be any poly (disubstituted siloxane) in which the substituents are primarily lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms or phenyl groups, wherein said alkyl or phenyl is substituted or unsubstituted can be. The substituents are most preferably alkyl groups of 1 to 6 Carbon atoms. A preferred non-fluoro-substituted polymer is PDMS. The second ingredient of the mixture, the fluorine-substituted polymer, may be, for example, a poly (dialkylsiloxane) wherein a certain amount of the alkyl groups on the Si atoms is replaced by 3,3,3-trifluoropropyl groups. A preferred example of such a polymer is poly (3,3,3-trifluoropropylmethylsiloxane) as mentioned above. A particularly preferred polymer of this type is a polymer having a number of 3,3,3-trifluoropropyl substituents as high as possible, such as the commercially available polymer having about 50% of the methyl substituents on the Si atoms 3,3,3-trifluoropropyl groups are replaced. An elastomer having a high permeation-retarding effect can be obtained by exclusively or mainly using the aforementioned polymer. Elastomers with less retarding influence on the permeation of the active agent can be obtained by using blends with increased amounts of the non-fluoro-substituted siloxane-based polymer.

One other elastomer that can be used in this invention includes poly (alkylene oxide) groups such that the poly (alkylene oxide) groups in said elastomer either as alkoxy-terminated grafts of Polysiloxane units or as blocks are present, said grafts or blocks with the Polysiloxane units are crosslinked by silicon-carbon bonds. The poly (alkylene oxides) can also as a mixture of the mentioned options to be available. The second elastomer may be a siloxane-based elastomer, suitably a poly (dimethylsiloxane) based elastomer. Said second elastomer may possibly also poly (alkylene oxide) groups include. These poly (alkylene oxide) groups may also be terminated as either alkoxy-terminated Grafts of poly (dimethylsiloxane) units or present as blocks be, wherein said grafts or blocks with the poly (dimethylsiloxane) units are crosslinked by silicon-carbon bonds. The poly (alkylene oxides) can also in this elastomer as a mixture of the above-mentioned possibilities to be available.

According to one embodiment invention, the elastomer composition may be a mixture a siloxane-based elastomer, e.g. made of PDMS and at least one straight-chain polysiloxane copolymer, the poly (alkylene oxide) groups includes. In this case, the poly (alkylene oxide) groups in said polymer either as alkoxy-terminated grafts of Polysiloxane units or as blocks present, said grafts or blocks with the polysiloxane units via silicon-carbon bonds are networked. The poly (alkylene oxide) groups can, of course, in the polymer as a Mixture of the mentioned Forms exist. In this embodiment, the siloxane-based Elastomer include poly (alkylene oxide) groups, said poly (alkylene oxide) groups in the elastomer either as alkoxy-terminated grafts of polysiloxane units or as blocks are present, said blocks or grafts with the polysiloxane units through silicon-carbon bonds connected are. The poly (alkylene oxide) groups can also be used as a mixture of mentioned Forms exist.

Of course you can the elastomeric composition also consists of two elastomers which together and at least one straight-chain polysiloxane copolymer, comprising the poly (alkylene oxide) groups as described above be.

The Poly (alkylene oxide) groups of the elastomer composition may suitably e.g. Poly (ethylene oxide) groups (PEO groups).

• – teilweise freie Gruppen, die gleich oder verschieden sind und die eine Niedrigalkylgruppe oder eine Phenylgruppe sind. In diesem Fall können die genannten Alkyl- oder Phenylgruppen substituiert oder unsubstituiert sein, oder Alkoxy-terminierte Poly(alkylenoxid)gruppen mit der Formel:
  
  worin alk eine Niedrigalkylgruppe, geeigneterweise Methyl, ist, R Wasserstoff oder Niedrigalkyl ist, m 1... 30 ist, und R³ eine geradkettige oder verzweigte C₂-C₆-Alkylgruppe ist,
• – teilweise von den Wasserstoff- oder Alkylengruppen zu anderen Polymerketten im Elastomer gebildete Bindungen und
• – möglicherweise teilweise nicht-umgesetzte Gruppen, wie z.B. Wasserstoff, Vinyl oder Vinyl-terminiertes Alken, und
• – q 1... 3000 ist.

The polysiloxane units of the elastomeric composition are preferably groups having the formula: - (SiR'R''O) _q SiR'R '' - wherein R 'and R''are:

• Partially free groups which are the same or different and which are a lower alkyl group or a phenyl group. In this case, said alkyl or phenyl groups may be substituted or unsubstituted, or alkoxy-terminated poly (alkylene oxide) groups having the formula:
  
  wherein alk is a lower alkyl group, suitably methyl, R is hydrogen or lower alkyl, m is 1 ... 30, and R ^{3 is} a straight or branched C ₂ -C ₆ alkyl group,
• - Partly formed by the hydrogen or alkylene groups to other polymer chains in the elastomer bonds and
• Possibly partially unreacted groups, such as hydrogen, vinyl or vinyl-terminated alkene, and
• - q is 1 ... 3000.

The term "lower alkyl" here and generally in the description of the invention stands for C ₁ -C ₆ alkyl groups.

The mentioned above R 'and R "groups are suitably a lower alkyl group, preferably methyl.

Of the Term "poly (alkylene oxide) group" means that the group mentioned at least two alkyl ether groups, the successful connected to each other includes.

worin R Wasserstoff ist, ein Niedrigalkyl oder Phenyl,
R₁ ist Wasserstoff oder Niedrigalkyl, y ist 2... 6 und m ist 1... 30.In a preferred embodiment, the poly (alkylene oxide) groups in the elastomer are in the form of the poly (alkylene oxide) block having the formula

wherein R is hydrogen, a lower alkyl or phenyl,
R ₁ is hydrogen or lower alkyl, y is 2 ... 6 and m is 1 ... 30.

preferred Elastomeric combinations are PDMS with poly (ethylene oxide) PDMS for the nasal Delivery devices and PDMS with fluorine-substituted PDMS for the otological Delivery devices.

The Elastomer composition preferably comprises a filler, such as. amorphous silica, around the membrane, from the mentioned Elastomer is produced, enough To give strength. It is also possible to use other additives taking into account that they are biocompatible and harmless for the patient or the animal must be.

The pharmaceutical active agent

Various active agents can in the dispenser according to the invention be used. Suitable active agents or active substances which a inventive device may include those having the desired release profile deliver and the desired therapeutic effect and an acceptable low level of ototoxicity and / or nasal toxicity exhibit. Some of the states delivered with a dispensing device according to the invention active agents can be treated are nasal inflammatory disorders, allergic reactions, asthma and fungal infections or fungal infections, as well as otitis, acute infections, cochlear and vestibular disorders, Vertigo and Meniere's disease, sudden deafness, sensoneurinal Hearing loss; Tinnitus and motion sickness. Other states to be treated include endolymphatic hydrops, endolymphatic hypertension, perilymphatic High pressure blood, perilymphatic hydrops, perilymphatic fistulas, intracochlear fistulae and cracks in various membrane structures inside the ear.

Generic examples for pharmaceutically active agents include antimicrobial agents, e.g. antibacterial agents, anti-infective agents including antibiotics, Antimyotics ("antifungals") and antivirals Substances, antihistamines, antivertigo drugs (for example for treatment Menier's disease), sympathomimetics, corticosteroids, Vasodilators (for the treatment of sudden hearing loss), Genes, vectors, chemotherapeutic agents and adenovirus-type agents.

Specific examples of pharmaceutically active agents include: acedapsone, acediasulfone sodium, aconiazide, acrosoxacin, amifloxacin, amikacin, amikacin sulfate, aminosalicylates, aminosalicylic acid, calcium amino salicylate, calcium benzamidosaricylate, phenylaminosalicylate, potassium aminosalicylate, sodium aminosalicylate, amoxyalline, amoxycillin sodium, amoxycillin trihydrate, amphomycin, Ampicillin, ampicillin sodium, ampicillin trihydrate, apalcillin sodium, apramycin, arbekacin sulfate, arsanilic acid, sodium arsanilate, aspoxicillin, astomycin sulfate, avoparcin, azidamfenicol, aziclocillin, azithromycin, azlocillin sodium, aztreonam, bacampicillin bacitracin, bacitracin zinc, balofloxacin, Bambermycin, Bekanamycin Sulfate, Benethamine Penicillin, Benzathine penicillin, benzathine phenoxymethylpenicillin, senzylpenicillin, benzylpenicillin potassium, benzylpenicillin sodium, biapenem, brodimoprim, calcium sulphaloxate, capreomycin sulphate, carbadoxin, carbenicillin sodium, carfecillin sodium, carinclacillin sodium, carumonam sodium, cefaclor, cefadroxil, cefapirin Sodium, cefatrizine, cefazedone sodium, cefbuperazone sodium, cefcanel-daloxate, ceffliffir, cefflitoren, cefepime hydrochloride, cefetamet, cefixime, cefmenoxime hydrochloride, cefrnetazole sodium, cefinninox sodium, cefdizim sodium, cefonicid sodium, cefoperazone Sodium, ceforanide, cefotaxime sodium, cefotetan disodium, cefotiam hydrochloride, cefoxitin sodium, cefozopran, cefpimizole sodium, cefpiramide, cefpiramide sodium, cefpirome, celpodoxime proxetil, cefprozil, cefroxadine, cefsulodin sodium, ceftazidime, cefteram , Ceftezole sodium, ceftibuten, ceftiofur sodium, ceftizoxime sodium, ceftriaxone sodium, cefuroxime, cefuroxime axetil, cefuroxime sodium, cefuzonam, cephacetr ill sodium, cephalexin, cephalexin hydrochloride, cephalonium, cephaloridine, cephalothin sodium, cephamandole, cephamandole nafate, cephamandole sodium, cephazoline, cephazoline sodium, cephradine, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, chlorquinaldol, and chloroquinaldol, respectively , Chlortetracycline, chlortetracycline hydrochloride, ciclacillin, cilastatin sodium, cinoxacin, ciprofloxacin, ciprofloxacin hydrochloride, ciprofloxacin lactate, clarithromycin, clavulanic acid, potassium clavulanate, clemizole penicillin, clinafloxin hydrochloride, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin Phosphate, cliochinol, clofazimine, clofoctol, cloxacillin, cloxacillin benzathine, cloxacillin sodium, colistin sulfate, colistin sulfomethate sodium, co-tetroxazine, co-trifamol, co-trimazine, co-trimoxazole, cranberry, cyacetazice, cycloserine , Dapsone, daptomycin, demeclocycline, demeclocycline hydrochloride, dibekacin sulfate, dicloxacillin, dicloxacillin sodium, Diflox acin, dihydrostreptomycin sulfate, dirithromycin, doxycycline, doxycycline calcium, doxycycline fosfatex, doxycycline hydrochloride, enoxacin, enramycin, enrofloxacin, epicillin, erythromycin, erythromycin acistrate, erythromycin-estolate, erythromycin ethyl succinate, erythromycin gluceptate, erythromycin lactobionate, Erythromycin propionate, erythromycin stearate, ethambutol hydrochloride, ethionamide, fibracillin, fleroxacin, flomoxef, flucloxacillin, flucloxacillin magnesium, flucloxallin sodium, flumechin, flurithromycin, formosulfathiazole, fosfomycin, fosmidomycin, framycetin sulfate, furaltadone hydrochloride, fusalfungin, Fusidic Acid, Diethanolamine Fusidate, Sodium Fusidate, Gentamicin Sulfate, Gramicidin, Grepafloxacin, Halchinol, Heracillin, Hetacillin Potassium, Hexamine, Hexamine Hippurate, Hexamine Mandelate, Hydrabamine Phenoxymethylpenicillin, Imipenem, Iseparnicin, Isoniazic, Josamycin, Josamycin Propionate, kanamycin sulfate, kanamycin sulfate, kitasamycin, latamoxef disodium, lenampicillin Hydrochloride, levofloxacin, lincomycin hydrochloride, lomefloxacin hydrochloride, loracarbef, lymecycline, mafedin acetate, magainine, mandelic acid, mecillinam, meclcycline sulfosalicylate, meropenem, metampicillin, metampicillin sodium, methacycline hydrochloride, methanazelcene, methicillin sodium, methocidin , Metioprim, mezlocillin sodium, micronomicin sulfate, midecamycin, minocycline hydrochloride, miocamycin, mocimycin, morinamide, mulpirocin, nadifloxacin, nakillin sodium, nalidixic acid, neomycin, neomycin sulfate, neomycin undecenoate, netilmicin sulfate, nifuroxazide, nifurtoinol , Nifurzicle, nisin, nitrofurantoin, nitrofurantoin sodium, nitrofurazone, nitroxoline, norfloxacin, nosihepticle, novobiocin, novobiocin calcium, novobiocin sodium, ofloxacin, oleandomycin phosphate, oxacillin sodium, oxolinic acid, oxytetracycline, oxytetracycline calcium, oxytetracycline hydrochloride , Panipenem, paromomycin sulfate, pefloxacin mesylate, penimepicycline, phenethicillin potassium, phenoxymethylpenicilli n, Phenoxymethylpenicillin calcium, Phenoxymethylpenicillin potassium, Phthalyisulfathiazole, Pipemic acid, Piperacillin sodium, Piromic acid, Pivampicillin, Pivampicillin hydrochloride, Pivcephalexin hydrochloride, Pivmecillinam, Pivmecillinam hydrochloride, Pristinamycin, Procaine penicillin, Procaine penicillin, Prothionamide, Pyrazinamide, Ramoplanin, Ribostamycin Sulfate, Rifabutin, Rifampicin, Rifamycin Sodium, Rifapentin, Rifaximin, Rokitamycin, Rolitetracycline, Rolitetracycline Nitrate, Rosaramicin, Roxithromycin, Rufloxacin, Silver Sulfadiazine, Sissomicin Sulfate, Sparfloxacin, Spectinomycin, Spectinomycin Hydrochloride, Spiramycin, Stearylsulfamide, Streptomycin, streptomycin hydrochloride, streptomycin sulfate, succinylsulfathiazole, sulbactam, sulbactam sodium, sulbenicillin sodium, sulfabenzamide, sulfacytine, sulfadicramide, sulfadoxine, sulfamerazine, sulfamerazine sodium, sulfamethylthiazole, sulfametopyrazine, sulfametrol, sulfaperine, sulfachinoxaline, sulfasuccinamide, sulfenazone, Sulfacetam id, sulfacetamide sodium, sulfadiazine, sulfadiazine sodium, sulfadimethoxine, sulfadimidine, sulfadimidine sodium, sulfafurazole, acetyl-sulfafurazole, sulfafurazole-diethanolamine, sulfaguanidine, sulfaguanol, sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, acetyl-sulfamethoxypyridazine, sulfamoxol, sulfanilamide, sulfapyridine, Sulfapyridine sodium, sulfasomidine, sulfathiazole, sulfathiazole sodium, sulfatolamide, sulf (a) urea, sultamicillin, talampicillin hydrochloride, talampicillin napsylate, taurolidine, tazobactam sodium, tercoplanin, temafloxacin, temocillin sodium, terizicone, tetracycline, tetracycline Phosphate complex, tetracycline hydrochloride, tetroxoprim, thiophenecarboxylic acid ("thenoic acid"), thiacetazone, polymyxin B sulfate, thiamphenicol, thiamphenicol glycinate hydrochloride, thiocarlide, thiostrepton, ticarcillin sodium, tigemonam, tobramycin, tobramycin sulfate, tosufloxacin , Triacetyloleandomycin, trimethoprim, trospectomycin sulfate, trovafloxacin, tylosin, tylosin tartrate , Tyrothricin, vancomycin hydrochloride, viomycin sulfate, virginiamycin and xibornol as an antibacterial agent; Adrenaline, adrenaline tartrate, adrenaline hydrochloride, adrenaline hydrochloride, ammonium acetate sulfate ("methyl acetate"), angiotensin amide, arbutamine hydrochloride, bambuterol hydrochloride, bitolterol mesylate, broxaterol, buphenin hydrochloride, carbuterol hydrochloride, Clenbuterol hydrochloride, clonazoline hydrochloride, clorprenalin hydrochloride, denopamine, dimepropion hydrochloride, dimetofrin hydrochloride, dipivefrine hydrochloride, dobutamine hydrochloride, docarpamine, dopamine hydrochloride, dopexamine hydrochloride, eformoteroifumarate, ephedra, ephedrine, ephedrine hydrochloride, Ephedrine sulfate, etafedrine hydrochloride, ethylnoradrenaline hydrochloride ("ethylenoradrenaline hydrochloride"), etifelmin hydrochloride, etilefrine hydrochloride, fenoterol hydrobromide, fenoxazoline hydrochloride, gepefrin tartrate, hexoprenaline hydrochloride, hexoprenaline sulfate, hydroxyamphetamine hydrobromide , Ibopamine Hydrochloride, Indanazoline, Inclanazoline Hydrochloride, Isoetharine Hydrochloride, Isoetharine Mesylate, Isomethiophene Hydrochloride, Isometheptane Mucate, Isoprenaline, Isoprenaline Hydrochloride, Isoprenaline Sulfate, Isoxsuprine Hydrochloride, Levonordefrin, Mabuterol, Mephetermine, Mephetermine Sulfate , Metaraminol tartrate, methoxamine hydrochloride, methoxyphenamine hydrochloride, Methylep hedrin hydrochloride, midodrine hydrochloride, naphazoline, naphazoline hydrochloride, naphazoline nitrate, norepinephrine, noradrenalic acid tartrate, norepinephrine hydrochloride, norfenefrine hydrochloride, octodrin, octopamine, orciprenaline sulfate, oxedrine, oxedrine hydrochloride, oxedrine tartrate, Oxilofrin, Oxilofrin hydrochloride, Oxymetazoline, Oxymetazoline hydrochloride, Phenylephrine, Phenylephric acid tartrate, Phenylephrine hydrochloride, Phenylpropanolamine, Phenylpropanolamine hydrochloride, Pholedrine sulfate, Pirbuterol acetate, Pirbuterol hydrochloride, Prednazoline, Prenfalterol hydrochloride, Procaterol hydrochloride, Protokylol hydrochloride, pseudoephedrine, pseudoephedrine hydrochloride, pseudoephedrine sulfate, reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salbutamol, salbutamol sulfate, salmeterol xinafoate, terbutaline sulfate, tetrahydrozoline hydrochloride, tramazoline hydrochloride, tretoquinol Hydrochloride, Tuaminoheptan, Tuarninolheptan sulfate, tulobuterol hydrochloride, tymazoline Hydrochloride, xamoterol, xamoterol fumarate and xylometazoline hydrochloride as sympatomimetics; Acrivastine, antazoline hydrochloride, antazoline mesylate, antazoline phosphate, antazoline sulfate, astemizole, azatadine maleate, azelastine hydrochloride, bannipine, bromodiphenhydramine hydrochloride, bromopheniramine maleate, dexbromopheniramine maleate, buclizine hydrochloride, carbinoxamine maleate, Cetirizine hydrochloride, Chlorcyclizine hydrochloride, Chloropyril citrate, Chlorpheniramine maleate, Dexchlorpheniramine maleate, Chlorphenoxamine hydrochloride, Cinnarizine, Clemastine fumarate, Clemizole hydrochloride, Clocinizine hydrochloride, Cyclizine, Cyclizine hydrochloride, Cyclizine lactate, Cyclizine Tartrate, cyproheptadine hydrochloride, deptropine citrate, dimenhydrinate, dimethindene maleate, dimethothiazine mesylate, diphenhydramine, diphenhydramine citrate, diphenhydramine di (acefyllinate), diphenhydramine hydrochloride, diphenylpyraline hydrochloride, doxylamine succinate, ebastine, embraminate Hydrochloride, emedastine, epinastine hydrochloride, flunarizine hydrochloride, halopyramine hydrochloride, histapyrrodine, histapyrrodine hydrochloride, Homochlorcyclizine hydrochloride, hydroxyethylpromethazine chloride, hydroxyzine embonate, hydroxyzine hydrochloride, isothipendyl hydrochloride, levocabastine hydrochloride, loratadine, melbhydroline, melbhydroline napadisylate, meclozine hydrochloride, mefenidramium methyl sulfate ("Mefenidramium Methyisulphate"), mepyramine hydrochloride, mepyramine Maleate, mequitazine, methapyril fumarate, methapyril hydrochloride, methdilazine, methdilazine hydrochloride, mizolastine, niaprazine, noberastine, oxatomide, oxomemazine, oxomemazine hydrochloride, phenindamine tartrate, pheniramine, pheniramine aminosalicylate, pheniramine maleate, phenyltoloxamine citrate, Pimethixene, piprinhydrinate, promethazine, promethazine hydrochloride, promethazine theoclate, propiomazine hydrochloride, propiomazine maleate, setastine hydrochloride, tazifylline hydrochloride, terfenadine, thenalidine tartrate, thenyidiamine hydrochloride, thiazinamium methylsulfate ("thiazinamium methylsulfate"), thiethylperazine, Thiethylperazine malate, thiethylperazine maleate, thonzyla ninin hydrochloride, tolpropamine hydrochloride, trimeprazine tartrate, trimethobenzamide hydrochloride, tripelennamine citrate, tripelennamine hydrochloride, triprolidine hydrochloride, and tritoqualin as antihistamines.

muscarinic and / or opioid drugs used for the treatment of tinnitus, e.g. an anticholinesterase inhibitor, such as. Neostigmine. The opioid drug can be an agonist. Other possible Active ingredients are morphine, DAMGO, heroin, hydromorphone, dermorphin, Spiradolin, U50,488, dynorphin A, DPDPE, deltorphin, DSLET, oxymorphone, Levorphanol, methadone, meperidine, fentanyl, codeine, hydrocodone, Oxycodone, propoxyphene, tramadol, etorphine, EKC, meperidine or theirs pharmaceutically acceptable Salts, prodrugs and derivatives. Preferred opioid receptor agonist antagonists include, but are not limited to, buprenorphine, butorphanol pentazocine and Nalbuphin. A botulinum toxin can also be used, as well such as benzodiazepine tranquilizers, e.g. Valium and Alprazolam. Similarly, a local anesthetic, e.g. Lidocaine, tetracaine, prilocaine, bupuivacaine, mepivacaine, procaine and / or benzocaine. It was also reported loop diuretics are used to treat tinnitus can, such as. Furosemide, Et (h) acrymic acid ( "Etharymic acid ") and bumetanide.

The called botuline toxin can also be used to cochlear Nervous dysfunction and relieve Menier's disease. pharmaceutical active agents, e.g. For Nerve cells damage can be used in cochlear diseases, can also in the device according to the invention used, as well as antiviral and osmotic agents, such as e.g. Salts or glycerin.

Ear infections such as. Otitis, can with amoxicillin, ampicillin, a mixture of ciprofloxacin and Hydrocortisone be treated. Anti-infective agents, e.g. Iodine, aminoglycosides, Penicillins, cephalosporins, polymyxin, ofloxacillins, gentamicin, Cephazoline, clindamycin, tetracyclines and their analogues are widely used also used, as well as anti-inflammatory agents, e.g. Steroids and non-steroidal anti-inflammatory agents. Nonsteroidal Anti-inflammatory agents include compounds, e.g. propionic acid derivatives, e.g. Benoxaprofen, Carprofen, Flurbiprofen, Fenoprofen, Fenbufen, Ibuprofen, Indoprofen, Ketoprofen, Naproxen, Miroprofen, Oxaprozin, Pranoprofen, pirprofen, suprofen, tiaprofen acid, fluprofen, alminoprofen, bucloxic acid ( "Bucloxic acid ") and the like; Acetic acid derivatives, such as Alcofenac, Acematacin, Aspirin, Diclofenac, Indomethacin, Ibufenac, Isoxepac, furofenac, fentiazac, clidanac, oxpinac, sulindac, tomletin, Zomepirac, zidometracin, tenclofenac, tiopinac and the like; fenamic acid derivatives, such as. mefenamic, flufenamic, niflumic, meclofenamic, tolfenamic and the same; biphenylcarboxylic, such as. Diflunisol, flufenisol and the like; oxicam derivatives, such as. Isoxicam, piroxicam, sudoxicam and the like; cyclosporine, Indomethacin and naproxen. Other agents include potassium chloride, Potassium carbonate and the like. Anti-prostaglandins can too be used.

Some specific examples of corticosteroids include alclometasone dipropionate, Aldosterone, amcinonide, beclomethasone dipropionate, benclacort, betamethasone, Betamethasone acetate, betamethasone benzoate, betamethasone dipropionate, Betamethasone sodium phosphate, betamethasone valerate, budesonide, ciclomethasone, Ciprocinonide, clobetasol propionate, clobetasone butyrate, clocortolone pivalate, Cloprednol, cortisone acetate, cortivazole, deflazacort, deoxycorton acetate, deoxycortorol pivalate, Deprodone, Desonide, Deoxymethasone Dexamethasone, Dexamethasone Acetate, Dexamethasone isonicotinate, Dexamethasone phosphate, dexamethasone sodium metasulfobenzoate, sodium dexamethasone phosphate, Dichloroacetate acetate, diflorasone diacetate, diflucortolone valerate, difluprednate, Domoprednate, endrysone, fluazacort, fluclorolone acetonide, fludrocortisone acetate, Flumethasone, flumethasone pivalate, flunisolide, fluodnolone acetoride, Fluocinonide, fluocortin-butyl, fluocortolone, fluocortolone hexanoate, fluocortolone pivalate, Fluorometholone, fluorometholone acetate, flupredniden acetate, ruprednsolone, Flurandrenolone, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, Halomethasone, hydrocortamate hydrochloride, Hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cypionate, Hydrocortisone hemisuccinate, Hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone valerate, Medrysone, meprednisone, methylprednisolone, methylprednisolone acetate, Methylprednisolone hemisuccinate, methylprednisolone sodium succinate, Mometasone furcat, paramethasone acetate, prednicarbate, prednisolamate hydrochloride, Prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone hexanoate, prednisolone pivalate, Precinisolone sodium metasulfobenzoate, prednisolone sodium phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate, Prednisone, Prednisone acetate, prednylidene, procinonide, rimexolone, suprarenal Cortex, tixocortol pivalate, triamcinolone, triamcinolone acetonide, Triamcinolone diacetate and triamcinolone hexacetonide.

The Use of antifungal and antiviral agents the treatment of the various diseases listed above is also known. Antifungals or antifungals are added in the polymer for the treatment of fungal sinusitis and anti-inflammatory and anti-infective agents are used for treatment e.g. of chronic bacterial sinusitis. Examples for antifungals Agents include nystatin, griseofulvin, lotrimin, mycostatin, ketoconazole, Amphotericin B and analogs thereof and examples of antiviral agents Idoxuridine, amantadine, vidarabine, interferon, acyclovir and analogs from that.

The Devices according to the invention can Furthermore, fluoride or other drugs for the treatment of Otosclerosis included.

Other pharmaceutically active agents used in the otological Dispenser may include urea, mannitol, Sorbitol, glycerin, lidocaine, xylocaine, epinephrine, immunoglobulins, Sodium chloride, steroids, heparin, hyaluronidase, aminoglycoside antibiotics (Streptomycin / gentamycin), antioxidants, neurotrophins, nerve growth factors, various therapeutic peptides and polysaccharides.

It has also been described to be calcium channel blockers, free-radical scavengers ( "Free radical scavengers "), Corticosteroids, glutamate antagonists of N-methyl-D-aspartate (NMDA) - and non-NMDA receptors and various thrombolytic agents in the treatment of hearing loss, Tinnitus and Vertigo are used.

For nasal devices, anti-asthma agents, such as those from the β2-adrenocep tor agonist, antimuscarinic, cromoglycate, leukotriene, xanthine or corticosteroid type, among others.

As from the above lists, any pharmaceutical agent, this is an acceptably low level toxicity at the position of the dispenser, in a device according to the invention be used. Therefore, the above list should not be considered the scope of protection the current one claims restrictive be understood. A person skilled in the art is naturally capable of Amount of active (active) resources and nature as well as the nature of any mixture of active ingredients, the for a special purpose is used to determine.

suitable Indications for Nasal devices are e.g. Allergies, such as perennial allergic Rhinitis. Suitable indications for otic devices are e.g. senso-neuronal hearing loss, sudden deafness, Menieresche Illness and tinnitus. Suitable active ingredients for these indications are corticosteroids, Antibiotics of the gentamycin class, growth factors and antiviral Medium.

placement the dispenser

The Otological device can be placed in any suitable place be placed in the inner or middle ear. It can also be partial in the outer ear and partially placed in the middle ear. With "outer ear" here are the auricle and the ear canal meant. With "middle ear" are the tympanic cavity or the tympanum ("eardrum"), the ossicles and the Eustachian tube. "The inner ear stands for the posterior and superior bony archways ("posterior and superior semicircular canals "), as well as for the vestibular, facial and cochlear nerves.

The Dispensing device is preferably inserted through the Eustachian tube and with fibrin glue ("fibrin glue ") or one glued to other suitable material. In the unexpected case of detaching the Device would they just lie on the bottom of the middle ear cavity, where they do no harm would cause. It was found out that the round-window niche in particular permeable towards is many substances. Therefore, the dispensing device according to the invention advantageously for the placement of at least part of it in the round window niche shaped and sized.

The Nasal device may be in the turbinate or the eustachian tube be positioned. It is preferably in the lower turbinate positioned.

The Otological device is preferably in the round-window niche positioned. Since the round window is approximately cylindrical, that would be largest releasing surface that of a cylinder, both for direct as well as for collateral release.

A or multiple devices into the ear or nose of the patient (e.g., or one or more each nostril) are used and these devices can the same or a different active ingredient.

The The invention will now be described in more detail by the following non-limiting drawings and examples are described.

SHORT DESCRIPTION THE DRAWINGS

1 describes a dispenser according to a first embodiment of the invention.

2 describes a dispenser according to a second embodiment of the invention.

3 describes a dispenser according to the invention in an ear.

4 describes a dispensing device according to the invention in a nose.

5 describes the results from Example 1.

6 describes the results from Examples 2 to 5.

PRECISE DESCRIPTION THE DRAWINGS

1 describes a dispenser according to a first embodiment of the invention, said apparatus comprising a core 1 includes.

2 describes a dispenser according to a second embodiment of the invention. The device comprises a core 1 and a membrane 2 which surrounds the said core and is arranged next to it. In the figure, however, the membrane 2 to some extent removed from the core for clarity

3 describes a dispenser according to the invention placed in an ear of a patient. The ear is shown in cross-sectional view. The figure shows the external auditory canal ("ear canal") 3 , the eardrum 4 , the round-window niche 5 , the round window membrane 6 and the inner ear 7 , The figure further shows a dispenser positioned near the round window membrane.

4 describes a dispenser according to the invention positioned in the nose of a patient. The nose is shown in cross-sectional view. The figure shows the upper turbinate 10 , the middle turbinate 11 , the lower turbinate 12 and the Eustach tube 8th , The figure further shows a dispenser 13 in the use position in the lower turbinate 12 ,

5 and 6 will be discussed in detail below.

In this description, unless the context requires otherwise, The words "comprise," "comprises," and "comprising," "comprising," and "comprising." is described or defined that the invention specific Features include different embodiments the same invention also additional Features include.

EXPERIMENTAL PART

example 1

The Concentrations of the therapeutically active agent beclomethasone were in ng / ml or pg / ml in the perilymph of the ipsilateral ear of guinea pigs using round-window implants according to the invention were treated, measured.

implants of PDMS without therapeutically active agents (placebos), PDMS with 0.5 mg beclomethasone (low-dose implant), PEO-PDMS with 0.5 mg Beclomethasone (high-dose implant) or not treated at all (detection limit 2.25 pg / μl) were used. The preparation of various implants is described below.

Low-dose implant

39.4 Parts of commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.4 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker, 0.02 parts Ethinylcyclohexanol inhibitor and 10 ppm Pt catalyst (reaction species) in vinylmethylsiloxane were mixed in a two-chamber mixer. 60 parts by weight of active ingredient were mixed in a two-chamber mixer. The mixture was through nozzles in the desired dimensions (diameter (OD) 1.14 mm) and crosslinked in an oven by means of heat. The cores were removed, cooled and to the desired Cut length (0.8 mm). The active ingredient content was 60% (w / w), based on the HPLC content.

High-dose implant

39.4 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 0.4 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, 0.02 Parts of ethynyl cyclohexanol inhibitor and 10 ppm Pt catalyst (reaction species) in vinylmethylsiloxane were mixed in a two-chamber mixer. 60 parts by weight of active ingredient were mixed in a two-chamber mixer. The mixture was through nozzles in the desired Dimensions (diameter (OD) 1.14 mm) and crosslinked in an oven by means of heat. The cores were removed, cooled and to the desired Cut length (0.8 mm). The active ingredient content was 60% (w / w), based on the HPLC content.

placebo

99.4 Parts of commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.4 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker, 0.02 parts Ethynyl cyclohexanol inhibitor and 10 ppm Pt catalyst (reaction species) in vinylmethylsiloxane were mixed in a two-chamber mixer. The mixture was through nozzles in the desired Dimensions (diameter (OD) 1.19 mm) and crosslinked in an oven by means of heat. The cores were removed, cooled and to the desired Cut length (0, 8 mm).

A according to the invention, like device described above, the device being one of the above mentioned Elastomer compositions consisted and said amount of therapeutic active agent or no agent was added to the perilymph of the ipsilateral ear of guinea pigs (25 animals in each group) introduced into the round window of the right ear of the animal, with Exception of one animal in each group.

The Release of beclomethasone was followed on days 1, 14 and 28 the treatment, i. Positioning of the device, measured. All PEO-PDMS implants released until day 28 during one of the five PDMS implants this did not seem to be happening on day 28. The concept of drug release from round-window polymer implants in the inner ear fluid is thus proved.

• * Tag nach Implantateinsetzung

In general, concentrations of beclomethasone were higher for PEO-PDMS polymers. The results are shown in Table 1 below. Table 1.

• * Day after implant placement

The untreated animals were not killed on days 1 and 14. On day 21, all five became Animals were killed and there was no release of beclomethasone. There was also no release of beclomethasone in the animals that received the placebo. The remaining results can be seen from the table and will continue in 5 illustrated. In 5 The squares are the high-dose implants, and the diamonds are the low-dose implants.

Of Further, the release rates of a nasal device in examined in vitro. For the study produced the following membranes and cores, followed by the manufacture of the implant.

Example 2

Preparation of the 30% PEO-b PDMS membrane

29 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 69 parts silica-filled Poly (dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm Pt catalyst (reactive form) and 0.03 part inhibitor (ethynylcyclohexanol), about 2 parts poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker were with a 2-roll mill mixed. The mixture became a tubular shape with a Wall thickness of 0.3 mm extruded and cured by heat.

manufacturing of the core

19.7 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 19.7 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.02 part inhibitor (ethynylcyclohexanol), about 0.6 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker were with a 2-roll mill and 60 parts of drug substance were added. The mixture was through nozzles to the desired Dimensions (OD 1.6 mm) are extruded and heat-treated in an oven networked. The cores were removed, cooled and adjusted to the desired length (10 mm) cut. The content of active ingredient was 60% (w / w) based on the HPLC content.

manufacturing of the implant

11 mm membranes were swollen with cyclohexane and the cores used. Cyclohexane was allowed to evaporate and the ends were washed with a Silicone adhesive sealed. After 24 hours, the ends were cut off, whereby 0.5 mm end caps ("end caps") were obtained.

Example 3

Producing a 25% PEO-b-PDMS membrane

24 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 74 parts silica-filled Poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.03 part inhibitor (ethynylcyclohexanol), about 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker with a 2-roll mill mixed. The mixture became a tubular shape with a Wall thickness of 0.3 mm extruded and cured by heat.

manufacturing of the core

19.7 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 19.7 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.02 part inhibitor (ethynylcyclohexanol), about 0.6 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker were with a 2-roll mill and 60 parts of drug substance were added. The mixture was through nozzles to the desired Dimensions (OD 1.6 mm) are extruded and heat-treated in an oven networked. The cores were removed, cooled and adjusted to the desired length (10 mm) cut. The content of active ingredient was 60% (w / w) based on the HPLC content.

manufacturing of the implant

11 mm membranes were swollen with cyclohexane and the cores used. Cyclohexane was allowed to evaporate and the ends were washed with a Silicone adhesive sealed. After 24 hours, the ends were cut off, whereby 0.5 mm end caps ("end caps") were obtained.

Example 4

Producing a 20% PEO-b-PDMS membrane

19 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 79 parts silica-filled Poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.03 part inhibitor (ethynylcyclohexanol), about 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker with a 2-roll mill mixed. The mixture became a tubular shape with a Wall thickness of 0.3 mm extruded and cured by heat.

manufacturing of the core

19.7 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 19.7 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.02 part inhibitor (ethynylcyclohexanol), about 0.6 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker were with a 2-roll mill and 60 parts of drug substance were added. The mixture was through nozzles to the desired Dimensions (OD 1, 6 mm) and extruded in an oven by means of heat networked. The cores were removed, cooled and adjusted to the desired length (10 mm) cut. The content of active ingredient was 60% (w / w) based on the HPLC content.

manufacturing of the implant

11 mm membranes were swollen with cyclohexane and the cores used. Cyclohexane was allowed to evaporate and the ends were washed with a Silicone adhesive sealed. After 29 hours, the ends were cut off, whereby 0.5 mm end caps ("end caps") were obtained.

Example 5

Producing a 10% PEO-b-PDMS membrane

9 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 89 parts silica-filled Poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.03 part inhibitor (ethynylcyclohexanol), about 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker with a 2-roll mill mixed. The mixture became a tubular shape with a Wall thickness of 0.3 mm extruded and cured by heat.

manufacturing of the core

19.7 Parts of commercial triethylene oxide vinyl ether-terminated poly (tetraethylene oxide-b-deca (dimethylsiloxane)), 19.7 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 10 ppm Pt catalyst (reactive form) and 0.02 part inhibitor (ethynylcyclohexanol), about 0.6 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) cross-linker were with a 2-roll mill and 60 parts of drug substance were added. The mixture was through nozzles to the desired Dimensions (OD 1.6 mm) are extruded and heat-treated in an oven networked. The cores were removed, cooled and adjusted to the desired length (10 mm) cut. The content of active ingredient was 60% (w / w) based on the HPLC content.

manufacturing of the implant

11 mm membranes were swollen with cyclohexane and the cores used. Cyclohexane was allowed to evaporate and the ends were washed with a Silicone adhesive sealed. After 24 hours, the ends were cut off, whereby 0.5 mm end caps ("end caps") were obtained.

Drug-release test

The release rates of the drug from the implant were measured in vitro as follows: Implants were fixed in a stainless steel holder in an inverted position and the holders with the implants were placed in glass bottles containing 75 ml of a dissolution medium. The glass bottles were shaken in a shaking water bath at 100 rpm at 37 ° C. The dissolution medium is removed at predetermined time intervals and replaced with a fresh dissolution medium, and the released drug analyzed by HPLC. The concentration of the dissolution medium and the time of change (removal and Er medium) were chosen to maintain sink conditions during the test.

The results are in 6 illustrated. 6 shows that the release rates are clearly dependent on the nature of the membrane. In 6 the diamonds illustrate the results of Example 2, the squares the results of Example 3 and the triangles illustrate the results of Example 4 and the stars illustrate the results of Example 5.

Claims (12)

An otorhinological delivery device comprising at least one pharmaceutically active agent, characterized in that the device comprises: - a core comprising at least said one pharmaceutically active agent, said core being an elastomeric composition selected from the group consisting of poly (dimethylsiloxane), a Siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si atoms of the siloxane units, a siloxane-based elastomer comprising poly (alkylene oxide) groups, and mixtures thereof, and - a membrane, which surrounds the core, wherein the membrane is made of a same or different from the core elastomer composition. Dispensing device according to claim 1, characterized in that the elastomeric composition is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si atoms the siloxane units are bound, and in the siloxane-based Elastomer 1 to about 50% of the Si atoms of the siloxane units bonded substituents are 3,3,3-trifluoropropyl groups. Dispensing device according to claim 1, characterized in that in that the elastomeric composition comprises a poly (alkylene oxide) group Siloxane-based elastomer and the poly (alkylene oxide) groups as alkoxy-terminated grafts or blocks containing the polysiloxane units connected by silicon-carbon bonds or as one Mixture of these forms are present. Dispensing device according to claim 3, characterized in that the poly (alkylene oxide) groups are poly (ethylene oxide) groups. Dispensing device according to claim 1, characterized in that that the membrane and the core of the same elastomer composition are made. Dispensing device according to claim 1, characterized in that that the membrane and the core of a different elastomer composition are made. Dispensing device according to claim 1, characterized in that that it is an otological dispenser and that the elastomer composition Poly (dimethylsiloxane) and comprising a poly (ethylene oxide) group Siloxane-based elastomer. Dispensing device according to claim 7, characterized in that the pharmaceutically active agent is a glucocorticoid. Dispensing device according to claim 8, characterized in that in that the pharmaceutically active agent is selected from the group consisting from dexamethasone, betametasone, beclomethasone, budesonide and mixtures from that. Dispensing device according to claim 1, characterized in that that it is a nasal delivery device and that the pharmaceutical active agents selected is from the group consisting of antiallergic agents, anti inflammatory Agents, antifungals, glucocorticoids and mixtures thereof. Dispensing device according to claim 7 for treatment of otological disorders, selected from the group consisting of otitis, acute infections, cochlear and vestibular disorders, Dizziness or vertigo, Menier's disease, sudden Deafness, sensoneurinal hearing loss, Tinnitus, motion sickness, endolymphatic hydrops, endolymphatic Hypertension, perilymphatic hypertension, perilymphatic Hydrops, perilymphatic fistulas, intracochlear fistulas and Cracks in various membrane structures within the ear. Dispensing device according to claim 10 for treatment of nasal disorders, selected from the group consisting of nasal inflammatory disorders, allergic reactions, asthma and fungal infections or fungal infections.