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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
  • A61K9/7061—Polyacrylates
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• This invention relates to a device for transdermal administration of reboxetine, optionally encompassing salts, prodrugs and metabolites thereof, to the use of reboxetine, optionally encompassing salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered transdermally, and to methods of treating depression and/or symptoms associated with this condition and/or for treating addictive disorders and withdrawal syndromes, adjustment disorders, age-associated learning and mental disorders, anorexia nervosa, apathy, attention-deficit disorders due to general medical conditions, attention-deficit hyperactivity disorders, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclothymic disorders, depression, dysthymic disorders, fibromyalgia and other somatoform disorders, stress incontinence, generalized anxiety disorders, inhalation disorders, an intoxication disorders, obesity, obsessive compulsive disorders and related spectrum disorders, op- positional defiant disorders, panic disorder,
• Reboxetine is the generic name of the pharmaceutical substance having the chemical name 2-( ⁇ -(2-ethoxyphenoxy)benzyl)-morpholine and its pharmaceutically acceptable salts.
• Reboxetine can be a free base, or it can include reboxetine methanesul- fonate (also called reboxetine mesylate) or any other pharmaceutically acceptable salt that does not significantly affect the pharmaceutical activity of the substance.
• Reboxetine and a method of synthesis thereof are described in US 4,229,449. Methods of preparation are described in US 5,068,433 and US 5,391,735.
• Reboxetine is also known under the trade name EDRONAX ® .
• Reboxetine is a selective and potent inhibitor of the reuptake of noradrenaline; it also has a weak effect on serotonin reuptake.
• Pharmacodynamic studies performed in vivo and in vitro indicate that reboxetine possesses antidepressant activity and a lower incidence of side effects than commonly is seen with the tricyclic antidepressants.
• Reboxetine is highly potent, with central nervous system (CNS) effects demonstrated at doses of 1 and 3 mg.
• CNS central nervous system
• Phase II studies in patients with Major Depressive Disorders identified the non-tolerated dose in patients as 12 mg/day, which produced dose-limiting hypotension. Therefore, daily doses of 8 and 10 mg were selected for subsequent development, since these doses were associated with maximal response and minimal side- effects.
• reboxetine Pharmacokinetic studies of reboxetine indicate that the drug is rapidly and extensively absorbed after oral administration. Soon after peak plasma levels are obtained reboxetine plasma levels decay with a half-life of 12-16 hours. Unchanged drug, extensively bound to plasma proteins, is the main molecular species that is present in the systemic circulation. Clearance from the systemic circulation is mainly taking place by hepatic metabolism. The amount excreted by the renal pathway accounted for 78 % of the administered dose, of which 13 % was unchanged reboxetine. Reboxetine is an equimolar mixture of two enantiomers. The pharmacokinetics of each enantiomer have been evaluated, and neither chiral inversion nor interactions between enantiomers have been observed after racemic administration.
• Reboxetine has a molecular weight of 313,4 g/mol and 409,5 g/mol as the methanesulphonate salt.
• Reboxetine base is freely soluble in ethanol, propylene glycol, ethylacetate and isopropylmyristate. It is slightly soluble in water and 0,05 M phosphate buffer, pH 7,4.
• the partition coefficient (Log P) between n-octanol and phosphate buffer at pH 7,4 is 0,86.
• the present invention pertains to transdermal administration of reboxetine as R- isomer, S-isomer or as a racemic mixture.
• Properties supporting the feasibility of the patch principle are that depression and symptoms associated with this condition, as well as with the other conditions mentioned above, might benefit from a flat serum concentration profile.
• WO 99/11208 discloses transdermal delivery of a large number of medical agents, including reboxetine, using a matrix of a lecithin gel such as a lecithin organogel.
• WO 99/11208 does not disclose transdermal delivery of reboxetine from any other transdermal system.
• a transdermal formulation with reboxetine as active ingredient will provide an alternative to the tablet formulation for the oral route.
• the transdermal delivery route avoids the risk for dose dumping with extended release oral forms of administration. Moreover, patient compliance will be increased as
• a first object of the present invention is to provide a device for transdermal administration of reboxetine, optionally encompassing salts, prodrugs and metabolites thereof, for achieving an antidepressant effect and/or for obtaining an effect in treating addictive disorders and withdrawal syndromes, adjustment disorders, age- associated learning and mental disorders, anorexia nervosa, apathy, attention-deficit disorders due to general medical conditions, attention-deficit hyperactivity disorders, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclo- thymic disorders, depression, dysthymic disorders, fibromyalgia and other somatoform disorders, stress incontinence, generalized anxiety disorders, inhalation disorders, an intoxication disorders, obesity, obsessive compulsive disorders and related spectrum disorders, oppositional defiant disorders, panic disorder, peripheral neuropathy, post- traumatic stress disorder, premenstrual dysphoric disorder, psychotic disorders
• a second object of the invention is to provide a device for transdermal administration of reboxetine, optionally encompassing salts, prodrugs and metabolites thereof, for achieving an anti-reserpine effect and/or a noradrenaline reuptake inhibiting effect.
• a third object of the invention is to provide use of a compound having an anti- depressant effect, comprising reboxetine for the manufacture of a composition to be administered transdermally for treating depression or symptoms associated with this condition and/or for treating addictive disorders and withdrawal syndromes, adjustment disorders, age-associated learning and mental disorders, anorexia nervosa, apathy, attention-deficit disorders due to general medical conditions, attention-deficit hyperac- tivity disorders, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclothymic disorders, depression, dysthymic disorders, fibromyalgia and other somatoform disorders, stress incontinence, generalized anxiety disorders, inhalation disorders, -an intoxication disorders, obesity, obsessive compulsive disorders and .
• SSRI serotonin reuptake inhibition
• a fourth object of the invention is to provide use of a compound having an anti- reserpine effect and/or a noradrenaline reuptake inhibiting effect, comprising reboxetine for the manufacture of a composition to be administered transdermally for treating conditions in need for such effects.
• a fifth object of the invention is to provide a method of treating depression or symptoms associated with this condition and/or for treating addictive disorders and withdrawal syndromes, adjustment disorders, age-associated learning and mental disorders, anorexia nervosa, apathy, attention-deficit disorders due to general medical conditions, attention-deficit hyperactivity disorders, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclothymic disorders, depression, dysthymic disorders, fibromyalgia and other somatoform disorders, stress incontinence, generalized anxiety disorders, inhalation disorders, an intoxication disorders, obesity, obsessive compulsive disorders and related spectrum disorders, oppositional defiant disorders, panic disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, psychotic disorders, seasonal affective disorder, sleep disor- der, social phobia, specific developmental disorders and selective serotonin reuptake inhibition (SSRI) "poop out” syndrome by administering reboxetine transdermally
• a sixth object of the invention is to provide a method of treating diseases, in humans or animals, which are treatable with anti-reserpine agents and/or noradrenaline uptake inhibiting agents by administering reboxetine transdermally.
• the present invention relates to transdermal administration of reboxetine, op- tionally encompassing salts, prodrugs and metabolites thereof for achieving an antide- pressant effect and/or an anti-reserpine effect and/or a noradrenaline reuptake inhibiting effect. Said effects are primarily achieved through the systemic effect of reboxetine. Anyhow other actions are not excluded.
• Figures 1 A - ID are schematic drawings of different types of devices for transdermal delivery of drugs.
• Figure 2 is a diagram showing in vitro skin permeation of reboxetine base from saturated solutions, according to Example 1.
• Figure 3 is a diagram showing in vitro skin permeation of 5 % reboxetine base solutions, according to Example 2 and Example 3.
• Figure 4 is a diagram showing in vitro skin permeation across synthetic membranes from 5 % reboxetine base solutions, according to Example 4.
• Figure 5 is a diagram showing in vitro skin permeation of reboxetine base from different transdermal systems, according to Example 6.
• Figure 6 is a diagram showing in vitro skin permeation of reboxetine base from different transdermal systems, applying human skin, according to Example 7.
• Figures 7 and 8 are diagrams showing in vitro dissolution of reboxetine base from different transdermal systems, according to Example 8.
• Figure 9 is a diagram showing in vitro skin permeation of different concentra- tions of reboxetine base from a transdermal system, according to Example 10.
• Figure 10 is a diagram showing in vitro dissolution of reboxetine base from reservoir patches, according to Example 12.
• Figure 11 is a diagram showing in vitro skin permeation of 5 % reboxetine methanesulphonate solutions, according to Example 13 and Example 14.
• Figure 12 is a diagram showing in vitro skin permeation of reboxetine methane- sulphonate from different transdermal systems according to Example 16.
• Figure 13 is a diagram showing in vitro skin permeation of reboxetine methane- sulphonate enantiomers from different transdermal systems, according to Example 18.
• Figure 14 is a diagram showing in vitro dissolution of reboxetine methanesul- phonate enantiomers from different transdermal systems, according to Example 19.
• Transdermal delivery of drugs can be achieved from topical products such as ointments or cremes or from transdermal devices.
• the present invention primarily re- lates to administration via transdermal devices, which usually are called transdermal patches. But other forms for topical administration, such as creams and ointments are also included.
• transdermal devices usable as transdermal patches can be categorized in many different ways. A comprehensive categorization of transdermal devices is found in Wick S. De- veloping A Drug-In- Adhesive Design for Transdermal Drug Delivery. Adhe Age 1995; 38: 18-24.
• Wick essentially divides transdermal devices into the below four, main groups:
• the reservoir type in which the drug is placed in a liquid or a gel and delivered across a rate-moderating membrane to the skin
• - the matrix type in which the drug is placed within a non-adhesive polymeric material, typically a hydrogel or soft polymer
• multi-laminate type which is similar to the drug-in-adhesive design but which incorporates an additional layer of pressure sensitive adhesive to cover the entire device and affix it to the skin.
• a membrane can also be incorporated into this multi- laminate type as shown in Fig. IB.
• an electrical potential gradient is used for transferring the drug through the skin - see further e.g. Singh P et al. Iontophoresis in Drug Delivery: Basic Principles and Applications. Crit Rev Ther Drug Carrier Syst 1994; 11 : 161-213.
• electroporation. electroosmosis. electroincorporation and jet injection can be used.
• Electroporation is the creation of transient aqueous pores in lipid bilayer membranes by the application of a short (msec) electric pulse (Prausnitz MR et al. Proc Lit Symp Control. Rel Biact Mater 1993; 20: 95-96). By using electroporation the skin permeability will be altered such that resistance to drug transport is reduced. Electroporation has been employed in transdermal drug delivery by coupling it with iontophoresis (Bommannan D et al. Pharm Res 1994; 11: 1809-1814, Prausnitz MR et al. Proc Na Acad Sci USA 1993; 90: 10504-10508, and Riviere JE et al. J Controlled Release 1995; 36: 299-233). In these cases, a short (few milliseconds) pulse of high voltage alters the skin permeability such that subsequent iontophoresis is facilitated.
• electroincorporation With electroosmosis the electric field creates a convective flow of water which allows hydrophilic compounds to be transported. Closely related to electroporation is electroincorporation but here particles (microspheres, liposomes) are placed on the sur- face of the skin and subsequent high voltage electrical pulses are employed (Riviere JE and Heit MC. Pharm Res 1997; 14: 687-697).
• Jet injection can be used both for powders and liquids (Muddle AG et al. Proc Int Symp Control. Rel Biact Mater 1997; 24: 713-714, and Seyam RM et al. Urology 1997; 50: 994-998.
• a drug can be administered by a no-needle painless injection.
• a multi-laminate type device encompass a device with many layers in a sandwich construction, such as the drug in one layer, excipients such as enhancers in a further layer, a membrane in another layer and an adhesive in still another layer. Or it could be composed of several drug-in-adhesive layers or combinations of the above layers.
• the liquid or gel used in the above reservoir type device could be hydrophilic or lipophilic, such as water, alcohols, mineral oils, silicone fluids, various copolymers, such as ethylene vinyl acetate, vinyl acetate or polyvinyl alcohol polyvinyl pyrrolidone.
• the reservoir may also include dyes, inert fillers, diluents, antioxidants, antiirritants, antisensitizers, permeation enhancers, stabilizers, solubilizing agents and other pharmacologically inactive pharmaceutical agents being well known in the art.
• the adhesives used are generally of three types, being the rubber type, encompassing inter alia polyisobutylenes, the acrylate type and the silicone type.
• the adhesiv- es may be chemically modified, and may have a wide range of molecular weights.
• To the adhesive could be added several types of excipients such as fillers, stabilizers, plasti- cizers, buffering agents, permeation enhancers, permeation retarders, antiirritants, an- tisensitizers, solubilizing agents and other pharmaceutical ingredients being well known in the art.
• Polymer films that may be used for making the rate-moderating membrane include, without limitation, those comprising low- and high-density polyethylene, ethyl vinyl acetate copolymers and other suitable polymers.
• the backing layer serves the purposes of preventing passage of the drug and/or environmental moisture through the outer surface of the patch, and also for providing support for the system, where needed. Further the backing layer can provide occlusion, and thus increasing the rate of delivery of the drug into the skin.
• the backing layer may be chosen so that the end product is appealing to the users, whether children, adults, elderly people or other customer groups.
• the backing layer is impermeable to the pas- sage of reboxetine or inactive ingredients being present in the formulation and can be flexible or nonflexible. Suitable materials include, without limitation, polyester, polyethylene terephthalate, some type of nylon, polypropylene, metallized polyester films, polyvinylidene chloride and aluminium foil.
• the release liner can be made of the same materials as the backing layer.
• the invention according to the present application encompasses administration of reboxetine via all hitherto known types of devices for transdermal administration. Mainly the above categorization will be adhered to in this application. Anyhow this does not exclude that transdermal devices which might fit better according to some other categorization also are included in the present invention. It is well known in the art that the properties of the skin as such influence the permeation of the drug through the skin into the systemic circulation. It could thus be said that the skin controls the drug permeation rate. Anyhow as the skin as such is no part of the present invention the behaviour of the skin in connection with transdermal drug delivery will not be discussed in detail.
• Hydrogels used for the matrix type and reservoir transdermal systems are materials, which swell when placed in excess water. They are able to swell rapidly and retain large amount of water in their swollen structure. The materials do not dissolve in water and maintain three-dimensional networks. Hydrogels are usually made of hydro- philic polymer molecules that are crosslinked either by chemical bonds or other cohesion forces such as ionic interaction, hydrogen bonding or hydrophobic interaction.
• Hydrogels are elastic solids in the sense that there exist remembered reference configurations to which the system returns even after being deformed for a very long time (Park K et al. Biodegradable Hydrogels for Drug Delivery. Technomic Publishing Co., Inc. 1993).
• Examples of hydrogels are polyvinylpyrrolidone and cellulose hydrogels such as methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carboxymethyl- cellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and microcrystalline cellulose (colloidal).
• Guar gum Guar gum, gum arabic, agar, tragacanth, carrageenan, xanthan gum, algin, carbomer, dextran and chitin.
• a polymer-system with no foils consisting of 1, 2 or more polymers in a solvent and added drug and e g plasticizers and enhancers.
• the polymers could be a blend of hydrophilic and hydrophobic species. This product should be applied to the skin using an appropriate device where the solvent evaporates and leaving a thin invisible film.
• This type of systems can also be of a multilayer type where the drug could be incorporated in different layers of polymers with different release characteristics and/or alternative layers without drug that could act as a rate limiting membrane.
• the outer layer is most preferable hydrophobic to obtain occlusion.
• the rate control ability is often a very important feature for a transdermal de- vice in order to deliver the correct amount of drug to the patient at the correct time.
• the drug-in-adhesive and the reservoir type device are presently considered to be the best modes for carrying out the present transdermal delivery of reboxetine.
• transdermal permeation enhancing substance(s) in order to increase the amount of reboxetine which may permeate the skin and reach the systemic circulation, or in order to reduce the size of the patch.
• Enhancers suitable in the present invention may be categorized in the below groups, although enhancers not belonging to any of these groups are not excluded.
• - alcohols such as short chain alcohols, e.g. ethanol and the like, long chain fatty alcohols, e.g. lauryl alcohols, and the like, and polyalcohols, e.g. propylene glycol, glycerin and the like;
• amides such as amides with long aliphatic chains, or aromatic amides like N,N-diethyl-m-toluamide;
• - essential oils i.e. essential oils or constituents thereof, such as 1-carvone, 1- menthone-menthol, and the like;
• fatty acids and fatty acid esters such as oleic acid, lauric acid and the like, further esters of fatty acids, such as isopropyl myristate, and various esters of lauric acid and of oleic acid and the like;
• - macrocyclic compounds such as cyclopentadecanone and cyclodextrins;
• phospholipid and phosphate compounds such as phospholipids
• - miscellaneous compounds like sulphoxides, such as dimethyl sulphoxides, and fatty acid ethers, such as Laureth-9 and polyoxylaurylether. Combinations of enhancers from different groups in the above categorization may prove very useful and efficient.
• Reboxetine methanesulphonate was supplied by Pharmacia & Upjohn (Kalama- zoo, USA).
• Eudragit E 100 aqueous and organic based were supplied by Rohm GmbH Chemische Fabrik, Polyethylene glycol 400 (PEG 400) was supplied by Merck-Schu- chardt, Polyvidone 90 (PNP 90) was supplied by BASF, MA-24 was from Adhesive Research Inc., Durotak 387-2287, 387-2516 and 387-2852 were supplied by National Starch & Chemical.
• Drug-in-adhesive patch The siliconized polyester release liner (FL2000-75 PET IS) was obtained from Rexam Release and the pigmented occlusive backing membrane (Scotchpak 1109) was obtained from 3M Corp.
• Azone was obtained from Discovery Therapeutics Inc., Methyllaurat was supplied by Fluka.
• Patch formulation studies Patch formulations were prepared by adding reboxetine base to each of the chosen polymers (acrylates, polyisobutylenes, PVP PEG). The drug gels were coated onto a siliconized polyester release liner (FL2000-75 PET IS) by using a coating equipment (Lab Drawdown Coater, Type LC-100) The laminates were dried and having a dry coat weight of approximately 100 g/m 2 . A backing membrane (Scotchpak 1109) was lami- nated onto the dried drug gel, resulting in a drug-in-adhesive laminate. Patches were die-cut from the finished sheet, pouch-packed in Barex foil and stored at room temperature until use. Any deviation from the above will be mentioned under the individual examples.
• Reservoir patch formulation study 5 % reboxetine base was dissolved in ethanol and 5 % reboxetine ethanesul- phonate was dissolved in water. The solutions were thereafter filled in reservoir patches by use of a reservoir patch machine (A&D, GmbH, Type PF-80).
• As backing membrane Scotchpak 9732 was used and as release liner Scotchpak 9733 was used.
• the rate controlling membranes consisted either of CoTran 9702 (9 % vinyl acetate) or CoTran 9728 (19 % vinyl acetate).
• the content of reboxetine was determined using a HPLC method.
• the system consisted of a HP 1100 pump or the equivalent, a HP 1100 autosampler or the equivalent with a 20 ⁇ l loop, a HP 1100 detector or the equivalent and a HP Chemstation integrator or the equivalent.
• the column was Nuclosil 5C8, 150 x 4,6 mm and the mobile phase was a mixture of 0, 1 M phosphate buffer pH 3,0 - acetonitrile (70+30).
• the flow was 1,0 ml/min and the detection wavelength was 280 mm.
• the skin was mounted in the diffusion cells with an available diffusion area of 1,8 cm 2 .
• the inner side of the epithelium was exposed to 12,1 ml receptor phase (0,05 M phosphate buffer, pH 7,4) at 37 ⁇ 1°C, corresponding to 32°C on the donor side of the skin. Samples were withdrawn periodically from the receptor phase up to 12,1 ml receptor phase (0,05 M phosphate buffer, pH 7,4) at 37 ⁇ 1°C, corresponding to 32°C on the donor side of the skin. Samples were withdrawn periodically from the receptor phase up to
• Solution 1 Reboxetine base was dissolved in water equal to 6,6 mg/ml.
• Reboxetine base was dissolved in propylene glycol equal to 280 mg/ml.
• Reboxetine base was dissolved in isopropylmyristate equal to 119 mg/ml.
• Membranes of the following types were used: CoTran 9702 (microporous polyethylene film) with 9 % vinylacetate (NA), CoTran 9728 with 19 % vinylacetate and an experimental CoTran membrane with 28 % vinylacetate.
• the three mentioned CoTran membranes were applied to solution 9, whereas only CoTran (19 % NA) and CoTran (28 % NA) were applied to solution 10.
• the membranes were placed on top of dermatomed pigskin.
• Patches containing approximately 1 mg/cm 2 reboxetine base in Durotak 387- 2287, 387-2516 and 387-2852 were manufactured according to the "patch formulation studies" described previously.
• the drug gels were coated and dried at 80°C for 10 min., resulting in a dry coat weight of approximately 100 g/m 2 .
• System 2 drug-in-adhesive, hydrophilic matrix
• a patch containing approximately 1 mg cm 2 reboxetine base in a mixture of polyvidone 90 : polyethylene glycol 400 (1:1) was manufactured. Reboxetine base, polyvidone 90 and polyethylene glycol 400 were dissolved in ethanol 99,9 %. The drug gel was coated and dried at 50°C for 4 hours, resulting in a dry coat weight of approximately 100 g/m 2 .
• Example 6 In vitro skin permeation studies of the transdermal drug delivery System 1, 2, 3 and 4 according to Example 5 (Fig. 5).
• Table 2 shows quantitative determination of reboxetine base after 0, 1, 2 and 3 months of storage, according to Example 8.
• Patches containing approximately 0,7 mg/cm 2 , 1,05 mg/cm 2 and 1,4 mg/cm 2 re- boxetine base in Durotak 387-2287 were manufactured according to the "patch formu- lation studies" described previously.
• the drug gels were coated and dried at 80°C for 10 min, resulting in a dry coat weight of approximately 140 g/m 2 .
• a patch containing approximately 1 mg/cm 2 reboxetine methanesulphonate in Durotak 387-2287 was manufactured according to the "patch formulation studies" described previously.
• the drug gels were coated and dried at 80°C for 10 min., resulting in a dry coat weight of approximately 100 g/m 2 .
• System 8 drug-in-adhesive, hydrophilic matrix
• a patch containing approximately 1 mg/cm 2 reboxetine methanesulphonate in a mixture of polyvidone 90 : polyethylene glycol 400 (1:1) was manufactured. Re- boxetine methanesulphonate, polyvidone 90 and polyethylene glycol 400 were dissolved in ethanol 99,9 %. The drug gel was coated and dried at 50°C for 4 hours, resulting in a dry coat weight of approximately 100 g/m 2 .
• Eudragit E 100 aqueous based, was manufactured.
• the drug gel was coated and dried at 60°C for 10 min, resulting in a dry coatweight of approximately 100 g/m 2 .
• a iontophoretic type device may be manufactured essentially according to embodiments disclosed in e.g. Parminder Singh et al, "Iontophoresis in Drug Delivery: Basic Principles and Applications", Critical Reviews in Therapeutic Drug Carrier Sys- tems, 1994; 11 (2&3): 161-213.
• the administration of reboxetine or derivatives thereof is not disclosed in this reference. Anyhow it lies within the present invention to modify, using the disclosure in the present application, the embodiments according to said reference to become suitable for the administration of reboxetine.
• Various carriers and vehicles for reboxetine may be used in the transdermal administration.
• One such carrier is cyclodextrine, especially ⁇ -cyclodextrine.
• Reboxetine can be bound in the cavities of cyclodextrines to form so called inclusion complexes. Binding reboxetine to a cyclodextrine leads either to increased delivery rate or to decreased delivery rate depending on the reboxetine-cyclodextrine ratio.
• a useful dosage of trans- dermally administered reboxetine according to the present invention for the conditions stated above would preferably range from 0.1 mg/day to 20 mg/day. Thereby is not excluded that also lower and higher daily dosages would be useful.
• the exact amounts should be determined in accordance with acknowledged principles, taking into account age, weight, condition to be treated and other relevant parameters.
• the data of Fig. 13 show that an apparent 0-order delivery of reboxetine through the skin takes place from about 5 to 48 hours. This 0-order delivery may continue for at least up to a week. Such a once-weekly patch will greatly improve patient compliance, which is important for patients, which often use tolterodine.
• a device for transdermal delivery during 2 or more days would further facilitate the use of the transdermal formulation. It is possible to design a device delivers reboxetine for a predefined period of time, preferably 12, 24 or 48 hours, or even up to 7 or 14 days.
• reboxetine it might be desirable to use higher dosages of reboxetine during the day or night. It is within the present invention to administer reboxetine in such a way that a therapeu- tically effective systemic level of reboxetine prevails to a higher extent during the day or the night.
• the above object is achievable by applying the transdermal device at the appropriate time during day or night in combination with designing the device with the appropriate release profile. The same rules for a device designed to deliver reboxetine to a lower extent during the day or the night.
• reboxetine When reboxetine is administered in a transdermal device the latter should preferably be occlusive, which means that the device does not permit water to migrate outwardly from the skin area covered by the device or at least with a lower rate than the rate of the skins ordinary transepidermal water loss. Thereby the hydration of the skin is increased which favors the penetration of reboxetine through the skin.
• a set of formulations of reboxetine optionally encompassing salts, prodrugs and metabolites thereof, which comprises at least one device for transdermal delivery and at least one formulation for oral, sublingual, buccal, nasal, pulmo- nary, rectal and/or other transmucosal administration.
• reboxetine may be present in just one of its above-presented forms or as a mixture of two or more forms.

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• 1999
  • 1999-12-23 SE SE9904750A patent/SE9904750D0/xx unknown
• 2000
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  • 2000-10-12 EP EP00971947A patent/EP1244431A1/de not_active Withdrawn
  • 2000-10-12 AU AU10681/01A patent/AU1068101A/en not_active Abandoned
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