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WO2004047795A2 - Application cutanee de flupirtine - Google Patents

Application cutanee de flupirtine Download PDF

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Publication number
WO2004047795A2
WO2004047795A2 PCT/EP2003/012875 EP0312875W WO2004047795A2 WO 2004047795 A2 WO2004047795 A2 WO 2004047795A2 EP 0312875 W EP0312875 W EP 0312875W WO 2004047795 A2 WO2004047795 A2 WO 2004047795A2
Authority
WO
WIPO (PCT)
Prior art keywords
flupirtine
dermal
skin
application
carrier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/012875
Other languages
German (de)
English (en)
Other versions
WO2004047795A3 (fr
Inventor
Dirk Mertin
Gerald Beddies
Sabine Becker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Priority to AU2003289876A priority Critical patent/AU2003289876A1/en
Publication of WO2004047795A2 publication Critical patent/WO2004047795A2/fr
Publication of WO2004047795A3 publication Critical patent/WO2004047795A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the invention relates to a system for dermal application of flupirtine and its salts to humans and animals.
  • Flupirtin (CAS name 2-Amino-6 - [[(4-fluorophenyl) methyl] amino] -3-pyridinyl] - carbamic acid ethyl ester) is a centrally effective, moderately potent analgesic which is used in human medicine in the form of capsules and suppositories and an injection solution is used. Its representation and application is described in US 3,513,171 and
  • US 4,481,205 (flupirtine maleate).
  • the usual dosage is 4 - 8 mg / day and kg body weight (body weight) for oral, 6 - 12 mg / day and kg body weight for rectal and 1.5 mg / kg body weight for parenteral administration.
  • the dosage in veterinary medicine differs depending on the species. The therapeutic efficacy after dermal application has not yet been described.
  • Dermestril ® among others fentanyl (Durogesic ® ), levonorgestrel (Fem7 ® Combi), nicotine (Nicotinell ® among others), norethisterone acetate (Estracomb ® among others), scopolamine (Scopoderm ® TTS) and testosterone (Androderm ® ) administered as transdermal patches.
  • Good Permeationsseigenschaften also have substances with low molecular weight, such as nitroglycerin (Nitroderm ® TTS, Deponit ® NT etc.) or pronounced lipophilicity. An increase in the pavement area and thus less applicability Effective substances in humans are not readily possible for cosmetic reasons.
  • systemic active substances In veterinary medicine, the dermal application of systemic active substances is easier because one is not bound to the limited area of a plaster, but in principle the entire body surface is available for application when a suitable formulation is given.
  • systemic active ingredients can only be used here if they are effective in low doses or if they permeate the skin very well. In addition, they should be ecotoxicologically safe.
  • lipophilic drugs examples include the endoparasiticidal avermectins, such as ivermectin (Ivomec ® ), Doramectin (Dectomax ® ), Eprinomectin (Eprinex ® ) and Selamectin (Stronghold ® ) and the structurally related moxidectin (Cydectin ® ).
  • Praziquantel (Droncit ® ) due to its pronounced lipophilicity and Levamisol (Citarin ® ) due to its low molecular weight (MG 204) are also easy to get through in cats. Therefore, the dermal application of systemic drugs in both human and veterinary medicine has so far been largely limited to highly effective, lipophilic substances or those with a small molecular size.
  • Dermal application of an active pharmaceutical ingredient has numerous advantages over oral or parenteral administration: it is very easy and painless to use and can also be used if you have difficulty swallowing (e.g. after surgery). The slow flooding in the body prevents side effects caused by concentration peaks. Since an active ingredient depot forms in the skin, in the skin appendages or in the formulation itself, this has to be done
  • Dermal application is particularly desirable in the case of chronic pain conditions, since therapy has to be carried out for a very long time.
  • Flupirtin and its salts are particularly well suited for the treatment of chronic musculoskeletal pain due to their additional muscle-relaxing effects.
  • the substance is neither effective in low doses, nor is it pronouncedly lipophilic.
  • Their molecular weight of 304.3 does not suggest a good skin penneation either.
  • flupirtine and its salts in a suitable formulation, have an extraordinarily high permeation rate through dog and cat skin.
  • the invention relates to a preparation of flupirtine or its salts, which is intended for dermal application.
  • the invention relates to:
  • the medicine can be liquid, semi-solid or solid. It can also be in the form of a patch. It is possible to achieve sufficient systemic active ingredient levels with medicaments according to the invention for an effect. According to a preferred Ausföhiungsfo ⁇ ri, the invention therefore relates to drugs for dermal systemic application of flupirtine and its salts.
  • the medicament according to the invention usually contains the flupirtine or its salt in an amount of 0.1-25% m / V, preferably 0.5-10% m / N (for example, 1 g of flupirtine or flupirtine salt corresponds to a content of 1 per 100 ml of medicament % m / V). All pharmaceutically acceptable salts are suitable as salts, flupirtine maleate being mentioned as a preferred example.
  • the flupirtine or its salt is present in the carrier in dissolved or suspended form.
  • Suitable carriers are, for example, 2-pyrrolidone, N-methylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, monohydric alcohols (for example short-chain alkanols with 1 to 5 carbon atoms such as ethanol, isopropanol and solketal, glycerol formal, tetrahydrofuryl alcohol, benzyl alcohol, octyldodecanol, 2-hexyldodecanol, polyhydric alcohols (e.g. glycerol, propylene glycol, polyethylene glycol), ethers (e.g. glycofurol, dicaprylyl ether), glycol ethers (e.g.
  • oleyl oleate 2-octyldodyloethylolate, octyldateyloethyl, cetylateoateolate, cetylateoateolate, cetylateoateolate, octylateatolate, cetylate, cetylate, cetylate, cetylate, Octyl palmitate), hydrocarbons (e.g. Paraffins), silicone oils, dimethicone and water or mixtures of the substances mentioned.
  • hydrocarbons e.g. Paraffins
  • silicone oils dimethicone and water or mixtures of the substances mentioned.
  • the medicament according to the invention usually contains at least 40% w / v, preferably at least 75% w / v on carrier.
  • Preferred carrier systems are mixtures of medium chain triglycerides or medium-propylene glycol fatty acid ester (as in various grades. E.g., under the trade name Miglyol ® are available) and monohydric alcohols, particularly alkanols having from 1 to 5 carbon atoms. In these carrier systems the two mixture components are usually present in a ratio of 1: 9 to 9: 1, preferably 2: 8 to 8: 2.
  • the active ingredient can be applied to the skin in liquid, semi-solid or solid form.
  • Liquid preparations are, for example, solutions, suspensions and
  • Emulsions. Semi-solid preparations are e.g. Gels, creams, ointments and pastes, solid preparations e.g. Powder.
  • the active ingredient can also be applied in the form of a patch.
  • a suitable carrier filled into a reservoir and this is fixed on the skin with the aid of an adhesive layer.
  • the reservoir can consist of a plastic bag, for example of polyethylene, polyethylene vinyl acetate or polyurethane.
  • Active ingredient and the adhesive also contain other auxiliaries, such as penetration-improving or solubility-improving additives, antioxidants, additives modifying the adhesive property or crystallization inhibitors. Active substances and adhesives can also be separated from one another in the form of a two-layer or multilayer matrix patch.
  • auxiliaries such as penetration-improving or solubility-improving additives, antioxidants, additives modifying the adhesive property or crystallization inhibitors.
  • Active substances and adhesives can also be separated from one another in the form of a two-layer or multilayer matrix patch.
  • Polymethyl methacrylates, silicones or polyolefins e.g. polyisobutylene
  • silicones or polyolefins e.g. polyisobutylene
  • liquid formulations e.g. as a spot-on, pour-on or spray.
  • the pharmaceutical forms mentioned are applied to the fur or skin of the animal.
  • a spray brings the liquid containing the active ingredient to the skin or fur in finely divided form.
  • the preparation can spread over the surface of the skin after application and the active ingredient can enter the body through the skin.
  • the medicaments according to the invention can contain further customary, pharmaceutically acceptable additives and auxiliaries.
  • additives and auxiliaries include:
  • Penetration accelerators such as fatty acids (e.g. oleic acid, linoleic acid),
  • Fatty acid esters e.g. isopropyl myristate, ethyl oleate
  • fatty alcohol esters e.g. octyldodecanol
  • ethers e.g. diethylene glycol monoethyl ether (Transcutol ® )
  • terpenes limonene, .. eucalyptoi
  • laurocapram Alurocapram
  • Preservatives such as carboxylic acids (sorbic acid, benzoic acid, lactic acid), phenols (cresols, p-hydroxybenzoic acid esters such as methylparaben, propylparaben etc.), aliphatic alcohols (benzyl alcohol, butanol etc.), quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride)
  • Antioxidants such as, for example, sulfites (Na sulfite, Na metabisulfite), organic sulfides (cystine, cysteine, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols (tocopherols, butylhydroxyanisole, butyl-hydroxy-toluene, octylgallat and dodec) , organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid) and their salts and esters Wetting agents such as, for example, fatty acid salts, fatty alkyl sulfates, fatty alkyl sulfonates, linear alkylbenzenesulfonates, fatty alkyl polyethylene glycol ether sulfates, fatty alkyl polyethylene glycol ethers, alkylphenol polyethylene glycol ethers, alkyl polyglycosides
  • Crystallization inhibitors such as cellulose ethers (e.g. methyl cellulose, hydroxyethyl cellulose, Na-carboxymethyl cellulose, hydroxypropyl cellulose, methyl hydroxypropyl cellulose, ethyl cellulose), polyvinyl pyrrolidone, sugar (e.g. glucose, sucrose, fructose), sugar alcohols (e.g. sorbitol, mannitol, xylitol), polyethylene
  • Additives that increase the viscosity such as cellulose ethers, polyacrylates, polymethacrylates, polymethane methacrylates, polysaccharides (e.g. xanthan, guar, gum arabic, tragacanth), highly disperse silicon dioxide, aluminum stearate
  • the pharmaceuticals according to the invention can be produced by dissolving or suspending the active ingredient and, if appropriate, further auxiliaries in the carrier.
  • Figure 1 In vitro permeation of flupirtine from saturated solutions through dog skin, Franz diffusion cell, diffusion area 1, 77 cm 2 .
  • Figure 3 Plasma level of flupirtine after application of 4 ml of a 1.5% solution of flupirtine base in Miglyol 840 / isopropanol (1: 1)
  • Dog skin is described below in the biological example.
  • flupirtine base 0.75 g of flupirtine base were dissolved in about 40 g of a mixture of Propylenglykoldicapry- lat / dicaprate (Miglyol ® 840, 50% m / m) and isopropanol (50% m / m) dissolved.
  • the mixture was made up to 50 ml with the solvent mixture in the volumetric flask and filled into 4 ml HDPE pipettes (1.5% m / N flupirtine base).
  • Flupirtin maleate are added. After adjusting the solution to pH 6 with 2.35 g of 2N NaOH solution, the active ingredient (3.0% m / V flupirtine maleate) is dissolved.
  • flupirtine maleate 3.0 g of flupirtine maleate are suspended in 92.2 g of medium-chain triglycerides (for example Miglyol ® 812) and homogenized with a rotor stator (for example Ultra-Turrax) (3.0% -m / N fiupirtine maleate).
  • medium-chain triglycerides for example Miglyol ® 812
  • a rotor stator for example Ultra-Turrax
  • Figure 1 shows the ner run of in vitro permeation through dog skin after application of saturated solutions
  • Figure 2 shows the ner run of in vitro permeation through cat skin after application of saturated solutions.
  • Table 1 shows the amount of active ingredient permeating in steady-state (48 - 72 h) per time and area (flux).
  • Table 1 Amount of flupirtine which permeates through dog and cat skin in steady-state (48-72 h) per time and area in vitro
  • the bioavailability of the preparation according to Examples 9-11 was checked on 4 cats each.
  • the contents of a pipette (Example 9) or an amount corresponding to 10 mg / kg body weight of active ingredient (Examples 10 and 11) were distributed evenly along the back line.
  • Blood samples were taken after 0 - 0.5 - 1 - 2 - 4 - 6 - 10 - 24 - 30 and 48 h and examined for the concentration of flupirtine.
  • the determined blood level curve of the active ingredient is shown in Figure 3.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Zoology (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un médicament pour l'application cutanée de flupirtine ou de ses sels.
PCT/EP2003/012875 2002-11-28 2003-11-18 Application cutanee de flupirtine Ceased WO2004047795A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003289876A AU2003289876A1 (en) 2002-11-28 2003-11-18 Cutaneous application of flupirtine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10255415A DE10255415A1 (de) 2002-11-28 2002-11-28 Dermale Applikation von Flupirtin
DE10255415.3 2002-11-28

Publications (2)

Publication Number Publication Date
WO2004047795A2 true WO2004047795A2 (fr) 2004-06-10
WO2004047795A3 WO2004047795A3 (fr) 2004-09-10

Family

ID=32308774

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/012875 Ceased WO2004047795A2 (fr) 2002-11-28 2003-11-18 Application cutanee de flupirtine

Country Status (3)

Country Link
AU (1) AU2003289876A1 (fr)
DE (1) DE10255415A1 (fr)
WO (1) WO2004047795A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065713A3 (fr) * 2004-01-10 2006-05-11 Bayer Healthcare Ag Medicament destine a etre administre a des animaux par voie topique
WO2009012908A3 (fr) * 2007-07-26 2009-06-11 Bayer Animal Health Gmbh Médicaments pour l'administration transdermique à des animaux

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3601195A1 (de) * 1985-01-23 1986-07-24 Degussa Ag, 6000 Frankfurt Synergistische kombination von flupirtin und nicht-steroidalen antiphlogistika
IN172468B (fr) * 1990-07-14 1993-08-14 Asta Medica Ag

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065713A3 (fr) * 2004-01-10 2006-05-11 Bayer Healthcare Ag Medicament destine a etre administre a des animaux par voie topique
AU2005203884B2 (en) * 2004-01-10 2011-04-14 Bayer Intellectual Property Gmbh Topically applied medicament for animals
WO2009012908A3 (fr) * 2007-07-26 2009-06-11 Bayer Animal Health Gmbh Médicaments pour l'administration transdermique à des animaux

Also Published As

Publication number Publication date
WO2004047795A3 (fr) 2004-09-10
DE10255415A1 (de) 2004-06-09
AU2003289876A8 (en) 2004-06-18
AU2003289876A1 (en) 2004-06-18

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