EP2395971A2 - Promédicaments du type amidines, guanidines et/ou aminohydrazones n-hydroxylées pour une application cutanée - Google Patents

Promédicaments du type amidines, guanidines et/ou aminohydrazones n-hydroxylées pour une application cutanée

Info

Publication number
EP2395971A2
EP2395971A2 EP10707206A EP10707206A EP2395971A2 EP 2395971 A2 EP2395971 A2 EP 2395971A2 EP 10707206 A EP10707206 A EP 10707206A EP 10707206 A EP10707206 A EP 10707206A EP 2395971 A2 EP2395971 A2 EP 2395971A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
prodrug
group
skin
aminohydrazone
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.)
Withdrawn
Application number
EP10707206A
Other languages
German (de)
English (en)
Inventor
Rudolf Matusch
Hans-Rainer Hofmann
Bodo Asmussen
Andreas Koch
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.)
LTS Lohmann Therapie Systeme AG
Original Assignee
LTS Lohmann Therapie Systeme 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 LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Publication of EP2395971A2 publication Critical patent/EP2395971A2/fr
Withdrawn legal-status Critical Current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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the invention relates to N-hydroxylated amidines, guanidines and aminohydrazones for administration via the skin.
  • the invention relates to transdermal therapeutic systems containing N-hydroxylated amidines, guanidines and aminohydrazones as prodrug, as well as to methods of making such systems.
  • Drugs of the type of amidines eg pentamidine as the gold standard for the treatment of Pneumocyctis carinii pneumonia in AIDS patients
  • guanidines eg debrisoquine
  • aminohydrazones eg guanabenz for the treatment of hypertension
  • TTSs transdermal therapeutic systems
  • N-hydroxylated derivatives for guanidines such.
  • B. Guanoxabenz are also already known, without evidence of use as prodrugs for transdermal application.
  • WO 97/23499 describes amidoximes of certain thrombin inhibitors. Oral and parenteral applications are common among others Application types mentioned.
  • Transdermal Therapeutic Systems have been known and launched in the industry for a number of years.
  • Transdermal therapeutic systems are skin-applied, self-adhesive galenic preparations with a fixed application area, which deliver a drug in time and quantity controlled to the human or animal body.
  • the therapeutic advancement of these systems over traditional forms of application is that the active ingredient is not supplied to the body intermittently, such as when taking tablets, but continuously.
  • layered, flat shapes are usually formed using various polymers, e.g. For example, polyethylene terephthalate, polyisobutylene or polysiloxane used.
  • the abovementioned active substances of the amidines, guanidines and aminohydrazones type are unfortunately not suitable for use as TTSs due to their high basicity, since they would inevitably lead to massive and severe skin irritations (comparable to caustic soda burns) and thus to acceptance close by the patient.
  • the object of the present invention was accordingly to supply amidines, guanidines and aminohydrazones in a suitable manner to a transdermal application.
  • This object is achieved by a system for the transdermal administration of active substances, comprising at least one compound which has at least one derivatized amidine, guanidine or aminohydrazone group of the following general formula Ia-c:
  • the information in parentheses indicates the type of compound resulting from the derivatization.
  • R 1 is a radical of the formula II (II) .
  • R is -R 4 or -A 1 C (O) N (R 5 ) R 6 or -A 1 C (O) OR 5 ;
  • a 1 is C r C 5 alkylene;
  • R 4 is H, C 1 -C 10 -alkyl or C r C 3 -alkylphenyl (where the last-mentioned group is unsubstituted or substituted by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, -NO 2 or Cl, Br or J);
  • R 5 and R 6 independently of one another are H, C r C 6 alkyl, phenyl or 2-naphthyl or, when R -A 1 C (O) N (R 5 ) R 6 , together with the nitrogen atom to which they are attached are pyrrolidinyl or piperidinyl.
  • n benzyl
  • Bu butyl
  • Ch cyclohexyl
  • Et ethyl
  • Me methyl
  • Men (1R, 2S, 5R) -menthyl
  • Pr propyl
  • PrI N-pyrrolidinyl.
  • n, s, i and t have their usual meaning: normal, iso, secondary and tertiary.
  • N-hydroxylation and possible further derivatization of the N-hydroxyl group to the corresponding amidoxime esters or 1,2,4-oxadiazoles the pk s values can be lowered below 5.
  • these compounds are now at physiological pH values mainly unprotonated and thus lipophilic, so that lipid membranes can be easily passed again. This simultaneously increases the bioavailability and thus the degree of pharmacological action.
  • these N-hydroxylated forms (amidoximes) are also suitable for use as TTSs, especially as the increased lipophilicity of the amidoximes surprisingly simultaneously increases the degree of skin irritation (see Example 1).
  • N-hydroxylation by endogenous enzymes such as esterases and N-reductases such as cytochrome P 450, cytochrome b5, NADH cytochrome b5 reductase or even NADH alone is reversible, represent the N-hydroxyl derivatives of the above-mentioned groups of substances suitable prodrugs, which are converted back into the active form in the body.
  • polymers such as rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic acid esters and their copolymers, polyurethanes copolymers of ethylene, polyisobutylene, polybutylene and polysiloxanes may be mentioned by way of example.
  • polymers are suitable which are essentially water-insoluble and do not exert any adverse effects on humans in direct and indirect contact with the skin.
  • the base material does not necessarily have to be primarily pressure-sensitively bonded, but this property is preferred for a particularly thin and flexible, non-applied system structure which would also enable a single-layer system.
  • Suitable auxiliaries for the prodrug-containing formulation are water-soluble or water-swellable polymers.
  • polyvinyl alcohol and its copolymers polyvinylpyrrolidone and its copolymers, polyethylene glycols, preferably having a molecular weight of over 1000 daltons (which are thus solid at room temperature).
  • the above polymers may be advantageous for the controlled dispersion of the prodrugs in the base material of partially cross-linked structures.
  • Other readily applicable polymers are alginates, pullulan, guar gum with gum arabic or other vegetable gums, cellulose, especially microcrystalline cellulose and its derivatives such.
  • methyl cellulose As methyl cellulose, hydroxyethyl cellulose, hydroxymethylpropyl cellulose, etc., but also other carbohydrates such. As starch, particularly preferably in derivatized or modified form.
  • peptidic polymers such as collagen and gelatin may also be considered.
  • Water-soluble and water-swellable polymers have the advantage that they do not suddenly become more ductile and diffusible when water is absorbed, and thus give off the enclosed prodrug (s) more uniformly. This is particularly useful in applications where the prodrugs are to be included gradually in the dispensing process.
  • water-soluble substances should be used advantageously as sole or mixed auxiliaries for the construction of the prodrug-containing formulation.
  • sugars and their derivatives come into consideration, primarily sucrose, glucose, lactose, fructose, but also sugar alcohols, such as sorbitol or mannitol.
  • all pharmaceutically compatible water-soluble substances which have the property of liquefying under a water vapor tension of about 98 percent relative humidity (as provided by the skin), such as.
  • common salt, urea, malic acid, citric acid for example, common salt, urea, malic acid, citric acid.
  • additives to achieve known in the art further functionalities such.
  • stabilizers especially antioxidants
  • fillers but also micellar modifiers (lecithins) can be provided according to the respective requirement.
  • essential prodrug-containing base material that can form a complete TTS system in the simplest case together with a backing layer, are more system components that are known to the art, with the inventive principle can be reasonably combined.
  • the TTS according to the invention preferably in the form of a trandermal patch, may in principle be constructed as known from the prior art systems.
  • polymer-containing layers or membranes which may have a pro-drug inflow to the skin controlling property or moderate the too rapid absorption of moisture from the skin.
  • materials for such membranes are polyethylene, polyamide, ethylene-vinyl acetate copolymers, but also filled with low molecular weight porous layers common and known in the art.
  • the essential auxiliaries are already mentioned above in the explanation of the base materials.
  • highly diffusible lipophilic polymers such.
  • polysiloxanes and acrylate copolymers As polysiloxanes and acrylate copolymers.
  • the inventive principle can also be combined with other methods of absorption enhancement.
  • penetration enhancers can be added which increase the permeability of the skin and use physical principles such as iontophoresis, electroporation or even ultrasound and microneedles.
  • the backing layer of transdermal systems for the purpose of the invention may, for. B. in a water vapor-occlusive-acting polyester (polyethylene terephthalate) membrane, which protects against both prodrug loss and moisture loss.
  • a water vapor-occlusive-acting polyester polyethylene terephthalate
  • a moderation of the water vapor loss can take place.
  • the production of the systems according to the invention itself is possible in manifold ways. Particularly emphasized and preferred, but ultimately exemplary are the following possibilities, which relate in particular to the production of the prodrug reservoir according to the invention (base material with prodrug-containing formulation).
  • the construction / production of the TTS according to the invention can be carried out as described according to the methods known to the person skilled in the art (see, for example, "Dermatological Formulation and Transdermal Systems", Kenneth A Walters and Keith R. Brain in Dermatological and Transdermal Formulations, NY 2002, Marcel Dekker, pages 319-399).
  • the active ingredient precursor can be supplied to a solution or suspension of the base material produced in organic solution or even free of solvent (hot melt rapid process), whereupon, after subsequent coating on the backing layer and drying of the layer, a product which is already functional after punching is obtained.
  • the prodrug reservoir base material and prodrug formulation
  • Benzamidoxime is according to Tiemann and Kruger (Tiemann, F., Chem. Berichte 17, 126
  • Acceptance medium Phosphate buffer pH 5.5 + 0.1% NaN 3 according to DAB 10
  • Active substance Benzamidine, Benzamidoxime (from Ex. 1)
  • Vehicle suspension in olive oil (2% by weight, 50 mg suspension per cell) applied to a circular nonwoven disc made of viscose staple fiber
  • Figure 1 shows the permeated amounts of benzamidine or benzamidoxime in comparison, the advantage of Benzamidoxims is clearly visible.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des amidines, guanidines et aminohydrazones N-hydroxylées pour une application cutanée. En particulier, l'invention porte sur des systèmes thérapeutiques transdermiques qui contiennent des amidines, guanidines et aminohydrazones N-hydroxylées, ainsi que sur des procédés pour la fabrication et l'utilisation de tels systèmes.
EP10707206A 2009-02-10 2010-02-05 Promédicaments du type amidines, guanidines et/ou aminohydrazones n-hydroxylées pour une application cutanée Withdrawn EP2395971A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009008256A DE102009008256A1 (de) 2009-02-10 2009-02-10 Prodrugs vom Typ N-hydroxylierter Amidine, Guanidine und/oder Aminohydrazone zur Applikation über die Haut
PCT/EP2010/000715 WO2010091822A2 (fr) 2009-02-10 2010-02-05 Promédicaments du type amidines, guanidines et/ou aminohydrazones n-hydroxylées pour une application cutanée

Publications (1)

Publication Number Publication Date
EP2395971A2 true EP2395971A2 (fr) 2011-12-21

Family

ID=42173971

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10707206A Withdrawn EP2395971A2 (fr) 2009-02-10 2010-02-05 Promédicaments du type amidines, guanidines et/ou aminohydrazones n-hydroxylées pour une application cutanée

Country Status (8)

Country Link
US (1) US20110311593A1 (fr)
EP (1) EP2395971A2 (fr)
JP (1) JP2012517404A (fr)
KR (1) KR20110120282A (fr)
CN (1) CN102497852A (fr)
BR (1) BRPI1008538A2 (fr)
DE (1) DE102009008256A1 (fr)
WO (1) WO2010091822A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011117128A1 (de) * 2011-10-28 2013-05-02 Christian-Albrechts-Universität Zu Kiel Verbindungen zur Therapie der Influenza
CN106361728B (zh) * 2015-07-22 2021-03-26 广东东阳光药业有限公司 经皮吸收制剂及制备经皮吸收制剂的方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5230897A (en) * 1991-10-31 1993-07-27 G. D. Searle & Co. Transdermal pentamidine
DE4321444A1 (de) 1993-06-28 1995-01-05 Bernd Prof Dr Clement Pharmazeutische Zubereitung
TWI238827B (en) 1995-12-21 2005-09-01 Astrazeneca Ab Prodrugs of thrombin inhibitors
GB9614098D0 (en) * 1996-07-05 1996-09-04 Orion Yhtymae Oy Transdermal delivery of levosimendan
US20020004065A1 (en) * 2000-01-20 2002-01-10 David Kanios Compositions and methods to effect the release profile in the transdermal administration of active agents
CA2449544A1 (fr) * 2001-06-08 2002-12-19 Cytovia, Inc. 3-aryl-5-aryl-[1,2,4]-oxadiazoles et leurs analogues, activateurs des caspases et inducteurs de l'apoptose, et leurs utilisations
WO2003043657A1 (fr) * 2001-11-19 2003-05-30 Control Delivery Systems, Inc. Administration topique de medicaments combines
US20030149406A1 (en) * 2002-02-07 2003-08-07 Lucie Martineau Multi-layer dressing as medical drug delivery system
CA2530407A1 (fr) * 2003-07-23 2005-02-03 The Regents Of The University Of California Combinaisons d'amplificateurs de penetration pour administration transdermique
MX2007004315A (es) * 2004-10-08 2008-03-11 Noven Pharma Dispositivo para suministro transdermico de farmaco que incluye un respaldo oclusivo.
DE102004062614B4 (de) * 2004-12-24 2011-12-29 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System mit aktivierbarer Übersättigung und kontrollierter Permeationförderung sowie Verfahren zu dessen Herstellung
GB0625648D0 (en) * 2006-12-21 2007-01-31 Glaxo Group Ltd Compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010091822A2 *

Also Published As

Publication number Publication date
CN102497852A (zh) 2012-06-13
WO2010091822A8 (fr) 2011-08-11
JP2012517404A (ja) 2012-08-02
WO2010091822A2 (fr) 2010-08-19
WO2010091822A3 (fr) 2011-10-13
DE102009008256A1 (de) 2010-08-12
KR20110120282A (ko) 2011-11-03
US20110311593A1 (en) 2011-12-22
BRPI1008538A2 (pt) 2016-03-15

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