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WO2006032624A1 - Composition pharmaceutique a administration transdermique - Google Patents

Composition pharmaceutique a administration transdermique Download PDF

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Publication number
WO2006032624A1
WO2006032624A1 PCT/EP2005/054575 EP2005054575W WO2006032624A1 WO 2006032624 A1 WO2006032624 A1 WO 2006032624A1 EP 2005054575 W EP2005054575 W EP 2005054575W WO 2006032624 A1 WO2006032624 A1 WO 2006032624A1
Authority
WO
WIPO (PCT)
Prior art keywords
approximately
amount
alprazolam
pharmaceutical composition
permeation
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/EP2005/054575
Other languages
English (en)
Inventor
Isabel REIG LÓPEZ
Antonio de Padua BOIX MONTAÑÉS
Luís SOLER RANZANI
Carlos Nieto Abad
José DOMENECH BERROZPE
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.)
Laboratorio Reig Jofre SA
Original Assignee
Laboratorio Reig Jofre SA
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 Laboratorio Reig Jofre SA filed Critical Laboratorio Reig Jofre SA
Publication of WO2006032624A1 publication Critical patent/WO2006032624A1/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
    • A61K9/70—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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • composition for transdermal administration is provided.
  • This invention is related to the field of the human medicine and, specifically, with formulations of transdermal administration of medicaments which include mixtures of various percutaneous absorption promoter agents of said drugs. Particularly, it is referred to the transdermal administration of alprazolam using cutaneous permeation promoters.
  • Alprazolam is the common international denomination (International Nonproprietary Name (INN)) of
  • This compound is a benzodiazepinic anxiolytic of short action, which acts increasing the activity of the gamma-aminobutyric acid (GABA) facilitating its coupling with the GABA-aergic receptor. It has hypnotic, anticonvulsive, sedative, muscular relaxing and amnesic activity, with specific activity at the crises of anguish, furthermore it has anti-depressive activity.
  • Alprazolam can be used in the treatment of anxiety, panic, schizophrenia, anxiety associated to depression, furthermore in the treatment of other psychiatric diseases, in fertility problems and for the treatment of Crohn's disease.
  • Alprazolam is a triazolobenzodiazepine with moderated lipophilia. Its octanol/water partition coefficient, expressed as logarithm (logP), ranges from 1.72 to 2.12. In the human being, the therapeutic plasmatic concentrations range from 5 to 50 ng/ml, depending on the treated indication. To reach these therapeutic levels by a transdermal administration, values of permeation flow through the skin between 0.25 and 5.50 ⁇ g.cm 2 /h are needed. In the Patent Application WO 93/03694 flow values from 1 ⁇ g.cm 2 /h are indicated to provide therapeutically effective amounts of alprazolam. These permeation flows depend on the surface of the formulation and the permeation promoters used.
  • transdermal administration of certain drugs allows to improve their pharmacokinetic profile, thus their clinic efficiency.
  • some formulations for topical application facilitate a controlled liberation of the medicaments, which allows to assure their posology for a long period of time and, thus, to assure the fulfillment of the prescription by the patient.
  • Alprazolam is a drug which has characteristics that make it ideal for transdermal administration, as its reduced daily dose, the clinical need of use it in long treatments and the pharmacokinetic requirement of be administered in some daily intakes which currently requires the oral administration.
  • a permeation promoter or a combination of them should have the capacity to raise the permeability of the skin for the drug, and it should neither be toxic nor irritant at the used concentration.
  • the behavior of the permeation promoter depends on the drug which has to penetrate and on the transdermal device used. Nevertheless, it cannot be a priori known which promoters will be the most adequate to improve the transdermal flow of a certain drug. In fact an effective promoter or an effective combination of promoters for a certain drug can be not effective with other drugs.
  • a lot of potential promoters interact adversely with other components of the administering device, being the incompatibility with medically acceptable contact adhesives or other components of the device one of the main problems. This incompatibility can provoke failures in the adherence of the adhesives.
  • alprazolam in an adhesive matrix which includes C6-C16 aliphatic promoters, being fatty acids or alcohols, saturated molecules and/or monounsaturated.
  • composition useful to be formulated as a device of transdermal administration of alprazolam which have an enough permeation speed to reach therapeutic plasmatic concentrations, an acceptable tolerability and a satisfactory adhesive ability over the skin.
  • the inventors have surprisingly found that the combination of alprazolam, together with the following permeation promoters: 1-decyl alcohol, diethylene glycol monoethyl ether, 1-dodecylhexahydro-2-N-azepin-2-one and polyethylene glycol mono-oleyl ether, has an improved capacity of permeation and tolerability with regard to other known formulations, due to an unexpected synergic effect.
  • a pharmaceutical composition for transdermal administration which comprises a therapeutically safe and effective amount of alprazolam, a pharmacological acceptable combination of 1-decyl alcohol, diethylene glycol monoethyl ether, polyethylene glycol mono-oleyl ether and 1-dodecylhexahydro-2-N-azepin-2-one as permeation promoters, optionally with suitable amounts of pharmaceutically acceptable excipients, dispersed in a suitable polymeric support to constitute a transdermal formulation.
  • alprazolam is comprised in an amount between approximately 0.5% w/w and approximately 15% w/w;the 1-decyl alcohol in an amount between approximately 0.5% w/w and approximately 15% w/w;the diethylene glycol monoethyl ether in an amount between approximately 0.5% w/w and approximately 15% w/w; the polyethylene glycol mono-oleyl ether in an amount between approximately 0.05% w/w and approximately 2% w/w; and the 1-dodecylhexahydro-2-N-azepin-2-one in an amount between approximately 0.5% w/w and approximately 15% w/w.
  • the alprazolam is comprised in an amount between approximately 2% w/w and approximately 10% w/w; the 1-decyl alcohol in an amount between approximately 2% w/w and approximately 10% w/w; the diethylene glycol monoethyl ether in an amount between approximately 2% w/w and approximately 10% w/w; the polyethylene glycol mono-oleyl ether in an amount between approximately 0.5% w/w and approximately 1.5% w/w; and the 1-dodecylhexahydro-2-N-azepin-2-one in an amount between approximately 2% w/w and approximately 10% w/w.
  • the most preferred embodiment comprises the following components in the w/w percentages: alprazolam in an amount of approximately 5% w/w; the 1-decyl alcohol in an amount of approximately 7% w/w; the diethylene glycol monoethyl ether in an amount of approximately 7% w/w; the polyethylene glycol mono-oleyl ether in an amount of approximately 1% w/w; and the 1 -dodecylhexahydro-2-N-azepin-2-one in an amount of approximately 5% w/w.
  • the pharmaceutical composition comprises also suitable amounts of pharmaceutically acceptable excipients to constitute a topical formulation.
  • the composition can comprise different types of excipients: spreading agents, agents which rises the viscosity, or solubilizers among others.
  • other components can be added to the compositions of this invention in suitable amounts to improve its pharmaceutical acceptability, as will be obvious to a person skilled in the art.
  • the 1-dodecylhexahydro-2-N-azepin-2-one also known as laurocapram, of formula (III), acts fluidizing the structure of the lipids of the intercellular channels.
  • the polyethylene glycol mono-oleyl ether, Brij 96V, of formula (IV), is a non-ionic surfactant which acts at level of the corneal stratum interacting at the level of the lipids of the membrane and, thus facilitating its permeability.
  • 1-decyl alcohol, of formula (V) is a long chain alkanol used because to its activity as absorption promoter seems to be related to the capacity for inserting itself among the membrane structured lipids and act as a plastifying agent thus increasing its permeability.
  • the combination at the suitable proportions said before of the permeation promoters together with alprazolam shows an improved capacity of permeation, due to a synergic effect of their properties.
  • a device for the transdermal administration of alprazolam which comprises a container of polymeric matrix or adhesive base which comprises a therapeutically safe and effective amount of the composition of the invention; and means to maintain the reservoir in contact with the skin.
  • the device is a patch of adhesive base which contain the components of the previously defined composition dispersed in the adhesive.
  • the device allows a permeation flow of alprazolam through the skin of at least 0.5 ⁇ g/cm 2 h for a long period of time.
  • a third aspect of the invention relates to the use of the previously disclosed composition for the manufacture of a medicament for the treatment of psychiatric dysfunctions, fertility and/or Crohn's disease.
  • the psychiatric dysfunction is selected from the group consisting of anxiety, panic, schizophrenia and anxiety associated to the depression.
  • the psychiatric dysfunction is anxiety associated to depression.
  • Another aspect of the present invention is also related to a treatment method of a human that suffer a psychiatric dysfunction, fertility or Crohn's disease.
  • This method comprises the administration to said patient, of a composition which comprises alprazolam, 1-decyl alcohol, diethylene glycol monoethyl ether, 1-dodecylhexahydro-2-N-azepin-2-one and polyethylene glycol mono-oleyl ether.
  • the administration is performed by a device which comprises a container of polymeric matrix or adhesive base which comprises a therapeutically safe and effective of the composition of the invention; and means to maintain the reservoir in contact with the skin.
  • FIG.1 is a comparison of average profiles of in vitro permeation for the formulation 9 from the Table 4 (squares) and the profile of basal permeation of the drug (triangles).
  • the objective of this study is to determinate the basal capacity of the medicament drug to diffuse by its own through the skin from an aqueous solution at physiologic pH.
  • Human abdominal skin was used as membrane of permeation. This skin was frozen at -20 0 C and previously to its use it was defrosted and cut to a thickness of 250 ⁇ m which includes the epidermal corneal stratum, which is the limiting histological layer of the permeation. This membrane was placed in the diffusion cells by a fixative system.
  • the donating solution was an aqueous solution saturated with alprazolam.
  • the receiving solution used consisted in a regulating solution of phosphates pH 7.0, diethylene glycol monoethyl ether and ethanol in a proportion of 80/15/5. The study was performed at a constant temperature of 32 0 C by a circuit which thermostatize the shirts of the diffusion cells.
  • Example 2 Synergic effect of the transdermal permeation promoters of the present invention.
  • compositions with 5% of alprazolam were prepared with different combinations of the promoters cited in Table 2.
  • Example 3 Synergic effect of the incorporation of a tensioactive to formulation 6 of Example 1
  • alprazolam for a final concentration of 5% was solved in a 1 :1 proportion ethanol-dichloromethane binary solvent by magnetic stirring for about 10 minutes.
  • appropriate amounts of 1-decyl alcohol, laurocapram, transcutol and polyethileneglycol mono-oleil ether for example, Brij 96V were incorporated to finally get concentrations of 7%, 5%, 7% y 1% respectively, and it was stirred for 10 minutes since the solution of every component.
  • an acrylate-vynil acetate base Durotack 87-2051 and Durotack 87-2196 were added in the enough amounts, in a proportion of 70/30, to complete the 100% of the final composition, it was stirred for about 15 minutes until a completely homogeneous and transparent dispersion was observed. Lately, the resulting solution was spread over a polyester-covered plate sheet (Scotchpak 1022, 3M) and it was laminated to 250 ⁇ m of thickness and the solvents were evaporated at 60 0 C of temperature for 30 minutes, all of this performed by a discontinuous laminating oven (Labcoater, Mathis AG). Finally, it was completed placing a polyester plate sheet (Scotchpack 1109, 3M).
  • Example 4 Study of potential tolerabilitv of the assayed formulations.
  • formulation 9 contain a surfactant at its composition, and surfactants are substances widely described in scientific bibliography as potential irritants (Kydonieus AF, WiIIe JJ. Biochemical Modulation of skin reactions. CRC Press, Washington 2000).

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

Abstract

Composition pharmaceutique à administration transdermique d'alprazolam avec différents promoteurs de perméation, et dispositif pour son administration transdermique sous forme de patch ou de réservoir. La composition présente une capacité de perméation et une tolérabilité à la perméation améliorées en raison d'un effet synergique insoupçonné. Son utilisation dans le traitement de dysfonctionnements psychiatriques, de troubles de la fertilité et/ou de la maladie de Crohn font également l'objet de cette invention.
PCT/EP2005/054575 2004-09-23 2005-09-14 Composition pharmaceutique a administration transdermique Ceased WO2006032624A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200402326A ES2265239B1 (es) 2004-09-23 2004-09-23 Composicion farmaceutica para administracion transdermica.
ESP200402326 2004-09-23

Publications (1)

Publication Number Publication Date
WO2006032624A1 true WO2006032624A1 (fr) 2006-03-30

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ID=35515708

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Application Number Title Priority Date Filing Date
PCT/EP2005/054575 Ceased WO2006032624A1 (fr) 2004-09-23 2005-09-14 Composition pharmaceutique a administration transdermique

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ES (1) ES2265239B1 (fr)
WO (1) WO2006032624A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021262A1 (fr) * 1993-03-17 1994-09-29 Alza Corporation Dispositif d'administration transdermique d'alprazolam
EP0913158A1 (fr) * 1997-09-17 1999-05-06 Permatec Technologie Ag Patch transdermal comprenant une combinaison de deux ou plus de deux acides ou alcools gras comme agents favorisant la pénétration cutanée
EP1323431A2 (fr) * 2000-08-03 2003-07-02 Antares Pharma IPL AG Composition pour l' administration percutanée et/ou par voie transmucosale de pricipes actifs assurant des niveaux d' efficacité thérapeutiques adéquats
WO2005039531A1 (fr) * 2003-10-10 2005-05-06 Antares Pharma Ipl Ag Formulation pharmaceutique transdermique visant a reduire les residus sur la peau

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021262A1 (fr) * 1993-03-17 1994-09-29 Alza Corporation Dispositif d'administration transdermique d'alprazolam
EP0913158A1 (fr) * 1997-09-17 1999-05-06 Permatec Technologie Ag Patch transdermal comprenant une combinaison de deux ou plus de deux acides ou alcools gras comme agents favorisant la pénétration cutanée
EP1323431A2 (fr) * 2000-08-03 2003-07-02 Antares Pharma IPL AG Composition pour l' administration percutanée et/ou par voie transmucosale de pricipes actifs assurant des niveaux d' efficacité thérapeutiques adéquats
WO2005039531A1 (fr) * 2003-10-10 2005-05-06 Antares Pharma Ipl Ag Formulation pharmaceutique transdermique visant a reduire les residus sur la peau

Also Published As

Publication number Publication date
ES2265239A1 (es) 2007-02-01
ES2265239B1 (es) 2008-02-01

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