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WO2006034902A1 - Compositions pharmaceutiques d'alpha-dihydroergocryptine pour application transdermique et/ou transmuqueuse - Google Patents

Compositions pharmaceutiques d'alpha-dihydroergocryptine pour application transdermique et/ou transmuqueuse Download PDF

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Publication number
WO2006034902A1
WO2006034902A1 PCT/EP2005/053630 EP2005053630W WO2006034902A1 WO 2006034902 A1 WO2006034902 A1 WO 2006034902A1 EP 2005053630 W EP2005053630 W EP 2005053630W WO 2006034902 A1 WO2006034902 A1 WO 2006034902A1
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WO
WIPO (PCT)
Prior art keywords
alpha
composition
composition according
extracts
melaleuca
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/EP2005/053630
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English (en)
Inventor
Daniela Monti
Luigi Saccomani
Marco Fabrizio Saettone
Patrizia Chetoni
Susi Burgalassi
Federico Mailland
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Polichem SA
Original Assignee
Polichem 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 Polichem SA filed Critical Polichem SA
Publication of WO2006034902A1 publication Critical patent/WO2006034902A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/7084—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention relates to novel pharmaceutical compositions of alpha- dihydroergocryptine, capable of allowing the absorption of the active ingredient through the patient's skin.
  • These formulations may be used in the form of transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations, vaginal preparations, for the treatment of diseases of the nervous system or of endocrine diseases.
  • Alpha-dihydroergocryptine, or dihydroergocryptine, or ergotaman-3',6',18-trione- 9, 10-dihydro- 12'-hydroxy-2'(l -methylethyl)-5 '-(2-methylpropyl)-(5 ⁇ ', 1 Oa), is a known compound derived by hydrogenation of the double bond in the 9,10 position of the natural alkaloid alpha-ergocryptine.
  • Alpha-dihydroergocryptine is a known prior art drug, and is used for the treatment of degenerative diseases of the central nervous system (US 4673681, EP 505608), with consequent disorders of cerebral neurotransmitters, or also of diseases of the endocrine system, connected with excessive secretion of hormones by the pituitary gland, with consequent modification of fertility in both men and women.
  • the drug In order to be effective, the drug must provide sufficient and enduring levels at the site of action in the brain or in the pituitary gland, and, since it has a half- life of the slow phase of approx. 10-15 hours in humans (Zanotti A., Proc. 2nd Eur. Winter Conference in Gynaecol.
  • alpha-dihydroergocryptine is intended for long-term use, for years or for the remainder of the patient's life. It has now surprisingly been discovered that when it is associated with lauric acid, or with essential oils of the Melaleuca or Tarchonanthus type, with terpenes such as eucalyptol, menthol, or with Tween 80, alpha-dihydroergocryptine is capable of passing through animal skin, and thus of being available to the systemic circulation and, ultimately, of being active when applied onto the patient's skin or mucous membranes.
  • the present invention accordingly provides pharmaceutical formulations of alpha- dihydroergocryptine for topical application, exhibiting high capability of the active ingredient to pass through skin and mucous membranes, which may readily be formulated in transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations and/or vaginal preparations, and which may readily be used in long-term treatment by patients suffering from degenerative diseases of the central nervous system, or of the pituitary gland, with consequent fertility impairment.
  • the object of the present invention is to provide a novel pharmaceutical composition
  • the invention furthermore relates to the use of this composition for topical application, capable of providing sufficient and effective systemic bioavailability, in the form of transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations or vaginal preparations.
  • the composition according to the present invention comprises alpha- dihydroergocryptine or a salt thereof as component a).
  • the salt of alpha- dihydroergocryptine is preferably the methanesulfonate salt (mesylate).
  • the quantity of component a) in the composition is between 0.01% and 50% by weight, more preferably between 0.1% and 10%, most preferably between 0.5% and 5%, relative to the total weight of the composition.
  • the composition furthermore contains as component b) at least one compound selected from among the following: dimethylsulfoxide (DMSO), low molecular weight solvents ( ⁇ 100 g/M); emollients, such as mineral oils, isopropyl myristate, isopropyl palmitate, vegetable oils; gelling agents, such as stearyl alcohol, polyvinyl alcohol; surfactants, such as lauric acid, sodium lauryl sulfate, glyceryl monooleate, polyoxyethylene sorbitan monooleate; emulsifiers, such as lanolin, oleic acid, sesame oil; plasticisers, such as acetyltributyl citrate; terpenes, such as menthol, d-limonene, limonene oxide, carveol, carvone, pulegone, 1,8-cineole, eucalyptol; keratolytics, such as salicic acid, urea
  • Particularly suitable compounds are those which do not have an irritant or sensitising action and which do not need to be carried in other substances with an irritant or sensitising action.
  • the quantity of component b) in the composition is between 0.1% and 50% by weight, more preferably between 1% and 30%, most preferably between 2.5% and 10% relative to the total weight of the composition.
  • composition according to the present invention may furthermore contain one or more compatible and pharmacologically acceptable excipients as additional components, and may furthermore contain other associated active ingredients with a complementary or at least useful activity.
  • Compatible and pharmacologically acceptable excipients may comprise aqueous or organic solvent and cosolvents, carriers capable of modifying the organoleptic properties of the product to make it pharmaceutically acceptable, together with stabilisers, preservatives, retarding agents, chelating agents, antioxidants, silicates, flavourings, humectants, emollients, lanolin derivatives and agents with antimicrobial activity.
  • Thermally thickening (thermosetting) agents and adhesives to allow effective and extended contact with the skin and mucous membranes may also be included.
  • composition according to the present invention may be prepared using the typical methods normally used for formulating liquid preparations, such as solutions, suspensions, lotions or foams, or for semisolid preparations, such as pomades, creams, gels and ointments, or for solid preparations, such as buccal tablets, transdermal systems, patches, vaginal tablets, pessaries, suppositories.
  • liquid preparations such as solutions, suspensions, lotions or foams, or for semisolid preparations, such as pomades, creams, gels and ointments, or for solid preparations, such as buccal tablets, transdermal systems, patches, vaginal tablets, pessaries, suppositories.
  • components a) and b) may be brought into contact with a solvent or with a mixture of solvents and other components either simultaneously or separately using standard mixing methods. No particular order of mixing of the components is required. It is preferable to stir in order to ensure complete dissolution or fine suspension of the components. If one or more ingredients are in solid form
  • components a) and b) may be mixed with acceptable excipients, such as solvents, emulsifiers, surfactants, thickeners and/or gelling agents, either simultaneously or separately by means of standard mixing methods.
  • acceptable excipients such as solvents, emulsifiers, surfactants, thickeners and/or gelling agents
  • components a) and b) may be mixed dry or wet with acceptable excipients, such as binders, diluents, disintegrants, lubricants and/or adhesives, either simultaneously or separately by means of standard mixing, granulation or compression methods.
  • components a) and b) may be mixed together with the adhesives and the other excipients by preparation of matrix systems, in which the drug is dispersed in the adhesive, or the drug is dispersed in a polymer, and the adhesive is applied subsequently.
  • components a) and b) may be prepared in liquid or semisolid preparations and applied to the systems and patches in special reservoirs.
  • composition according to the present invention is applied in liquid, semisolid or solid form to skin and/or mucous membranes, and contains a quantity of active ingredient, alpha-dihydroergocryptine, which is capable of releasing for one or more days, and is thus applied from once daily to once weekly.
  • the preferred component b) of the present invention exhibits a surprising effect of potentiating the transdermal or transmucosal absorption of alpha- dihydroergocryptine. This effect is particularly marked with lauric acid, essential oil of Melaleuca alternifolia, niaouli, eucalyptol, limonene, Tarchonanthus and/or polyoxyethylene sorbitan monooleate (preferably sold as Tween 80).
  • the composition of the present invention and its ability to pass through skin/membranes is illustrated, but not limited, by the following Examples. All quantities stated in percent are percentages of total weight. EXAMPLE 1
  • a solution with the following composition by weight was prepared: l. ethanol 89.0%
  • the formulation was prepared by means of a suitable container equipped with a stirrer. The ethanol and lauric acid were placed in the container until dissolution was complete. Once a clear solution had been obtained, the alpha- dihydroergocryptine mesylate was added and the mixture stirred for 30 minutes. Once applied onto the skin, the solution neither burnt nor caused irritation at the site of application.
  • EXAMPLE 2 A gel with the following composition by weight was prepared:
  • alpha-dihydroergocryptine mesylate 1.00%
  • composition of Carbopol® 1342 carbomer, viscosity in aqueous solution
  • the formulation was prepared by means of a suitable turboemulsifier.
  • the ethanol, alpha-dihydroergocryptine mesylate and essential oil of Melaleuca were placed in the container in order to obtain a solution.
  • the water and all the other components were added to this solution and mixed in the turboemulsifier until completely dispersed.
  • a homogeneous, semitransparent whitish gel was obtained. Once applied onto the skin, the gel could be rubbed in easily without burning or causing irritation at the site of application.
  • a gel with the following composition by weight was prepared:
  • alpha-dihydroergocryptine mesylate 1.00%
  • composition of Carbopol® 941 carbomer, viscosity in aqueous solution
  • the formulation was prepared as in Example 2.
  • a homogeneous, semitransparent whitish gel was obtained. Once applied onto the skin, the gel could be rubbed in easily without burning or causing irritation at the site of application.
  • a gel with the following composition by weight was prepared:
  • the formulation was prepared as in Example 2.
  • a homogeneous, semitransparent whitish gel was obtained. Once applied onto the skin, the gel could be rubbed in easily without burning or causing irritation at the site of application.
  • a gel with the following composition by weight was prepared:
  • alpha-dihydroergocryptine mesylate 1.00%
  • N.B. composition of Lutrol® F 127: polyoxyethylene/polyoxypropylene copolymer composition of PEG 200: polyethylene glycol.
  • the formulation was prepared by means of a suitable turboemulsifier.
  • the water and Lutrol were placed in the container and cooled to 4°C to obtain a solution.
  • the alpha-dihydroergocryptine mesylate, the PEG 200 and all the other components were added to the solution and mixed in the turboemulsifier until completely dispersed.
  • the resultant composition was left to stand at ambient temperature for 12 hours.
  • a homogeneous, semitransparent whitish gel was obtained. Once applied onto the skin, the gel could be rubbed in easily without burning or causing irritation at the site of application.
  • a vaginal tablet having the following composition by weight was prepared:
  • the formulation was prepared by initial granulation of the active ingredient, mixing and compressing using standard methods.
  • the alpha-dihydroergocryptine mesylate and a proportion of the lactose were mixed for 10 minutes in mixer and wetted with a solution of hydroxypropylmethylcellulose in water and granulated for 10 minutes. After 12 hours' drying, the granules were finely screened. During screening, the remainder of the lactose and the magnesium stearate were added and the mixture was mixed for 10 minutes in a stainless steel container. The mixture was then compressed.
  • EXAMPLE 7 A matrix-type transdermal system with the following structure was prepared: a) external cover: Scotchpat Film no. 1009 (polyester film, 3M) b) polymer matrix, with the following composition:
  • a reservoir type transdermal system having following structure was prepared: 1. impermeable support made from heat-sealable polyester laminate
  • microporous polyethylene membrane for controlled release of the drug
  • the system was prepared by heat sealing to form patches with an available area for release of 2.0 cm 2 .
  • the transdermal system is shown in section in Figure 1.
  • a solution with the following composition by weight was prepared: l. ethanol 89.0%
  • a matrix-type transdermal system with the following structure was prepared: a) external cover: Scotchpat Film no. 1009 (polyester film, 3M) b) polymer matrix, with the following composition:
  • the donating phase consisted of the preparation of the Example 1 or of a reference solution of the following composition: l. ethanol 99.0%
  • Example 9 containing M. alternifolia essential oil, in contrast allowed permeation of alpha- dihydroergocryptine (DHE) in an amount of up to approx. 60 ⁇ g/cm 2 after 5 hours.
  • DHE alpha- dihydroergocryptine
  • tea tree oil essential oil of Melaleuca alternifolia
  • tea tree oil essential oil of Melaleuca alternifolia
  • Niaouli Melaleuca alternifolia
  • Niaouli Melaleuca viridans
  • Eucalyptol 1,8 cineol
  • essential oil of Tarconanthus camphoratus TC - Di Schiena Holos, Milan, Italy
  • D-limonene LIM - Sigma
  • tween ⁇ O TW80 - Sigma
  • terpinen-4- ol TRO - Sigma
  • the DHE flux increased up to 2 ⁇ g/cm2h by adding 10% NIA, EUC or LIM to the 1% solution of DHE in EtOH (vehicles Al, A2 and A3) without any statistical difference; at the same time, the lag time value decreased to 0.43 ⁇ 0.18 in the case of vehicle A3.
  • the percent drug permeated at end of the experiments ranged between 0.47 and 0.78%.
  • A7 was 2.20 ⁇ 0.40 ⁇ g/cm2h, not different from those observed for vehicles Al,
  • A2 and A3 (10% NIA, EUC and LIM, respectively, Fig.6).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
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  • Biomedical Technology (AREA)
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Abstract

L'invention concerne de nouvelles compositions pharmaceutiques d'alpha-dihydroergocryptine qui assurent l'absorption transdermique et/ou transmuqueuse du principe actif, et l'utilisation de celles-ci comme formulations dans des préparations transdermiques, timbres, gels, crèmes, onguents, solutions, préparations buccales ou vaginales, pour traiter des maladies du système nerveux ou des maladies endocrines.
PCT/EP2005/053630 2004-09-29 2005-07-26 Compositions pharmaceutiques d'alpha-dihydroergocryptine pour application transdermique et/ou transmuqueuse Ceased WO2006034902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2004A001855 2004-09-29
IT001855A ITMI20041855A1 (it) 2004-09-29 2004-09-29 Composizioni farmaceutiche di alfa-diidroergocriptina per uso transdermico e-o transmucoso.

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WO2006034902A1 true WO2006034902A1 (fr) 2006-04-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129585A1 (fr) * 2008-04-24 2009-10-29 Sunnywipes Pty Ltd Formulation antiseptique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE881967A (fr) * 1980-01-23 1980-06-16 Lek Tovarna Farmacevtskih Solutions stables de derives d'alcaloides de l'ergot, procede de preparation et emploi
US4673681A (en) * 1985-04-04 1987-06-16 Poli Industria Chimica S.P.A. Pharmaceutical methods having dopaminergic activity
EP0342396A1 (fr) * 1988-05-09 1989-11-23 LEK, tovarna farmacevtskih in kemicnih izdelkov, n.sol.o. Onguents ophtalmologiques à base d'alcoloides peptidiques d'ergot pour le traitement du glaucome
EP0505608A2 (fr) * 1991-03-28 1992-09-30 POLI INDUSTRIA CHIMICA S.p.A. Compositions pharmaceutiques à l'alpha-dihydro-ergocryptine avec une activité neuroprotectrice
WO2000053228A2 (fr) * 1999-03-10 2000-09-14 Farmigea S.P.A. Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique
WO2000054773A1 (fr) * 1999-03-12 2000-09-21 Nitromed, Inc. Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE881967A (fr) * 1980-01-23 1980-06-16 Lek Tovarna Farmacevtskih Solutions stables de derives d'alcaloides de l'ergot, procede de preparation et emploi
US4673681A (en) * 1985-04-04 1987-06-16 Poli Industria Chimica S.P.A. Pharmaceutical methods having dopaminergic activity
EP0342396A1 (fr) * 1988-05-09 1989-11-23 LEK, tovarna farmacevtskih in kemicnih izdelkov, n.sol.o. Onguents ophtalmologiques à base d'alcoloides peptidiques d'ergot pour le traitement du glaucome
EP0505608A2 (fr) * 1991-03-28 1992-09-30 POLI INDUSTRIA CHIMICA S.p.A. Compositions pharmaceutiques à l'alpha-dihydro-ergocryptine avec une activité neuroprotectrice
WO2000053228A2 (fr) * 1999-03-10 2000-09-14 Farmigea S.P.A. Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique
WO2000054773A1 (fr) * 1999-03-12 2000-09-21 Nitromed, Inc. Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129585A1 (fr) * 2008-04-24 2009-10-29 Sunnywipes Pty Ltd Formulation antiseptique
EP2296713A4 (fr) * 2008-04-24 2013-01-09 Sunnywipes Pty Ltd Formulation antiseptique

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