EP1159009A2 - Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique - Google Patents

Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique

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Publication number
EP1159009A2
EP1159009A2 EP00911257A EP00911257A EP1159009A2 EP 1159009 A2 EP1159009 A2 EP 1159009A2 EP 00911257 A EP00911257 A EP 00911257A EP 00911257 A EP00911257 A EP 00911257A EP 1159009 A2 EP1159009 A2 EP 1159009A2
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EP
European Patent Office
Prior art keywords
per cent
weight per
alfa
niaouli
essential oil
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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.)
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Application number
EP00911257A
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German (de)
English (en)
Inventor
Marco Fabrizio Saettone
Boris Giannaccini
Daniela Monti
Enrico Farmigea S.p.A. BOLDRINI
Pietro Farmigea S.p.A. BIANCHINI
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Farmigea SpA
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Farmigea SpA
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Publication of EP1159009A2 publication Critical patent/EP1159009A2/fr
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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to the use of niaouli essential oil as enhancer for the transdermal permeation. More specifically the invention relates to formulations and systems for the transdermal administration of pharmaceutically active principles, particularly steroids, as for example estrogens, progestins and nonsteroidal anti-inflammatory drugs (FANS), as for example diclofenac, ammonium diethyl diclofenac, ketoprofen, piroxicam, nimesulide, wherein as enhancer of the percutaneous permeation and absorption of the drug, the natural essence known as niaouli oil, is included, or a mixture whose composition at least approximates that of the niaouli oil .
  • pharmaceutically active principles particularly steroids, as for example estrogens, progestins and nonsteroidal anti-inflammatory drugs (FANS), as for example diclofenac, ammonium diethyl diclofenac, ketoprofen, piroxicam, nimesulide, wherein as enhancer of the per
  • the transdermal administration of drugs designed to be active at systemic level has been the subject of a wide research and development activity in view of the advantages so provided with respect to other systemic administration ways, as conventional parenteral and oral.
  • the transdermal application certainly is accepted with less discomfort by the patients and does not require the action of skilled people, while in comparison to the oral administration way, which from the practical point of view is simpler and less traumatic, it provides all the advantages resulting from the direct release of the drug in the blood system.
  • the transdermal way allows to reduce the variability of the absorption amounts over the time and among the patients, providing a controlled and sustained release of the active principle within the organism.
  • this administration way prevents the occurrence of any undesired reaction or gastric or intestinal incompatibility from the drug itself and by avoiding the metabolism of the first hepatic pass prevents a portion of the drug, manor or minor depending on the nature thereof, from being subjected to a metabolic degradation thus loosing partially its biological activity .
  • the cutis is the widest and most easily accessible organ of the human body the development of drugs for transdermal release is hampered by the practical difficulty resulting from the necessity of the passage of the active compound through the complex membrane constituted of different cutaneous layers.
  • the cutis offers various possible penetration pathways, as the trans-eccnne through the ecc ⁇ ne sudoriparous glands, trans-sebaceous through sebaceous glands, trans-follicular through the hair follicles, mter-cellular, also called lipid pathway and trans-cellular, called also polar pathway, but almost all diffusing agents permeate through the horny layer substantially by two pathways: the mter-cellular and trans-cellular. Of these the tortuous intercellular pathway is considered the mam pathway and the most important barrier for the most drugs.
  • the passage of the drug involves the overcoming of the external horny layer and the diffusion through the epidermis and papillary derma and finally the penetration through the walls of the capillaries or lymphatic vessels and it is clear that such a phenomenon meets different resistances depending on each tissue type.
  • the horny layer due to its dense and highly horny cells, represents the primary barrier which contrasts the absorption of foreign substances in the skin and their passage through the same .
  • the characteristics of the horny layer which is to 500000 times less permeable for various substances than the underlying derma.
  • the permeability of the horny layer can depend not only on factors as age, race, presence of occlusive phenomena, cutaneous pathologies, but also and above all on its integrity and thickness, n addition to the temperature and hydration conditions and eventual preliminary contact with various solvents.
  • the thickness of the horny layer is highly variable depending on the anatomical zone, exposure to ultraviolet radiation or physical stresses and it is inversely proportional to the permeability.
  • Chemical modifications can also modify the permeability of the cutaneous layer: for example, it was detected that organic solvents and surface active agent solutions can result in the removal of lipids from the horny layer, increasing the permeability thereof (Behl C.R., Kreuter J., Flynn G.L., Walters K.A. and Higuchi W.I., Mechanism of solven t effects on percutaneous absorption . I : effects of methanol and acetone on the permea tion of n-alkanols through hairless mouse skin, A Ph. A. Abst. 10(1), 98, 1980).
  • the permeation enhancers which generally can act at level both of polar penetration, associated with the protein component of the horny layer, and not polar penetration, associated with the lipid component, can be classified according to different criteria depending on their structure, action mechanisms, and drug type against which the activity is experienced. According to one of the classifications, for example, substantially three different groups of transdermal permeation enhancers are identified: solvents, surface active agents and differently acting compounds (Walters K.A., Transdermal Drug Del ivery, J. Hadgraft and R. H. Guy Eds., Marcell Dekker, Inc, Ed., New York and Basilea, 1989) .
  • ethyl alcohol it was suggested ethyl alcohol to be suitable for the transdermal release of estradiol, in dosage forms presently known as transdermal therapeutic systems (STT or TTS), constituted of patch structures which maintain the active principle, together with the eventual enhancer and other excipients, if desiderd, firmly fixed on the cutis .
  • STT transdermal therapeutic systems
  • the hign permeation ability of ethyl alcohol in addition to cutaneous tolerability problems, exhibited the drawback in that a remarkable excess of enhancer was require ⁇ , in order to avoid the exhaustion in the transdermal system before the complete utilisation of the active principle.
  • STT of the type presently known as "reservoir”, called also “of the first generation”
  • reservoir wherem the drug and the enhancer are m the form of solution, which reservoir is separated from the skin on which it is adherent by means of a membrane able to control and limit suitably the flow of ethyl alcohol.
  • ethyl and isopropyl alcohol subsequently other alcohols were suggested to be suitable as enhancers, among which several aliphatic long chain alcohols (for example U.S. patents No. 4 906 169, Rutgers Univ.; patent application PCT No.
  • Theratec particularly with reference to oleic acid and corresponding alcohols, in combination with a lower alcohol), as well the esters of fatty acids, preferably iso-propyl miristate, which already had been successfully used in many pharmaceutical and cosmetic preparations (for example European patent No. 436 203, Nitto) and the esters of lauric acid (for example U.S. patent No. 4 568 343, to Alza, concerning polyethylene glycol monolaurate, U.S. patent No. 4 746 515, again to Alza, concerning glyceril monolaurate, U.S. paten No.
  • N- methyl-2-pyrrolidone and derivatives thereof as that just above mentioned, also received a successful consideration as permeation enhancers, although the base molecule exhibits toxicity at some degree.
  • Azone ® (1- dodecylazacycloeptan-2-one) and derivatives thereof
  • Azone ® (1- dodecylazacycloeptan-2-one) and derivatives thereof
  • alkanolamides N-hydroxyalkyl- or N-di- (hydroxyalkyl) amides of fatty acids
  • phospholipids and derivatives of phosphates as for example lecithin
  • This patent discloses a STT system of a type called “monolithic” (more frequently known as “matrix” system) which does not contain the reservoir of the drug but the latter is dispersed within an adhesive matrix, together with other adjuvants, if desired, and the whole formulation is coated on a plastic support layer so that the assembly constitutes a patch much thinner than those of the previous generation.
  • matrix more frequently known as “matrix” system
  • 1,8-cineole is added to the matrix as transdermal permeation enhancer.
  • 1,8-cineole which is present in the eucalyptus essential oil at concentrations usually higher than 70 weight per cent, is included in the formulation preferably as neat compound, but raw compounds (or not completely purified) , with the provision they contain at least 70 per cent 1,8-cineole, can also be used.
  • the document provides the association of the suggested enancher with another permeation enhancer, which preferably is N-methyl-2-pyrrolidone .
  • the drugs, the delivery of which can be enhanced by the enhancer are various and among these there are steroidal hormones.
  • the transdermal system is suggested to be suitable for release of any drug, including steroids (among which, specifically, there are 17-beta- estradiol and dehydroepiandrosterone) and nonsteroidal anti-inflammatory drugs (among which, specifically, there are piroxicam and ketoprofen) .
  • niaouli an essential oil, already known and used in tnerapeutic field, namely niaouli, is particularly effective in enhancing the penetration of pharmacologically active compounds through the skin.
  • niaouli essential oil is characterised also by the absence of toxic and allergenic properties, which is peculiar for many of such natural products.
  • niaouli essence is an oil obtained by steam distillation from fresh leaves of Melaleuca viridiflora Gaertn., a plant of the Myrtaceae family, principally frequent in Australia, New Caledonia, Indonesia and Madagascar.
  • This essence being normally a colourless or green-yellow colour liquid, smelling and tasting like camphor and peppermint , is commercially known as gomenolato oil or oleogomenol, and it is used above all for its balsamic, expectorant and antiphlogistic properties, usually in preparations to be administrated by nasal instillation and inhalation, for the therapy of the upper respiratory infection.
  • Products based on niaouli oil are also administrated by external use in the form of creams and liniments for stimulating massages or on fading skin, taking advantage of the hyperemia inducing effects of the essence .
  • composition of niaouli oil is somewhat variable depending on the geographical origin, plant variety, harvesting and extraction techniques and various other factors, but in any case it includes a remarkable amount of 1,8-cineole and significant amounts of alfa-terpineol and alfa- pinene, in addition to various other components, among which limonene, linalol, beta-pinene, sesquiterpene alcohols, valeraldehyde and benzaldehyde .
  • niaouli essential oil exhibits such an activity as transdermal penetration enhancer for drugs, steroidal and non steroidal, that it is significantly higher than that exhibited, at the same concentration, by any one of its main components, particularly 1,8-cineole, alfa-terpineol and alfa- pinene.
  • transdermal flow obtained by using niaouli oil is surprisingly higher than the sum of the flows obtained using individually the three above mentioned components, any one at the same concentration as it is contained in naiouli oil. It is therefore an object of the present invention a composition for the transdermal and dermal administration of pharmaceutically active principles including therapeutically effective amounts of one or more of said active principles, one or more percutaneous permeation enhancers and other pharmaceutically acceptable adjuvants and excipients, if desired, wherem said one ore more percutaneous permeation enhancer include niaouli essential oil.
  • niaouli oil can include amounts of the three mam components variable in the following ranges: from 40 to 65 weight per cent 1,8-cineole, from 6 to 30 weight per cent alfa-terpmeol and from 1 to 20 weight per cent alfa-pmene, preferred concentrations being from 50 to 55 per cent 1,8-cineole, from 7 to 14 per cent alfa- terpmeol and from 12 to 18 per cent alfa-pmene.
  • Drugs for which niaouli essence exerts an enhancing effect for the percutaneous permeation includes firstly the class of steroidal compounds, including, specifically, estrogens (for example estradiol and esters thereof, ethynyl-estradiol, est ⁇ ol), androgens (for example testosterone, methyl testosterone, fluoximesterone) , progestins (for example progesterone, noretisterone or noret drone, norgestrel, gestodene), steroidal anti-progestms (for example mifepristone) , steroidal anti-androgens (for example cyproterone) and corticosteroids (for example cortisone, hydrocortisone, betamethasone, prednisolone, triamcmolone and esters thereof) .
  • estrogens for example estradiol and esters thereof, ethynyl-estradiol, est ⁇ ol
  • androgens for example testosterone, methyl
  • niaouli essential oil exhibits a remarkable enhancing activity for the percutaneous permeation also against FANS (non steroidal anti-mflammatory drugs), among which are included, for example, diclofenac, piroxicam, ibuprofen, naproxen, ketoprofen, indomethacin and nimesulide .
  • FANS non steroidal anti-mflammatory drugs
  • estrogens are already widely used within formulations to be administered by transdermal route, which proved to be advantageous for carrying out the so-called estrogenic substituting therapy.
  • the purpose of the estrogenic substituting therapy substantially is to ameliorate various short and long term disorders, resulting from both physiologic and surgically induced menopause, for example.
  • this therapy takes advantage of oral administration of estrogens, in combination or subsequent to progestins, if desired.
  • the hormonal substituting therapy carried out by using transdermal therapeutic systems proved an efficiency comparable to that of oral systems, but providing the advantage resulting from avoiding the interactions with other orally ingested drugs and a specific pharmacokinetic profile which can results in better clinical results.
  • compositions of the invention can be included, being possible, for example, to prepare them as creams, pomades, ointments, gel, suspensions, emulsions, ecc .
  • a form designed to be administered by percutaneous way, specifically for carrying out the substituting estro-progestinic therapy, which has been recently suggested, is as gel, wherein the hormones containing products can be applied on a cutaneous surface much larger than that allowed by the use of a patch.
  • a recent study Hirvonen E., Cacciatore B., Wahlstrom T., Rita H., Wilten-Rosenquist G., Effects of transdermal estrogen therapy in postmenopausal women : a compara tive study of an estradiol gel and an estradiol delivering patch, Br .
  • compositions of the invention can include, in addition to one or more active principles, for example steroids or FANS, and other permeation enhancers and conventional ingredients, if desired, like, for example, pharmaceutically acceptable preservatives, antioxidants, thickening agents, surface active agents, stabilisers and plasticizers, a concentration of niaouli essential oil preferably within the range from 0,5 to 40 weight per cent based on the total weight of the composition.
  • active principles for example steroids or FANS
  • other permeation enhancers and conventional ingredients like, for example, pharmaceutically acceptable preservatives, antioxidants, thickening agents, surface active agents, stabilisers and plasticizers, a concentration of niaouli essential oil preferably within the range from 0,5 to 40 weight per cent based on the total weight of the composition.
  • Propylene glycol exhibiting the double function as solvent and transdermal permeation enhancer, proved to be a particularly advantageous ingredient.
  • the product can be prepared, for example, using as starting materials an aqueous dispersion containing carboxyvinyl polimers, like carboxypolymethylene (for example Carbopol" 1342) as gel forming and triethanol amine as neutralizing agents and an alcoholic solution containing the drug and permeation enhancer of the invention, together with other enanchers and/or excipients, if desired, mixing then the two solutions until the homogeneity is obtained.
  • carboxyvinyl polimers like carboxypolymethylene (for example Carbopol" 1342)
  • Triethanol amine as neutralizing agents
  • an alcoholic solution containing the drug and permeation enhancer of the invention
  • the suggested composition is provided as a therapeutic transdermal system, which can have one of the different structures up to now suggested for these administration forms, as for example those, already mentioned, known as “drug reservoir” or first generation ones.
  • drug reservoir or first generation ones.
  • the drug and enhancer are contained in a “reservoir”, from which the active principle spreads on the cutis through a polymeric membrane whose function is to control the rate of the drug release.
  • the membrane which can be microporous or not and has a well defined drug permeability, is kept m contact with the cutis by means of an adhesive, meanwhile on the side opposite to the membrane the "reservoir” is closed by a impervious plastic laminate protecting it from external environment.
  • the external support layer can be made of materials as poliethylene terephtalate, polypropylene, polyvmyl chloride or aluminum coupled poliethylene;
  • the drug reservoir can be constituted of ethanol hydroxypropyl cellulose gel containing the active principle together with niaouli oil and other enanchers and adjuvants, if desired;
  • the membrane can be produced using ethylene-vmyl acetate copolymer or it can be a polypropylene or polyethylene microporous membrane;
  • the adhesive can be constituted of polyisobutylene and mineral oil, acrylic or pressure silicon adhesives and, finally, the protective layer to be detached before the use can be made of silicone treated polyethylene terephtalate or PVC .
  • the presently preferred STT form is the so-called matrix type, already mentioned, wherem the active principle is directly adsorbed with an adhesive solid matrix.
  • the matrix transdermal patch is constituted of a first support layer, a second layer, which is the matrix, wherein the active principle, together with possible enhancers and excipients and a pressure adhesive, is contained, and a third protective layer to be detached before the use.
  • the use of this STT form is more and more increasing by virtue of the easy and cheap industrial production and small size thereof providing better compliance by the patient.
  • the object of the invention is to provide a system for the transdermal and dermal administration of pharmaceutical active principles constituted of a laminate comprising: a support layer impervious for the components of the adjacent layer; a matrix constituted of a solid mixture containing a therapeutically effective amount of one or more of said active principles, one or more percutaneous permeation enhancers, one thereof being said niaouli essential oil and one or more pressure adhesives, as well as other pharmaceutically acceptable adjuvants and excipients, if desired; a protective layer easy detachable from said matrix before the application.
  • compositions of the niaouli essence are as above already reported and the level of the latter within the solid mixture constituting the matrix is preferably variable from 0,5 to 40 weight per cent.
  • the support layer of the matrix transdermal system must fulfil the following requirements: to provide such flexibility and softness characteristics to adjust itself suitably to the skin, be impervious and chemically inert against both the active principle and other matrix components and, finally, adhere firmly to the matrix after protective film detaching therefrom.
  • polymers suitable as support are polyethylene, polyesters, polyurethanes, polypropylene and like.
  • the adhesive must be selected among products suitable for a long contact with the skin and providing, together with a stable adhesion, the continuity of administration; furthermore it must be compatible with all the components of the matrix and maintain their own adhesion and texture characteristics during the step of the STT production.
  • the detachable protective layer is constituted of a polymer, impervious and inert against the active principle and all other matrix components, which is made easy detachable from the matrix by means of a treatment using silicon and fluorine compounds on one or both the sides of the protective polymer surface.
  • transdermal systems can be produced according to standard methods, for example producing on the support or protective layer a film resulting, by the solvent evaporation, from a suitably concentrated solution containing the matrix ingredients. Then on the thus obtained initial structure, the remaining layers are laminated.
  • the pharmaceutical active principle and niaouli oil can be dissolved, together with other ingredients, if desired, in an alcoholic solution of polyaminomethacrylic polymer (Plastoid ® E35L) .
  • the thus obtained solution poured into a die coated with a polyethylene film (support layer) can be evaporated at 40°C until the weight is constant. At the end of the operation the protective layer is added.
  • figure 1 shows the transdermal permeation profiles for estradiol from solutions containing niaouli oil as enhancer, compared with solutions containing individually any one of its three main components
  • figure 2 shows profiles analogous to those in figure 1 relating to the transdermal permeation of noretindrone acetate
  • figure 3 shows the transdermal permeation profile for estradiol contained in gels together with niaouli oil enhancer compared to formulations without the enhancer
  • figure 4 shows the transdermal permeation profile for mifrepistone contained in solutions together with niaouli oil enhancer compared to solutions without the enhancer
  • figure 5 shows the transdermal permeation profile for diclofenac contained in solutions together with niaouli oil enhancer
  • Niaouli essential oil used in the hereinafter reported permeation tests was characterised by gas- chromatographic (GC) analysis in order to exactly determine the precise contents of the different components thereof.
  • Essential oils from two different sources were analysed: niaouli o.e., available from A.C.E.F. S.p.A. of Piacenza (hereinafter called NIA) and niaouli o.e. available from by from Muller & Koster (hereinafter called NIA*) .
  • the analyses were performed by means of an HP
  • the assembly was constituted of two pyrex glass symmetrical emi-cells having a relatively small capacity (8,5 ml), constituting the donor and the recipient compartments, respectively.
  • Each emi-cell had an upper opening for the filling and sampling and a glass or teflon closing to avoid the solvent evaporation.
  • the mixing of the system was carried out by means of a star type magnetic stirrer at a constant rate of 600 revolutions per minute.
  • the temperature is maintained constant by means of circulating water within cell double walls at 37°C. Between the two emi-cells a cutis fragment with 2 cm of exposed area is mounted and the cell is fixed on a platform containing the motors of the magnetic stirrers by means of a plexiglas support equipped with a screw providing the assembly a perfect tightness.
  • the described horizontal cells have been selected to carry out suitable experiments concerning the invention in order to study the mechanisms and kinetics of "in vitro" percutaneous permeation and the screening of substances suitable to affect the barrier properties of said cutis.
  • the drug content of the recipient phase was determined by HPLC analysis.
  • the equipment used included: Shimadzu LC-6A system, equipped with UV SPD- 6AV detector and C-R4A integrator; 20 microlitre capacity Rheodyne injection valve. Bondclone 300 x 3,0 inverted phase column, packed with a 10 micrometer Cis (Phenomenox) phase and pre-column was Guard-PaK Inserts, C18 micro-Bondapack (Waters) .
  • the mobile phase was an acetonitrile:water :methanol mixture (45:45:10) (methanol and acetonitrile supplied by J.T. Baker B.V.,
  • the flow was 1,0 ml/min, the detection was carried out at 280 nm wavelength with a 6 minute retention time.
  • the mobile phase was an acetonitrile : water mixture (60:40), the flow was 1,5 ml/min, the detection wavelength and the retention time were 240 nm and about 5 minutes, respectively.
  • the mobile phase was an methanol : water mixture (70:30), the flow was 1,0 ml/min, the detection wavelength and the retention time were 310 nm and about 5 minutes, respectively.
  • the mobile phase was a methanol : acetonitrile : Sorensen pH 7,0 phosphate buffer mixture (30:17:53), the flow was 0,8 ml/min, the detection wavelength and the retention time were 275 nm and about 9 minutes, respectively.
  • the quantitative analysis was carried out by comparison using an external calibration curve.
  • Example 1 Percutaneous permeation of estradiol from essential oil containing solutions .
  • niaouli essential oil as percutaneous penetration enhancer for estradiol was compared with that of other essential oils, among which there are cardamon, melissa, sweet orange, myrtle and cajeput oils. It is to be pointed out that the latter two essences are also extracted from plants of the
  • Myrtaceae family namely Myrtus communis and Malaleuca leucadendron, respectively.
  • the myrtle oil includes, as main components, pinene, 1,8-cineole, dipentene and camphor, while the cajeput oil, whose composition was more similar to that of niaouli, contains 1,8-cineole as the main component and remarkable amounts of limonene and alfa-terpineol and minor amounts of alfa- pinene .
  • the mentioned essential oils showed a very different behaviour in the enhancing of percutaneous penetration of steroidal drugs, as it results from the data reported in the following table. In all the reported tests propylene glycol was used as solvent and the concentration of 17-beta- estradiol in the solution was 1 weight per cent.
  • niaouli as percutenous penetration enhancer of estradiol was compared with that of ethyl alcohol and propylene glycol individually used as solvent/enhancer and with that of the three main components of niaouli, 1,8-cineole, alfa-terpineol , alfa-pinene, individually used, again in propylene glycol solution and at concentration similar to that they are present in niaouli essential oil.
  • NIA oil activity (No. 3L formulation) was compared with the activity of individually used three ma components thereof (No. 7L, 8L and 9L formulations), at the same concentration (10 weight per cent). Again this case NIA proved to be the most effective enhancer for estradiol: the J flow again was notably higher (p ⁇ 0,001) than that ootamed using same amount of 1,8-cineole, the ma component thereof. On the
  • alfa-pinene at 1,64 per cent concentration provided a flow about 2,7 times higher than that obtained using an about 6 times 5 higher amount of the same agent (No. 8L formulation, alfa-p ene at 10 per cent concentration) .
  • the flow is only half of that obtained using a formulation (No. 9L formulation at
  • NIA essential c_l was compared to NIA* called oil (No. 11L formulation) from a Different source and having a ternary in laboratory prepared composition constituted of 1,8-cineole, alfa-terpmeole and alfa- pmene combined at the predetermined per cent ratio 5 resulting from the gas-chromatographic analysis ("niaouli like" called mixture, No. 10L formulation).
  • niaouli essential o l as percutenous penetration enhancer of another steroidal drug, the progestin known as noretmdrone or noretisterone acetate.
  • the comparison was made with respect to alone used propylene qlyccl (as solvent/enhancer) and eacn ma component of niaouli, i.e. 1,8-cineole, alfa-terpineol, alfa-pmene, again individually used and each at concentration similar to that they are present in niaouli essential oil
  • estradiol gel containing niaouli essential oil as enhancer has been prepared from the following ingredients:
  • the first three ingredients were mixed to form a gel inducing aqueous solution, the three remaining ones were mixed to form an alcoholic solution, then the two mixtures were mixed to obtain an homogenous semi-solid product.
  • Enhancer J Papp Lag time Permeated ⁇ g cm _2 h _1 cm h _1 10 3 h Drug, %
  • niaouli essential oil was experienced with a steroidal drug different from estrogens and progestins, i.e. mifeprostone .
  • the latter known also as RU 486, is a synthetic steroid produced in 1980 (Roussel Uclaf) having an high bonding affinity with the progesterone receptor and therefore exhibit activity as competitive receptor antagonist of progesterone. Consequently the use of the product showed effectiveness as non surgical method for the pregnancy interruption and as emergency contraceptive.
  • Enhancer J P app Lag time Permeated FP No. 1 ' ⁇ g crrf 2 !.
  • the enhancing effect of the niaouli essential oil has been also experienced on an anti- inflammatory and analgesic non steroidal drug, i.e. diclofenac.
  • This drug included in the FANS group, is sodium salt of o- [ (2, 6-dichlorophenyl) amino] phenyl acetic acid, obtained by synthesis in 1966. It is used by taking advantage of its remarkable antiphlogistic, analgesic and antipyretic activity, which is electively exerted for the therapy of rheumatic affections with pronounced anti- inflammatory component, as well as in painful state resulting having extra-rheumatic or post-traumatic origin.
  • Diclofenac also exhibits activity as prostaglandin synthetase (cyclo-oxygenase) inhibitor (R. Menassee et al . , Scanf. J. Rheumatology, 22, 5-16 (1978); P.D. Fowler et al., J. Clin. Pharmacol., 25, 389 (1983); P. . Todd and E.M. Sorkin, Drugs, 35, 244 (1988) ) .
  • prostaglandin synthetase cyclo-oxygenase

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Abstract

L'invention concerne des compositions permettant une administration transdermique et dermique de principes pharmaceutiquement actifs, en particulier des stéroïdes, par exemple des oestrogènes, des progestérones ou des anti-progestérones stéroïdiques, et des anti-inflammatoires non stéroïdiques (FANS), comme le diclofénac, le diclofénac d'ammonium diéthylique, le kétoprofène, le piroxicam, ou le nimesulide. L'essence naturelle connue sous le nom d'huile de niaouli favorise en effet la pénétration transcutanée et l'absorption du médicament. En plus de faciliter l'absorption de médicaments à un niveau systémique, les formulations contenant de l'huile de niaouli peuvent être utilisées dans des applications dermatologiques nécessitant une pénétration améliorée d'un médicament, par exemple un anti-inflammatoire stéroïdique ou non stéroïdique, à travers la couche cornée de l'épiderme. Cette invention concerne également des systèmes thérapeutiques d'administration transdermique (STT) renfermant de l'huile essentielle de niaouli comme agent favorisant la pénétration transdermique.
EP00911257A 1999-03-10 2000-03-09 Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique Withdrawn EP1159009A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT1999RM000151A IT1305303B1 (it) 1999-03-10 1999-03-10 Uso dell'olio essenziale di niaouli come promotore per la permeazionetransdermica.
ITRM990151 1999-03-10
PCT/IT2000/000079 WO2000053228A2 (fr) 1999-03-10 2000-03-09 Utilisation d'huile essentielle de niaouli comme agent favorisant la penetration transdermique

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US5968547A (en) 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
DE10032132A1 (de) * 2000-07-01 2002-01-17 Lohmann Therapie Syst Lts Dermales Therapeutisches System enthaltend nichtsteroidale Antiphlogistika mit selektiver COX-2-Hemmung
DE10053383A1 (de) * 2000-10-27 2002-05-08 Bionorica Arzneimittel Gmbh Verwendung von Terpenen als Enhancer der transmucosalen Resorption und Terpene enthaltende pharmazeutische Zubereitungen
DE10056011A1 (de) * 2000-11-11 2002-05-16 Beiersdorf Ag Hautfreundliches Wirkstoffpflaster zur insbesondere transdermalen Verabreichung ätherischer Öle
ITMI20041855A1 (it) * 2004-09-29 2004-12-29 Polichem Sa Composizioni farmaceutiche di alfa-diidroergocriptina per uso transdermico e-o transmucoso.
EP2293777B1 (fr) * 2008-06-24 2015-02-25 Intervet International B.V. Compositions transdermiques pharmaceutiques et methode pour le traitement de l'inflammation chez le betail
CN106536054B (zh) 2014-06-30 2020-04-28 皇家飞利浦有限公司 用于生物样品的样品保持器
US10232048B1 (en) * 2014-11-18 2019-03-19 Divine Api-Logics, LLC Apitherapy method and composition
EP3723729B8 (fr) * 2017-12-11 2023-11-01 Meat & Livestock Australia Limited Formulation analgésique transdermique

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WO1993007901A1 (fr) * 1991-10-26 1993-04-29 Ian Flockhart Composition pour application locale
DE19518836C2 (de) * 1995-05-23 1997-05-22 Gisela Hartwig Arznei- oder Heilmittel, insbesondere zur Verhütung und Behandlung von Dekubitus
IT1297080B1 (it) * 1997-11-26 1999-08-03 Andrea Carnevali Composizione per il trattamento di ustioni, eritemi solari, abrasioni, piaghe e irritazioni cutanee

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See references of WO0053228A2 *

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ITRM990151A1 (it) 2000-09-10
WO2000053228A3 (fr) 2000-11-16
AU3324000A (en) 2000-09-28
WO2000053228A2 (fr) 2000-09-14

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