EP1159009A2 - Use of niaouli essential oil as transdermal permeation enhancer - Google Patents

Use of niaouli essential oil as transdermal permeation enhancer

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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
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.)
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Application number
EP00911257A
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German (de)
French (fr)
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/en
Withdrawn legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/18Sulfonamides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196Carboxylic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/405Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54Heterocyclic 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
    • A61K31/5415Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal 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

Compositions for transdermal and dermal administration of pharmaceutically active principles, particularly steroids, as for example estrogens, steroidal progestins or anti-progestins, and non steroidal anti-inflammatory drugs (FANS), as for example, diclofenac, ammonium diethyl diclofenac, ketoprofen, piroxicam, nimesulide, wherein the natural essence known as niaouli oil, as enhancer of the percutaneous permeation and absorption of the drug, is included. In addition to the absorption of the drugs at systemic level the formulations containing niaouli oil are suitable for dermatological applications wherein an improved penetration of a drug, for example a steroidal or nonsteroidal anti-inflammatory drug, through the horny layer is required. The invention further relates to therapeutic systems for the transdermal administration (STT) including niaouli essential oil as a penetration enhancer.

Description

USE OF NIAOULI ESSENTIAL OIL AS TRANSDERMAL PERMEATION ENHANCER
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 .
In the relatively recent years 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. In fact, in comparison to the injection administration route 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. Particularly 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. Furthermore, by avoiding the passage of the drug through the gastrointestinal tract, 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 . In spite of the above reported advantages and the fact that 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. Theoretically the cutis offers various possible penetration pathways, as the trans-eccnne through the eccπne 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. Globally 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. In any case 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 .
In effect the mam factors which affect the delivery of drugs through the skin are, in addition to the chemical-physical properties of the permeating agent and characteristics of the carrier wherem the drug is dissolved, 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. Particularly 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. As to the hydration state resulting from the absorption of water by the protein portion of the cutis, generally an increase of the pore size is observed and the diffusion of the water through the human horny layer increases when the latter is hydrated. The permeation of a few drugs appears to be enhanced by this hydration state whereas in the case of compounds very soluble in lipids, on the contrary, a decrease of the cutaneous permeation can occur (Blank I.H., The effect of hydra tion on the permeabil i ty of the skin , in Percutaneous Absorption, Bronaugh R.L. and Maibach H.I., Marcel Dekker, Inc, Ed., New York, pagg. 97-123, 1985) . 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).
If we consider that a successful transdermal administration depends on the capacity of the drugs to permeate through the horny layer in amounts and at enough high rate to produce the desired therapeutic effects, the importance of being able to increase the amount and rate of such a permeation clearly appears. The most drugs, the transdermal administration of which has been studied, could not penetrate through the skin or do at not sufficient level for a therapeutic use, if they were not together with special adjuvants known as "penetration enhancers" or "permeation enhancers" or also "absorption promoters". These substances, acting by various and not always understood mechanisms, enhance the active principle to overcome the barrier of the horny layer by increasing the transdermal flow, i.e. the amount of drug which goes through the skin for surface and time unit.
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) .
Accordingly the first studies about the permeation enhancers, published in 1970, relate to two solvents, dimethylsulfoxide and N, N-dimethylacetamide (U.S. patents No. 3 551 554, Crown Zellerbach and No. 3 472 931, Forster Milburn) . It was recognised that these compounds, together with other solvents like dimethylformamide and ethyl alcohol, increase the penetration through the skin by means of their capacity to dissolve the lipids of the horny layer. Particularly, in 1983 (U.S. patents No. 4 379 454 et al . , Alza) 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 . However the hign permeation ability of ethyl alcohol, in addition to cutaneous tolerability problems, exhibited the drawback in that a remarkable excess of enhancer was requireα, in order to avoid the exhaustion in the transdermal system before the complete utilisation of the active principle. For such a reason it was necessary to use a STT (of the type presently known as "reservoir", called also "of the first generation" ) equipped with a 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. In addition to 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. WO 90/04397, Schermg Plough) and polyfunctional alcohols as propylene glycol or glycerol, often associated with ethyl alcohol to enhance the tolerability thereof (for example U.S. patent No. 4 855 294, Theratech) . Also fatty acids have been widely used, both alone and m association with other enhancers (for example U.S. patent No. 4 626 539, Du Pont de Nemours; european patent No. 255 485, Warner Lambert, particularly with reference to lmoleic acid; U.S. patent No. 4 863 970, 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. 4 537 776, Procter & Gamble, concerning an association of methyl laurate and N-2-hydroxypropyl pyrrolidone) . 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.
Other groups of compounds which showed activity in enhancing the transdermal penetration of various active principles are Azone® (1- dodecylazacycloeptan-2-one) and derivatives thereof (US patents No. 3 989 816 and No. 4 316 893 and others, to Nelson) , the action mechanism of which is not yet clearly understood, alkanolamides (N-hydroxyalkyl- or N-di- (hydroxyalkyl) amides of fatty acids (for examples european patent No. 008 3371, to Key Pharmaceuticals), phospholipids and derivatives of phosphates, as for example lecithin (US patent No. 4 783 450, to Warner Lambert) and sorbitan monoesters, diesters and triesters of fatty acids, in association with lower aliphatic alcohols, if desired (for example U.S. patent No. 5 122 383, to Theratech) .
According to above, many essential oils and components thereof, principally terpenes, have been studied as enhancers of transdermal permeation of various drugs, as, for example, 5-fluorouracil, triamcinolone, indomethacin, ketoprofen and estradiol . The effectiveness of these agents in enhancing the percutaneous penetration of the active principle with which are in association would depend on an interaction with lipids of the horny layer resulting in the destruction of the structural order thereof and an increase of the diffusing capacity of the active principle by the lipid intercellular pathway. For example, in different patent documents (U.S. patents No. 4 931 283 and No. 4 933 184, to American Home Products, patent application PCT No. WO 91/115441, to Morimoto) menthol has been suggested to be suitable as permeation enahncer of various drugs and the cardamon essential oil (principally constituted of monocyclic terpenes) has been tested as permeation enhancer of piroxicam through the rabbit skin, with the recognition that the pre-treatment of the cutis by means of the enhancer during about one hour resulted in a strong increase of the cutaneous permeation of the drug (Huang Y.B., Wu P.C., Ko H.M. and Tsai Y.H., Effect of pre- trea tment by cardamon oil on m vi tro percutaneous penetra tion of piroxicam gel , Int. J. Pharm. , 131-41, 1996) .
One of the aspects which induced to study the use of the essential oils as possible permeation enhancers was that their use is well documented both m the cosmetic and pharmaceutical field and therefore it is less hazardous from the toxicity point of view. It is to be pointed out, indeed, that an ideal enhancer should be not toxic, pharmaceutically inert, not irritating and not allergenic and should allow the cutis to restore its usual integrity at the end of the application . Among the first published documents about the use of terpenes as transdermal permeation enhancers there is european patent No. 006 9385 (Merck & Co.), concerning eucalyptol or 1,8-cineole, a terpene compound contained in various essential oils, the most important of which is the eucalypt oil. This document suggests the use of 1,8-cineole as enhancer of the penetration of any drug, designed to be active at systemic level and for dermatological use. Also in the latter case, in fact, it is necessary that the active substance overcomes the surface barrier represented by the horny layer so that it is available in the derma and next lower tissues. While the pharmaceutical compositions suggested in this document are in the form of topic preparations, like lotion, cream, liniment or spray, the form of transdermal therapeutic system using eucalyptol as enhancer has been the subject of subsequent patents of Ciba-Geigy, as for example U.S. patent No. 5 079 008. 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. In such a system 1,8-cineole is added to the matrix as transdermal permeation enhancer. According to the description, 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. Furthermore the document provides the association of the suggested enancher with another permeation enhancer, which preferably is N-methyl-2-pyrrolidone . Again in this case the drugs, the delivery of which can be enhanced by the enhancer, are various and among these there are steroidal hormones.
Another patent document which suggests the use of components of essential oils in pharmaceutical compositions to be administered by transdermal way is patent application PCT No. WO 91/05529 (to Watson Laboratories), according to which a not aromatic terpene alcohol or ester thereof, is included in the matrix of a STT preparation in order to promote the release of the drug from said matrix. The tested formulation, which preferably includes also an absorption enhancer selected among known ones, is substantially based on alfa-terpineol as a not aromatic terpenic alcohol. 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) .
Again the patent application PCT No. WO 98/37871 (3M) concerns the use of terpenes as permeation adjuvants for transdermal systems, but with limitation to the testosterone release. Although in the specification various terpenes are mentioned as being suitable for the designed purpose, the formulations reported in the experimental examples include testosterone associated only with alfa-terp eol, with or without additional not terpenic permeation ad uvants .
Withm the context of the research about essential oils or derivatives thereof having characteristics suitable to be used as transdermal permeation enhancers it has been now found out that 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. In addition to remarkable enhancement of the passage of the drug with which is associated, niaouli essential oil is characterised also by the absence of toxic and allergenic properties, which is peculiar for many of such natural products.
As known, 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 .
The composition of niaouli oil, as well as all natural essences, 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 . According to Official Italian Pharmacopeia, the characteristic features of niaouli essential oil are a concentration of 1,8-cineole in the range from 50,0 to 60,0 weight per cent and the presence of alfa-terpineol at detectable concentrations. Based on what found out according to the present invention and as below will be disclosed in more detail, 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. Furthermore the 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. Depending on various possible sources derived from, 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, estπol), 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) . In addition to anti- lnfla matory steroidal drugs (corticosteroids) 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 .
Particularly, 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. As already known, 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. Usually 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. Almost all the presently commercially available STT estradiol forms (or estro-progestinic associations), a few of which make use of transdermal permeation enhancers, are to be replaced every 3-4 days and it is therefore clear that the purposes of a better formulation of these administration routes include the reduction of the active principle content in any patch, at the same daily release or, at the same active principle content, a longer activity period. In addition to the transdermal therapeutic systems there are various other pharmaceutical forms wherein the compositions of the invention can be included, being possible, for example, to prepare them as creams, pomades, ointments, gel, suspensions, emulsions, ecc . , depending on the choice and proportions of the excipients, making use of formulation techniques well known in the pharmaceutical field. Particularly, 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. According to 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 . , J. Obstet. Gynaecol., 104 (Suppl. 16) 26-31, 1997), the gel application forms proved, at the same effectiveness for the substituting hormonal therapy, to be more complied by the patients (96,4 and 90,7 per cent for gel and STT, respectively) and a lower incidence with respect to the cutaneous irritation.
Generally speaking, the 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. Propylene glycol, exhibiting the double function as solvent and transdermal permeation enhancer, proved to be a particularly advantageous ingredient. The synergistic activity of propylene glycol together with a few terpenes probably results form its ability in increasing the repartition of terpenes in the horny layer.
In the case of a gel formulation, 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. The drug and niaouli oil can be metered at variable amounts depending on the desired therapeutic and enhancing activity. In accordance to various specific embodiments 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. Within these structures the drug and enhancer (as a solution or colloidal dispersion, together with other excipients, if desired) 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. By way of example 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 . However 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. In its more recent version 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. Therefore, in accordance to a preferred embodiment thereof, 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.
Preferred 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. Examples of 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. Examples of suitable adhesives are polysiloxanes, polyurethanes, polyacrylates, polyisobutylene; among these polyacrilates with different cross-linking degrees, designed for this use and having Durotak® (National Starch Chemical Co.), Gelva (Monsanto) and Plastoid® (Rohm Pharma) trade names are preferred. Finally, as in the case of "drug reservoir" systems, 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. Above described 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. Again as an example, 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.
Although the foregoing considerations are concerning more directly the transdermal administration field, wherein a suitable formulation containing a pharmaceutically active principle is applied on a not degraded skin area in order to perform the penetration of the active principle through the surface tissues till it reaches the blood flow, it is clear that analogous problems and solutions characterise the dermatological topic administration wherein it is necessary that the drug goes through the horny layer and/or surface layers of a wound area in order to be available at optimum concentration in the involved cutaneous tissues. In the field of the active principles considered according to the present invention, for example, the corticosteroid drugs used as steroidal anti-inflammatory drugs, and non steroidal anti-inflammatory drugs can be exemplary.
Some experimental results obtained within the scope of the present invention, including the data concerning the characteristics and performances of niaouli essential oil and the comparison with other essential oils and components thereof, are below reported by way of example, together with a few diagrams represented in the enclosed drawings, wherein: 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 compared to solutions without the enhancer; figure 6 shows the transdermal permeation profile for ketoprofen contained in liquid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 7 shows the transdermal permeation profile for piroxicam contained in liquid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 8 shows the transdermal permeation profile for nimesulide contained in liquid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 9 shows the transdermal permeation profile for diethyl ammonium diclofenac contained in liquid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 10 shows the transdermal permeation profile for ketoprofen contained in semi-solid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 11 shows the transdermal permeation profile for piroxicam contained in semi-solid formulations together with niaouli oil enhancer compared to formulations without the enhancer; figure 12 shows the transdermal permeation profile for nimesulide contained in semi-solid formulations together with niaouli oil enhancer compared to formulations without the enhancer. Characterization of the niaouli oil by gas- chromatographic analysis
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
5890 Serie II gas-chromatograph equipped with HP-Wax and HP-5 (30 m x 0,25 cm) capillary columns, and the following temperature schedule was used: 10 minutes at 60°C, a 5°C/minute increase to 220°C, 20 minutes at 220°C; injector and detector temperature: 250°C; carrier gas: nitrogen (5 ml/minute), dual FID detector; 1:30 split ratio; injection volume; 0,5 microliters . The identification of the components was obtained by comparing the chromatograms from the two columns taking advantage of the retention times of the pure compounds, while as per cent contents the average value of the percentages obtained from the individual chromatograms was used. In the following Table 1 the contents of the three main components of NIA oil, both as determined using each column and as average values, are reported. Table 1 - GC analysis of the NIA components Essential oil Wax Column Sil Column Average Component (%) (%) (%)
1, 8-cineole 50,04 51,15 50,59 α-pinene 16,29 16,45 16,37 -terpineol 8,32 8,31 8,32 In order to compare the compositions of niaouli essences from different sources in the following Table 2 the average values, obtained as above, of the gas-chromatographic analysis of the NIA and NIA* products are reported. Table 2 - GC analysis of the NIA and NIA* components
Essential oil NIA NIA*
Components (%) (%)
1 , 8-cineole 50, 6 51,4 α-pinene 16, 4 13,5 α-terpineol 8,3 12,7
It is to be pointed out that the analysis showed that at least other 20 components were present, which represent about 20-25 per cent of the essential oil, among which there are beta-pinene (5 per cent), limonene (6 per cent), linanol (2 per cent) and para- cymene (4 per cent) .
Transdermal permeation tests In order to study the "in vitro" percutaneous permeation, hairless mouse skin, because of its easy availability and simplicity in the experimental work, was used. The skin, both on the dorsal and abdominal surface, does not adhere to the internal tissues and therefore it easily can be removed maintaining an uniform thickness without the use of the microtome. Male, hairless, 5-7 week old mice were used. Soon following their sacrifice by cervix dislocation of the spina dorsalis, the intact cutis was cut and the derma was carefully freed of any adherence of subcutaneous tissue and blood vessels. For the experiments portions having about a 3 cm side length were cut and used. The diffusion cell used for the study was of the horizontal type, as proposed by Chien and Valia (Chien Y.W. and Valia K.H., Development of a dynamic skin permea tion system for long-term permea tion studies, Drug. Dev. Ind. Pharm. , 10, 575-99, 1984), the passage having an horizontal direction through the vertically mounted skin lap. 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.
In the below reported tests drug solutions in ethanol (J.T. Baker B.V., Deventer, The Netherlands) or propylene glycol (Carlo Erba, S.p.A., Milan) solvents, containing the various products under investigations as permeation enhancers, at the different concentrations considered, were tested as donor phase . As recipien t phase a 66,7 mM, pH = 7,4, phosphate buffer, made isotonic using sodium chloride (0,44 g/100 ml) and containing sodium azide (0,003 per cent) as preservative, was used. At suitable time intervals during each test 5,0 ml solution samples were withdrawn from the recipient compartment, equal volumes of fresh buffer solutions being the replacement.
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) . For the analysis of estradiol the mobile phase was an acetonitrile:water :methanol mixture (45:45:10) (methanol and acetonitrile supplied by J.T. Baker B.V.,
Deventer, The Netherlands) . The flow was 1,0 ml/min, the detection was carried out at 280 nm wavelength with a 6 minute retention time. For the analysis of noretindrone acetate 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. For the analysis of mifepristone 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. For the analysis of doclofenac 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.
For each formulation to be tested the following parameters were determined: steady state flow, J, expressed as microgram of drug permeating the cutis over the time for area unit (μg cm" h~ ) ;
- apparent permability coefficient, Papp, obtained by the relationship Papp = J/Cv, where Cv is the initial concentration of the drug (expressed in cm h~ 10 ) ; - lag-time, time taken by the drug to saturate the cutis and reach the recipient compartment (expressed in h) ; permeated drug percentage at the end of the experiment (which lasted five hours); enhancing factor, FP, measure of the enhancer activity for propylene glycol (which was used as solvent in most formulations to be evaluated) , calculated from the ratio between obtained Papp using the enhancer to be evaluated and that obtained using alone propylene glycol.
Example 1 Percutaneous permeation of estradiol from essential oil containing solutions .
In a first step of the study of the enhancer of the invention, the activity of 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 . Although the presence of such components 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.
Table 3
Transdermal permeation of estradiol from essential oil containing solutions Enhancer J Papp Lag time Permeated μg cm h cm h o3 drug, % cardamon o.e. a) melissa o.e. -a - - sweet orange o.e. 5,43±0,2 0,54±0,02 1,0±0,15 0,052±0,01 myrtle o.e. 7,22±0,7 0,77±0,07 1,7±0,07 0,045±0,01 cajeput o.e. 3,35±0,1 0,34±0,01 1,6±0,1 0,026±0,008 niaouli o.e. 10,4310,79 1,04±0,079 1,8±0,36 0,073±0,004 Notes: althe percutaneous permeation of beta-estradiol resulted null
Example 2 Percutaneous permeation of estradiol from solutions - Comparison between niaouli and the main components thereof
In a second test group the activity of 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. Specifically the concentrations used for the three comparison solutions were those suggested by gas-chromatographic analysis of NIA oil (Tables 1 and 2) : 1,8-cineole 50,59 per cent alfa-pinene 16,37 per cent alfa-terpineol 8,32 per cent The tests were carried out according to the above reported protocol, using 17-beta-estradiol from Sigma Chemical Co. (St. Louis, USA) at 1 weight per cent concentration, 1,8-cineole from A.C.E.F. S.p.A. (Piacenza, Italy) , alfa-terpineol from Sigma Chemical and alfa-pinene from Fluka Chemie AG (Buchs, Switzerland) . The obtained results are reported hereinafter, in Table 4 (No. 1L-6L formulations).
As it is possible to see from the Table, both ethanol and propylene glycol, individually used as solvent/enhancer (No. IL and 2L formulations), proved to be little effective in the enhancing the estradiol permeation through the hairless mouse skin. Differently from the remarkable activity experienced by niaouli essential oil (No. 3L formulation, at 10 weight per cent concentration) each of the NIA individual components at the same concentrations they are present in equal amount of niaouli oil (No. 4L, 5L and 6L) gave results surprisingly lower than niaouli oil. The most remarkable aspect results from the consideration that the theoretical flow sum obtained using each of No. 4L,
5L and 6L formulations (4,092±0,54 micrograms cm —2 h—1 ) is equal to less than half of the flow obtained using the essential oil. Table 4 - Transdermal permeation of estradiol from solutions
Formulations Enhancer J Papp Lag time Permeated FP
No. " μg cirfV cm h_1103 h drug, %
IL ethanol2' 0,3210,05 0,0410,006 0 0,007/0,0011 2,2210,2 Λ a propylene glyco 2)
2L l 0,210,02 0,0210,002 0 0,00510,0004 1 Λ
3L NIA (10 %) 10,410,79 1,0410,079 1,7610,36 0,07310,0043 57,7814,82
4 L 1, 8-cineole (5, 06 %) 0,2510,06 0,02510,006 2,6310,193 0,001610,0003 1,4110,17 Λ
5L α-pinene (1 , 64%) 4,4510,42 0,44510,042 2,3310,073 0,03010,003 24,7211,65
61, α-terpineol (0,83%) 0,202+0,06 0,020210,006 0,0610,06 0,005+0,001 1,1210,14 O 7 L 1,8-cineole (10%) 6,6810,54 0,66710,054 2,1310,14 0,05310,0007 37,0813,12
8 L α-pinene (10%) 1,6610,07 0,16610,007 0,9010,199 0,01710,0014 9,0710,86 »
9L α-terpineol (10%) 0,4310,15 0,04310,015 0 0,00810,0026 2,4110,37
10L "niaouli like" 9,0010,70 0,86310,067 2,5410,06 0,052+0,0023 47,9614,56 mixture
11L NIA* (10%) ,4710,73 0,84710,073 2,2910,079 0,05510,0045 47,0414,52
Notes: In all the formulations except No. IL the solvent was propylene glycol
As solvent/enhancer
By means of a farther test group, whose results are also showed ir Table 4, the 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
1 C contrary, alfa-pinene and alfa-terpineol gave significantly low flow values. The permeation profiles obtained in this test group are also showed in Figure 1.
By comparison the flow values obtained 15 using the individual terpenes at different concentrations, it is to be pointed out that No. 4L formulation, containing 5,06 per cent 1,8-cineole, provided a flow 27 times lower than the No. 7L formulation (containing 10 per cent 1,8-cineole),
-.C exhibiting therefore an enhancing effect which increases with the agent concentration. On the contrary, alfa-pinene at 1,64 per cent concentration (No. 5L formulation) 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) . In the case of alfa-terpineol at 0,83 per cent concentration (No. 6L formulation) the flow is only half of that obtained using a formulation (No. 9L formulation at
X 10 per cent concentration) containing 12 times higher amount .
By means of a further test group 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). As it is possible to see Table 4 the comparison with a niaouli essential oil from different source (NIA*) did not point out statistically significant 1C differences (p<0,05) for the percutaneous permeation of estradiol and also the "niaouli like" mixture provided a flow value not statistically different (p<0,05) from that obtained using NIA (and in any case about twice the theoretical flow value obtained 15 from the sum of the individually considered tnree components) .
Although the use of the NIA is in any case advantageous with respect to the "niaouli like" mixture because of the shorter "lag-time" (and G statistically different, p<0,05), at least as to the estradiol permeation the thus formulated ternary mixture constituted of 1,8-cineole, alfa-pmene and alfa-terpineol is anyway more advantageous than the use of the individually considered terpenes. 5 Therefore this "niaouli like" formulation represents a further object of the present invention. Example 3 Percutaneous permeation of noretmαrone acetate from solutions - Comparison between n-_aoulι C and the main components thereof
By means of a further test group the activity of niaouli essential o l as percutenous penetration enhancer of another steroidal drug, the progestin known as noretmdrone or noretisterone acetate. Also in this case firstly 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
(according to the data n Tables 1 and 2) . The test protocol were the same as already described and noretmdrone acetate (supplied from Sigma Chemical Co., St. Louis, USA) was included in the propylene glicol solutions at 1 weight per cent concentration. The obtained results are reported hereinafter in Table 5 (No. 12L-16L formulations) .
The results reported in the table, although different from those obtained using estradiol, confirm anyway that niaouli o.e. is clearly better than each individually used component. In this case the theoretical sum of the flows obtained using each of No. 14L, 15L and 16L formulations (1,26310,2736 μgcm~2h~1) is little more than half of the flow obtained using the essential oil.
In the subsequent test group, whose results again are reported in Table 5, the niaouli activity at 10 weight per cent concentration (No. 13L formulation) was compared with that of individual terpenes at same concentrations (No. 17L, 18L and 19L formulations), demonstrating that the essential oil according to the invention is tne most effective enhancer also for noretmdrone acetate. The enhancing factor, calculated in comparison to the propylene glycol reference formulation (No. 12L) , is also nigher than that obtained for estradiol. The graphic comparison of the profiles cotamed using niaouli, 1,8-cineole, alfa-pmene and alfa-terpineol, all at 10 weight per cent concentrations, is reported in Figure 2.
Table 5 - Transdermal permeation of noretindrone acetate from solutions Formul tions Enhancer J Papp Lag time Permeated FP
No. " μg crN 1 cm h_1103 h drug, %
G Cv 12 propylene glycol2' 0,03071 0,0041 0,03110,0004 0 0,00051 0,00008 1 CΛ
H
H
C 13L IA (10 %) 2,1310,18 0,2110,018 1,6610,07 0,01610,0013 74,7416,21
H
M
CΛ 14L i-cineole (5,06 0,03+0,006 0,00310,0006 1,2610,64 0,0003+0,00009 1,0510,13
X H
15L α-pinene (1,64%) 1,1610,25 0,11510,0025 1,8610,62 0,00810,0008 40,62+5,57
70 c r 1 L α-terpineol (0,83%) 0,0731 0,0176 0,00710,0018 0,41+0,06 0,00081 0,00017 2,5510,3*
H
17L 1,8-cineole (10%) 0,3510,0815 0,03510,0081 0,4010,13 0,00410,000083 12,3111,81
α-pinene (10%) 0,418+0,115 0,04110,0113 0 0,00610,0022 14,4612,39
19L α-terpineol (10%) 0,48310,028 0,04810,0028 0,1510,15 0,00710,0008 16,8011,5
20L "niaouli like" 0,16810,024 0,01610,0023 0,6810,39 0,001710,00017 5,710,60
C mixture ca -j Notes: υ In all the formulations the solvent was propylene glycol
H 2)
G As solvent/enhancer H M CΛ
M tn H c r
O
Again with reference to the data in Table 5, comparing the flow values obtained using individual terpenes at different concentrations it is observed that No. 14L formulation, containing 5,06 per cent 1,8-cineole, gave a flow about 11 times lower than the No. 17L formulation (10 per cent 1,8-cineole) and, analogously, 0,83 per cent alfa-terpineol (No. 16 L formulation) gave a flow about 7 times lower than that obtained with a concentration of the same agent about 6 times higher (No. 19L formulation containing 10 per cent alfa-terpineol) . Exhibiting an opposite behaviour, 1,64 per cent alfa-pinene (No. 15L formulation) gave a much higher (almost 3 times) flow than that obtained using a formulation (No. 19L at 10 per cent) containing a 12 times higher quantity.
The result obtained in the last test group relating to the "niaouli like" mixture (prepared according to the previous example) is completely different from that obtained using estradiol: in this case the value of transdermal flow obtained using the "niaouli like" mixture is definitely lower in comparison both with that obtained using NIA (No. 13 L formulation) and the theoretical value obtained by the sum of the flows obtained using individually said three terpenes (No. 14L, 15L and 16L formulations), i.e. 1,251+0,2245 μg cirf n"1. The fact that the prepared in laboratory and called "niaouli like" mixture in this case did not exhibit analogous results to those obtained using NIA suggests that the effectiveness of the essential oil results also from its complex composition and does not depend only from the presence of the three considered terpene compounds . Example 4 Percutaneous permeation of estradiol form gel carriers
In order to verify the effectiveness of the niaouli essential oil as transdermal permeation enhancer of 17-beta-estradiol from gel formulations like those already described, the same experimental procedure as in the previous examples has been applied pouring the gel (in spite of solution) in the donor compartment of the described experimental apparatus. The estradiol gel containing niaouli essential oil as enhancer has been prepared from the following ingredients:
Carbopol® 1342 0,400 g Water 40,000 g
Triethanolamine 0,720 g
95 % Ethanol 56,820 g
Estradiol 0,060 g
Niaouli o.e. 2,000 g
100,000 g
As already described 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.
For comparison, the above described gel has been prepared in the absence of the niaouli oil and the permeation test results carried out using two different formulations are reported in the following table. The corresponding permeation profiles are also illustrated in Figure 3.
Table 6 Transdermal Permeation of estradiol from gel carriers
Enhancer J Papp Lag time Permeated μg cm_2h_1 cm h_1103 h Drug, %
1,4 2,3 2,0 5,0 Niaouli o.e. 2% 2,44 4,1 1,5 8,9
From the above data and more immediately from the permeation profiles compared in Figure 3 it appears that the addition of niaouli essential oil to the formulation in form of gel remarkably benefits the drug penetration through the skin.
Example 5 Percutaneous permeation of mifepristone from solutions
The enhancing effect of the 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. More recently the application field of mifepristone became wider being proved useful also in diseases like endometriosis, tumor of the endometrium, uterine dysfunctions and premenstrual tension syndrome (Hodgen G.D., Williams R.F., Grow D., Treatment of ovarian estrogen dependent conditions, Faming Zhuanli Shenquing Gonkai Shuomingshu CN 1144486 A5 March 1997, 15 pages; Kettel L.M., Trea tment of endometriosis with mifepristone, Int. Congr. Symp. Se in. Ser., 13 (Endometriosis Today) 334-338, 1997) . For the permeation tests two different solutions, one (No. 21L formulation) comprising 0,3 g mifepristone and propylene glycol q.b. to 30,0 g and the other (No. 22L formulation) comprising 0,3 g mifepristone, 3,0 g niaouli essential oil and propylene glycol q.b. to 30,0 g were compared. The results of permeation tests, carried out according to the same protocol as above, are reported in the following table, while the corresponding permeation profiles are reported in Figure 4. Table 7
Transdermal Permeation of mifepristone from solutions
Form. Enhancer J Papp Lag time Permeated FP No.1' μg crrf2!.""1 cm h_1103 h Drug, % 21L propylene 0,101 0,0101 0 0,00294 1 glycol21 +0,0053 ±0,0005 ±0,0005
22L NIA (10%) 0,991 0,0991 0,928 0,00947 9,83± ±0,154 ±0,0154 ±0,606 ±0,0006 0,995 Notes: 1) In both formulations the solvent was propylene glycol
2> As solvent/enhancer
From above data it results that, also for mifepristone, the enhancing activity of NIA is appreciable: in fact the enhancing factor (FP) obtained using the No. 22L formulation is over 9 times higher than reference solution (No. 21L formulation, using propylene glycol as solvent/enhancer) . Example 6
Percutaneous permeation of diclofenac from propylene glycol solutions
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) ) .
In the permeation test were compared two
different solutions, a first one (No. 23 formulation) comprising diclofenac 0,3 g and propylene glycol q.b. to 30,0 g and the second one (No. 24L formulation) comprising diclofenac 0,3 g, niaouli essential oil 3,0 g and propylene glycol q.b. to 30,0 g. The results of permeation tests, carried out in accordance to the same protocol as above, are reported in Table 8, while the corresponding permeation profiles are showed in Figure 5. - 42 -
Table 8
Transdermal Permeation of diclofenac from solutions
Form. . Enhancer J Papp Lag time Permeated FP
No.1' μg cirf n-1 cm h-110 h Drug, %
23L propylene 0,153 0,15 1,19 0,007 1 glycol2' ±0,03 ±0,004 ±0,26 ±0,0015
24L NIA (10%) 84,11 84,6 1,60 3,35 560±
±6,26 ±6,2 ±0,054 ±0,24 41,7 Notes: 1) In both formulations the solvent was propylene glycol
As solvent/enhancer From above data it results that the enhancing activity of NIA for diclofenac is remarkable: in fact the enhancing factor (FP) obtained using the No. 24L formulation is 560 against the reference solution (No. 23L formulation, containing propylene glycol as solvent/enhancer) .
Example 7 Percutaneous permeation of FANS from liquid formulations
The enhancing effect of the niaouli essential oil has been also experienced on complete liquid formulations containing FANS (Ketoprofen, piroxicam, nimesulide and diethyl ammonium diclofenac) .
For the permeation tests two different formulations were compared for each FANS, containing and not containing niaouli essential oil, respectively, the per cent compositions thereof being as below:
Drug * *
Polyethylene glycol 400 50 per cent
Pluronic L64 10 per cent NIA 10 per cent
Ethyl alcohol q.b. to 100 per cent
Drug
Polyethylene glycol 400 50 per cent
Pluronic L64 10 per cent
Ethyl alcohol q.b. to 100 per cent
**, 2 per cent nimesulide, 2,5 per cent ketoprofen, 1,0 per cent piroxicam, 1,16 per cent diethyl ammonium diclofenac.
The results of permeation tests, carried out according to the same protocol as above, are reported in Table 9, while the corresponding permeation profiles are showed in Figures 6-9.
Table 9
Percutaneous permeation data of anti-inflammatory drugs obtained from liquid formulations
Drug Enhancer J P Lag time FP Permeated drug, % μg cm" h_1 cm h~ 10 h after 5 hours
§ ketoprofen nothing 0,6510,06 0,026+0,0019 0,76±0,24 1,3210,12
CΛ d " NIA 10 % 2,8310,44 0,11610,0176 0,4910,085 4,4110,67 6,210,99
H
H piroxicam nothing 0,1710,025 0,01810,0026 1,2510,144 0,7810,104
P g " NIA 10 % 0,7810,185 0,082±0,019 0,87±0,37 4,46±1,06 3,6710,6
PI ,
Pi nimesulide nothing 0,410,06 0,02010,0029 - 1,4110,04
H
?3 " NIA 10 % 1,9710,088 0,10210,0044 0,7610,05 4,9210,22 5,1110,2
C
H diclofenac nothing 0,2 0,02 1,2510,14 0,001+0,00003 diethyl ammonium
NIA 10 % 2,8210,47 0,285±0,047 14,1212,34 14,1212,34 0,01110,0013
The foregoing data demonstrate a remarkable activity of NIA in enhancing the percutaneous permeation of FANS: in fact, using the formulations containing NIA, a flow which is 4,4, 5,2, 4,9 and 14,1 times higher than that obtained in absence of NIA, for ketoprofen, piroxicam, nimesulide and diethyl ammonium diclofenac, respectively, is obtained.
Example 8 Percutaneous permeation of FANS from semi- solid formulations
The enhancing effect of the niaouli essential oil was also verified for FANS (ketoprofen, piroxicam and nimesulide) based semisolid (gels) formulations.
For the permeation tests two different formulations were compared for each FANS, only one of which containing niaouli essential oil, the per cent compositions being as below: Control formulation:
Drug **
Polyethylene glycol 600 40,0
Pluronic L64 20,0
Carbopol 1342 2,0
Distilled water 10,0
Propylene glycol q.b to 100,0
NIA containing formulation Drug **
Polyethylene glycol 600 36,0
Pluronic L64 18,0
NIA 10,0
Carbopol 1342 2,0
Distilled water 8,0
Propylene glycol q.b to 100,0 **, 2 per cent nimesulide, 2,5 per cent ketoprofen, 1,0 per cent piroxicam.
The results of permeation tests, carried out according to the same protocol as above, are reported in Table 10, while the corresponding permeation profiles are showed in Figures 10-12.
Table 10 Percutaneous permeation data of anti-inflammatory drugs obtained from semi-solid formulations Drug Enhancer J P Lag time FP Permeated drug, % after 24 hours
C ketoprofen nothing 1,710,36 0,05810,012 5,6210,61 0,1110,025
CO
H " NIA 10 % 52,012,46 2,063+0,099 7,6410,18 30,611,45 3,3810,19
H
C piroxicam nothing 1,2310,09 0,12310,009 4,09±0,96 0,24+0,067 p
CΛ NIA 10 % 5,53+0,38 0,553±0,058 4,29+0,87 4,49±0,3 1,05±0,05
X M
PI nimesulide nothing 0,2 0,0089 0,875±0,5 0,02210,0015 H NIA 10 % 5,2310,75 0,28810,042 6,86+0,21 29,514,25 0,4910,07
C r
P3
The foregoing data prove a remarkable activity of NIA in enhancing the percutaneous permeation of FANS: accordingly, using the formulations containing NIA are obtained enhancing factors which are 30,6, 4,49, and 29,5, for ketoprofen, piroxicam, nimesulide, respectively, in comparison to that of control formulation .
The present invention has been described with reference to specific embodiments thereof but it is understood that variations and modifications can be carried out by those skilled in the field without departing form the scope thereof.

Claims

C l aims
1. Composition for the dermal and transdermal administration of pharmaceutical active principles comprising therapeutically effective amounts of one or more of said active principles, one or more percutaneous permeation enhancers and other possible pharmacologically acceptable adjuvants and excipients, characterised in that said one or more percutaneous permeation enhancers include niaouli essential oil.
2. Composition according to claim 1 wherein said pharmaceutical active principles are steroids or non steroidal anti-inflammatory drugs (FANS) .
3. Composition according to claim 1 or 2 wherein said niaouli essential oil contains from 40 to
65 weight per cent of 1,8-cineole, from 6 to 30 weight per cent of alfa-terpineol and from 1 to 20 weight per cent of alfa-pinene.
4. Composition according to claim 3 wherein said niaouli essential oil contains from 50 to 55 weight per cent of 1,8-cineole, from 7 to 14 weight per cent of alfa-terpineol and from 12 to 18 weight per cent of alfa-pinene.
5. Composition according to any one of claims 2-4 wherein said steroids are selected from the group consisting of estrogens, androgens, progestins, steroidal anti-progestins, anti-androgen steroids and corticosteroids .
6. Composition according to anyone of claims 2- 4 wherein said FANS are selected from the group consisting of diclofenac, piroxicam, ibuprofen, naproxen, ketoprofen, indomethacin and nimesulide.
7. Composition for the dermal and transdermal administration of estrogens comprising therapeutically effective amounts of one or more of said estrogens, one or more percutaneous permeation enhancers and other pharmacologically acceptable possible adjuvants and excipients, characterised in that said one or more percutaneous permeation enhancers include a ternary mixture of terpenes containing from 55 to 85 weight per cent of 1,8-cineole, from 8 to 40 weight per cent of alfa-terpineol and from 1,5 to 25 weight per cent of alfa-pinene .
8. Composition according to any one of claims 1-7 comprising in addition propylene glycol, as solvent and additional permeation enhancer.
9. Composition according to any one of claims 1-8 comprising from 0,5 to 40 weight per cent of said niaouli essential oil or mixture of terpenes.
10. Composition according to any one of claims 1-9 in the form of gel.
11.
Composition according to any one of claims 1-9 in the form of transdermal therapeutic system (STT or TTS) .
12. Composition according to claim 11 included in a solid matrix type STT, mixed with one or more suitable pressure adhesives.
13. System for transdermal and dermal administration of pharmaceutical active principles comprising a therapeutically effective amount of one or more of said active principles and the niaouli essential oil as a percutaneous permeation enhancer.
14. System for transdermal administration according to claim 13 wherein said pharmaceutical active principles are steroids or non steroidal anti- inflammatory drugs (FANS) .
15. System for transdermal administration according to claims 13 or 14 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 possible pharmaceutically acceptable adjuvants and excipients; a protective layer easy detachable from said matrix before the application.
16. System for transdermal administration according to claim 15 wherein said niaouli essential oil contains from 40 to 65 weight per cent of 1,8- cineole, from 6 to 30 weight per cent of alfa-terpineol and from 1 to 20 weight per cent of alfa-pinene.
17. System for transdermal administration according to claim 16 wherein said niaouli essential oil contains from 50 to 55 weight per cent of 1,8- cineole, from 7 to 14 weight per cent of alfa-terpineol and from 12 to 18 weight per cent of alfa-pinene.
18. System for transdermal administration according to any one of claims 14-17 wherein said steroids are selected from the group consisting of estrogens, androgens, progestins, steroidal anti- progestins, anti-androgen steroids and corticosteroids.
19. System for transdermal administration according to anyone of claims 14-17 wherein said FANS are selected from the group consisting of diclofenac, diethyl ammonium diclofenac, piroxicam, ibuprofen, naproxen, ketoprofen, indomethacin and nimesulide.
20. System for transdermal administration according to anyone of claims 15-18 wherein said matrix solid mixture contains from 0,5 to 40 weight per cent of niaouli essential oil.
21. System for transdermal administration of estrogens comprising therapeutically effective amounts of one or more of said estrogens and, as percutaneous permeation enhancer, a ternary mixture of terpenes containing from 55 to 85 weight per cent of 1,8- cineole, from 8 to 40 weight per cent of alfa-terpineol and from 1,5 to 25 weight per cent of alfa-pinene.
22. Composition for transdermal and dermal administration of pharmaceutical active principles and corresponding system for transdermal administration according to claims 1-21, substantially as above described.
EP00911257A 1999-03-10 2000-03-09 Use of niaouli essential oil as transdermal permeation enhancer Withdrawn EP1159009A2 (en)

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IT1999RM000151A IT1305303B1 (en) 1999-03-10 1999-03-10 USE OF NIAOULI ESSENTIAL OIL AS A PROMOTER FOR TRANSDERMAL PERMEAZION.
ITRM990151 1999-03-10
PCT/IT2000/000079 WO2000053228A2 (en) 1999-03-10 2000-03-09 Use of niaouli essential oil as transdermal permeation enhancer

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US5968547A (en) 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
DE10032132A1 (en) * 2000-07-01 2002-01-17 Lohmann Therapie Syst Lts Dermal therapeutic system containing non-steroidal anti-inflammatory drugs with selective COX-2 inhibition
DE10053383A1 (en) * 2000-10-27 2002-05-08 Bionorica Arzneimittel Gmbh Use of terpenes as enhancers of transmucosal absorption and pharmaceutical preparations containing terpenes
DE10056011A1 (en) * 2000-11-11 2002-05-16 Beiersdorf Ag Well tolerated plaster for controlled delivery of essential oils to skin or air, has active agent containing matrix comprising polyisobutylene, amorphous poly-alpha-olefin and optionally filler
ITMI20041855A1 (en) * 2004-09-29 2004-12-29 Polichem Sa PHARMACEUTICAL COMPOSITIONS OF ALFA-DIHYDROERGOCRIPTINE FOR TRANSDERMAL AND-OR TRANSMUCOUS USE.
EP2293777B1 (en) * 2008-06-24 2015-02-25 Intervet International B.V. Pharmaceutical transdermal compositions and method for treating inflammation in cattle
CN106536054B (en) 2014-06-30 2020-04-28 皇家飞利浦有限公司 Sample holder for biological samples
US10232048B1 (en) * 2014-11-18 2019-03-19 Divine Api-Logics, LLC Apitherapy method and composition
EP3723729B8 (en) * 2017-12-11 2023-11-01 Meat & Livestock Australia Limited Transdermal analgesic formulation

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WO1993007901A1 (en) * 1991-10-26 1993-04-29 Ian Flockhart Composition for topical application
DE19518836C2 (en) * 1995-05-23 1997-05-22 Gisela Hartwig Medicines or medicines, in particular for the prevention and treatment of pressure ulcers
IT1297080B1 (en) * 1997-11-26 1999-08-03 Andrea Carnevali COMPOSITION FOR THE TREATMENT OF BURNS, SOLAR erythema, ABRASIONS, SAGS AND SKIN IRRITATIONS

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