EP0748216A1 - Systeme d'administration par voie generale d'un medicament consistant a appliquer celui-ci sur les ongles - Google Patents

Systeme d'administration par voie generale d'un medicament consistant a appliquer celui-ci sur les ongles

Info

Publication number
EP0748216A1
EP0748216A1 EP95909904A EP95909904A EP0748216A1 EP 0748216 A1 EP0748216 A1 EP 0748216A1 EP 95909904 A EP95909904 A EP 95909904A EP 95909904 A EP95909904 A EP 95909904A EP 0748216 A1 EP0748216 A1 EP 0748216A1
Authority
EP
European Patent Office
Prior art keywords
nail
therapeutically active
active substance
nails
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95909904A
Other languages
German (de)
English (en)
Inventor
Sam Shuster
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TRANSONYCHA Ltd
Original Assignee
TRANSONYCHA Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by TRANSONYCHA Ltd filed Critical TRANSONYCHA Ltd
Publication of EP0748216A1 publication Critical patent/EP0748216A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A61Q3/02—Nail coatings

Definitions

  • This invention relates to a novel delivery system for achieving systemic delivery of drugs and other agents with pharmacological or physiological action and more specifically to a novel method of administering a therapeutically active substance to a subject.
  • therapeutically active substance is intended also to include substances having a physiological, pharmacological or prophylactic effect.
  • Improvements in this field may, for example, be necessary simply to provide alternatives available for patient preference or convenience, or to allow greater compliance: thus there may be objections to oral, rectal, sublingual or intravenous routes of administration.
  • Maintaining a constant effect by stable blood concentration is difficult to sustain by oral or parenteral administration because peak concentrations are followed by a decline; with depo-injection a more constant level may be achieved, but it is difficult to remove the drug, for example if unwanted effects are encountered in the course of such administration.
  • sustained dosage release patches have been introduced, first for scopolamine (hyoscine) and now for other substances e.g. nitroglycerin, oestradiol, clonidine, fentanyl and nicotine, (see e.g. EP-A-0 1 17 027). Whilst these have many of the advantages mentioned above, their use has been limited to these and a few other drugs because the use of patches does not overcome the problem of the impermeability of the stratum corneum of the skin, and the need to use a patch of acceptable size. Thus a relatively small daily dose of drug can be administered - usually the order of 0.2- 20 mg per day.
  • GB-A-2 206 493 describes an iontophoresis device for percutaneous or perungual administration of a dissolved substance, for example a drug.
  • a pair of electrodes are attached to a patient's skin or nail, separated by a pad of electrolyte and an e.m.f. of typically 1.35 - 1.83 volts applied.
  • e.m.f. typically 1.35 - 1.83 volts applied.
  • penetration enhancers such as dimethylsulphoxide, see e.g. GB-A-2 057 263, but the use of such penetration enhancers are generally restricted to compositions in liquid form and provide problems with respect to registration with drug registration bodies. Further, dimethylsulphoxide is irritant and toxic.
  • EP-A-0 515 312 discloses topical formulations containing terbinafine in the form of nail varnishes designed to treat onychomycosis.
  • WO-A-87/02580 describes further examples of compositions for delivering drugs topically to human nails. However all such compositions are restricted to uses wherein the composition is intended for local action without transport of the therapeutically active substance to the site remote from the finger or toe nail, in particular to a systemic tissue compartment.
  • the present invention which has all the advantages of the patch system, but without the disadvantages, is based upon a surprising discovery that finger nails and toe nails provide an effective route of systemic administration for a wide range of therapeutically active substances by simple local application. Nails also have the advantage that drug delivery through them is not complicated by the presence of hair follicles and sweat glands, as in skin, nor the very wide variation in permeability of the stratum corneum at different body sites and in different individuals.
  • a method of administering a therapeutically active substance to a subject which comprises applying the substance to the surface of one or more finger or toe nails whereby the substance is absorbed and transported systemically to a site of action remote from the finger or toe nail.
  • the invention further provides the use of a pharmaceutically acceptable carrier in the manufacture of a pharmaceutical composition adapted for application to finger nails and/or toe nails, characterised in that the composition contains at least one therapeutically active substance whereby in use the substance is absorbed and transported systemically to a site of action remote from the finger or toe nail.
  • a pharmaceutically acceptable carrier in the manufacture of a pharmaceutical composition adapted for application to finger nails and/or toe nails, characterised in that the composition contains at least one therapeutically active substance which is capable of passing from the applied composition, through the nail to which it is applied, and into a systemic tissue compartment also forms an aspect of the invention.
  • the therapeutically active substance may be applied in the form of a composition comprising one or more components for promoting retention of the composition within or on the nail surface.
  • the composition may comprise a film-forming component or it may be in the form of a varnish, lacquer, gel or solution.
  • the substance may be applied to the nail in a patch.
  • Film-forming components may be chosen so as to modulate the rate of penetration of the therapeutically active substance. I.e. it may enhance or restrict the rate of penetration or it may allow the nail itself to act as a reservoir.
  • the composition may include an additional component which has the capacity to modulate the rate of penetration of the therapeutically active substance in this way. Again the composition may itself enter the nail and modulate the inward absorption of the drug. Agents may also be added to decrease local effects such as irritancy arising from the therapeutically active agent or components of the formulation.
  • tne method of the invention does not require the application of electrodes to the finger or toe nails in order to provide an e.m.f. which promotes transport by electrophoresis or iontophoresis.
  • the therapeutically active substance is transported passively through the finger or the toe nail in accordance with the invention.
  • Passive transport in accordance with the invention can include transport by diffusion as well as transport that is mediated by physiological processes or by the application of penetration enhancers.
  • the method of the invention is applicable to adminstration of a wide variety of therapeutically active substances including, for example, ones having a therapeutic effect on the central nervous system, cardiovascular system, endocrine system or respiratory system as well as therapeutically active substances having an analgesic or anti-allergic effect.
  • the method of the invention may be applied to the administration of therapeutically active substances which have a therapeutic effect on the gastrointestinal tract or the genito-urinary system or ones which have a contraceptive activity.
  • the therapeutically active substances can include not only chemically synthesized drugs, but also biologically-derived molecules, for example physiological substances such as growth factors, hormones and their release factors, enzymes and lymphokines.
  • the substances to be delivered may act as vaccines or immunomodulators.
  • anti-infective agents for example antibiotics (including antimicrobial and antiviral drugs), drugs which affect metabolic processes such as calcium transport, iron metabolism and metabolic processes involving folic acid, cytostatic and anti-neoplastic drugs, haematopoietic drugs and drugs that act on the muscular/skeletal, neural and neuromuscular system.
  • Other therapeutically active substances include ones which affect gene structure and function.
  • the therapeutically active substance can have dermatological activity although it is to be understood that such activity should be at a site distal from the site of application to the nails.
  • Drugs that act on oral tissues e.g. drugs for treating dental or gingival pathologies are also included.
  • the substances to be delivered by the method of the invention may have an effect on pathological disorders which involve single or many body systems including those whose mechanism is still uncertain. It may also be used prophylactically or for physiological or social purposes.
  • the method can be used for the delivery of substances acting on any bodily system, organ or tissue in health or disease.
  • the term "therapeutically active substance” as used herein in intended to extend not only to substances which have a therapeutic action per se, but also to substances which comprise so called “pro-drugs", i.e. substances which convert to a therapeutically active form on administration.
  • the term “therapeutically active substance” extends not only to substances which are specifically adapted to cure or ameliorate the symptoms of a disease, but also to substances which have a palliative effect as well as substances which are used as so-called “recreational” drugs.
  • One example in this connection is the use of the method of the invention for administering nicotine as part of a therapy designed to wean a tobacco smoker from his or her addiction.
  • Figure 1 depicts the results of an experiment measuring trans ungual water loss.
  • Figure 2 depicts the results of an experiment measuring water loss with increasing stripping (as a normal curve).
  • Figure 3 depicts the results of an experiment measuring cumulative penetration of ( 3 H)-Nicotine through human nail following a single application of a 50% (v/v) solution in 0.1 M HEPES buffer, pH 7.4.
  • Figure 4 depicts the results of an experiment measuring cumulative penetration of ( 3 H)-Clonidine through human nail following a single application of a 52.8 mg/mL solution in 0.1 M HEPES buffer, pH 7.4.
  • Figure 5 depicts the results of an experiment measuring cumulative penetration of ( 3 H)-DAGO through human nail following a single application of an 8 mg/mL solution in 0.1 M HEPES buffer, pH 7.4.
  • Figure 6 depicts the results of an experiment measuring cumulative penetration of ( 3 H)-Propranolol through human nail following a single application of a saturated solution in 0.1 M HEPES buffer, pH 7.4.
  • Figure 7 depicts the results of an experiment measuring cumulative penetration of ( 3 H)-Melatonin through human nail following a single application of a saturated solution in 0.1 M HEPES buffer, pH 7.4.
  • the nail was 5 to 10 times more permeable to water than skin, despite the 100-fold greater thickness of the nail plate than the stratum corneum.
  • the nail is 1000 times more permeable than skin.
  • this greater permeability could be applied to the inward carriage of substances such as drugs and prodrugs.
  • the nail could be made to absorb drug at a rate of 100 times more rapidly than the skin, and even more rapidly if the nails were treated as discussed below.
  • the carrier to be used can vary with the different drugs; thus it could be, for example, in the form of a conventional nail lacquer, a peel-off applicator, a water soluble drying gel, a stable emulsion, an aerosol or liposomal or lipid or cream base; likewise a simple alcoholic or aqueous solution could be used, the choice depending on the characteristics of the drug to be delivered and the dosage required.
  • the drug application could be made in one particular carrier in which the drug or prodrug could be dissolved or suspended, and then the whole covered by further material, e.g.
  • an advantage of the invention is that a large range of carrier bases can be used and selected so that the effect of the nail itself could be optimised to act both as a reservoir and rate limiting delivery system for the applied drug, by using partitioning between the vehicle and nail and subsequent systemic absorption from the nail.
  • the absorptive characteristics of the nail could themselves be modified: thus nail thickness could be decreased e.g. by abrasion and other physical methods, and modifiers of permeability could be used e.g.
  • penetration enhancers as previously mentioned or enzymes to enhance delivery.
  • systemic absorption of drug from the nail could be limited by maintaining nail dehydration e.g. by using a hypertonic solution.
  • the use of the nail as a reservoir for the absorbed drug can be modulated in several ways. By prior application of saturated or even supersaturated solutions of drug the nail reservoir can be rapidly filled after which continued constant absorption can be achieved by further surface application as described.
  • a suitable source of fluid to the nail surface e.g. in a pad
  • drug can be rapidly extracted from the nail and its effect thereby terminated. Variations in such application would also permit specifically designed pulsed absorption of drugs.
  • the rate of delivery is related to the surface area of the nail, and since each nail has a different surface area and thickness, enabling a consistently different water flux (varying from for example 9 to 13 g/m 2 /hr in one study going from the first to the fifth digit on the hand and similarly for the feet), it will be possible to use nails singly or in combination to control the dose of drug absorbed by a range of some 50-fold.
  • the method provides a unique control of dosage delivery.
  • stratum corneum is best able to absorb substances which exhibit an approximately 50:50 distribution between aqueous and lipid phases or are more lipophilic
  • finger and toe nails have been found to be able to absorb therapeutically active substances which are more hydrophillic.
  • the range of therapeutically active substances which can be administered is not limited in the same way as the stratum corneum to particularly critical lipid/water solubility partition characteristics.
  • the compositions which are applied to the finger and toe nails do not need to be in the form of oil/water emulsions and effective compositions can be prepared which are essentially lipid-free.
  • substances having molecular weights in excess of 1000 daltons usually fail to pass through the stratum corneum in satisfactory quantities, higher molecular weights substances could be administered in accordance with the invention via finger and toe nails.
  • a therapeutically active substance in accordance with the invention has a further advantage that the active substances can be administered in a wide range of dosage amounts.
  • the dosage amount can be increased in multiples by applying the composition to 1 , 2, 3... 20 finger and toe nails.
  • the dosage range may be varied by up to 20 times simply by selecting the number of nails to which the composition is applied.
  • different nails have different surface areas (c.f. the thumb and first toe nails with the fifth finger and fifth toe nails) an even wider range of possible dosage rates can be achieved by applying the composition of the invention to different finger and toe nails.
  • the rate of administration may be further adjusted by incorporating penetration enhancers.
  • the therapeutically active substance can enter the systemic circulation without initially entering the hepatic circulation.
  • compositions for use according to the invention customary binding agents and film forming materials may be used.
  • any of the polymeric film forming substances normally used in nail varnishes may be used, provided that they are compatible with the therapeutically active substance.
  • examples include polyvinylacetate, acrylate and methacrylate esters and nitrocellulose.
  • the same range of adjuvants may be used for application to the nail for example emulsifying agents, surfactants, thickening agents, stabilisers, colorants, buffers, antioxidants, etc.
  • the concentration of therapeutically active substance can vary over a wide range but normally would not exceed about 100 or 200 milligrams per millilitre. Normally a concentration in the range of 10 micrograms to 100 milligrams per millilitre would be used, most preferably 0.1 to 50 milligrams per millilitre, and especially 0.5 to 20 milligrams per millilitre.
  • the transport of therapeutically active substances through nail tissue was examined for eleven drugs.
  • the drugs included those used in conventional patch delivery systems and others which are not known to be delivered in this way.
  • the drugs were chosen to include a range of molecular size, chemical characteristics - polar/non-polar, lipid/water solubility and a variety of pharmacological effects.
  • a modified Franz cell was used, and normal big toe nails (mostly obtained after surgical removal for ingrowing nails or injury) were stuck between two sheets of Teflon with aligned holes, separating a donor from receptor reservoir.
  • the nails were soaked in HEPES buffer pH7.4 for 24h, the donor reservoir was then served with 1 ml volume of a solution of the drug in buffer (see Table 1 for dose concentrations) and the passage of the radio-isotope of the drug into the receptor reservoir was measured at timed intervals up to 36h. When the experiment was completed residual isotope was measured in the nail after incineration. Replicates were made for all the drugs studied.
  • DAGO* (enkephalin analogue) 1.48 25 2.9 2-24 0.73
  • the results from the in vivo study confirms the in vitro findings that transungual absorption of drugs occurs and can provide quantities of drugs sufficient for systemic therapeutic action.
  • the in vitro studies used a range of drugs and absorption occurred with different levels of lipophilicity and water solubility, polarity, molecular size, etc. These results indicated that with suitably adjusted vehicles, including enhancing agents if necessary, far more drug could be made to pass through the nail because of selective partitioning. Thus, we can predict that transungual absorption could be increased still further. Nevertheless the quantities which were absorbed through the nail were in many instances adequate to provide systemic therapeutic effects. Some, like nicotine and clonidine are well absorbed through the transdermal patch system and nail application would provide an alternative system, but others e.g.
  • the nail provides a significant large reservoir from which systemic absorption of drugs can proceed.
  • a reservoir could supersede the use of an external reservoir as in a patch system, or indeed could be used further to amplify such a reservoir designed to compliment the specific characteristics of the nail.
  • Table 1 shows the magnitude of the reservoir in the nails (demonstrated by combustion and radioisotopic measurement and expressed as a percentage of the drug material applied to the donor reservoir).
  • the figures were 5.49 for nicotine, 4.89 for verapamil HCl, 2.39 for DL-propranolo HCl, 2.35 for clonidine HCl and 0.14 for DAGO (enkephalin analogue, Tyr Ala Gly Phe Gly; obtainable under catalogue E7384 from Sigma Chemical Company).
  • a nicotine containing nail varnish was prepared by dissolving 2 wt% nicotine in a commercially available thixotropic nitrocellulose collodion sold by SNPE Chimie under the designation Suspension Base 320
  • a second and third formulations were prepared as described in Example 1 , but containing 5 wt% and 10 wt% nicotine.
  • Formulations similar to those described in Examples 1 and 2 were prepared using a resin based thixotropic gel manufactured by SNPE Chimie and designated Thixotropic GEL 373.
  • Formulations similar to those described in Examples 1 -3 or alternatively in aqueous buffer solutions may be made using the drugs listed in Table 1.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte à un procédé d'administration à un sujet d'une substance active thérapeutiquement, consistant à appliquer cette substance sur la surface d'un ou de plusieurs ongle(s) de main et/ou de pied, cette substance étant absorbée et transportée par voie générale vers un site d'action éloigné de l'ongle de main ou de pied.
EP95909904A 1994-03-04 1995-03-03 Systeme d'administration par voie generale d'un medicament consistant a appliquer celui-ci sur les ongles Withdrawn EP0748216A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9404293A GB9404293D0 (en) 1994-03-04 1994-03-04 Drug delivery system
GB9404293 1994-03-04
PCT/GB1995/000459 WO1995023597A1 (fr) 1994-03-04 1995-03-03 Systeme d'administration par voie generale d'un medicament consistant a appliquer celui-ci sur les ongles

Publications (1)

Publication Number Publication Date
EP0748216A1 true EP0748216A1 (fr) 1996-12-18

Family

ID=10751375

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95909904A Withdrawn EP0748216A1 (fr) 1994-03-04 1995-03-03 Systeme d'administration par voie generale d'un medicament consistant a appliquer celui-ci sur les ongles

Country Status (9)

Country Link
EP (1) EP0748216A1 (fr)
JP (1) JPH09509676A (fr)
CN (1) CN1146721A (fr)
AU (1) AU1820495A (fr)
CA (1) CA2184075A1 (fr)
GB (1) GB9404293D0 (fr)
NO (1) NO963674L (fr)
NZ (1) NZ281304A (fr)
WO (1) WO1995023597A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19604190A1 (de) * 1996-02-06 1997-08-07 Hoechst Ag Nagelwachstumsfördernde Zubereitungen
US6727401B1 (en) 1998-02-12 2004-04-27 Watson Pharmaceuticals, Inc. Pressure sensitive adhesive matrix patch for the treatment of onychomycosis
GB0203276D0 (en) * 2002-02-12 2002-03-27 Novartis Ag Organic compounds
EA200601630A1 (ru) * 2004-03-04 2007-02-27 Макото Юаса Ниосома, имеющая внедрённый в неё маталлопорфириновый комплекс, способ её получения и лекарственное средство с её использованием
EP1627610A1 (fr) * 2004-08-21 2006-02-22 TLT Medical Ltd Administration de médicaments par application dans des ongles

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247142B1 (fr) * 1985-11-04 1993-01-07 Owen/Galderma Laboratories Inc. Vehicules pharmaceutiques filmogenes pour l'application de medicaments sur les ongles, compositions pharmaceutiques a base de ces vehicules, et leurs procedes d'utilisation
CA1273878A (fr) * 1987-01-15 1990-09-11 Richard Philip Moody Preparation de nicotine pour administration transdermique
FR2616333A1 (fr) * 1987-06-12 1988-12-16 Cird Procede d'ionophorese pour administrer une substance dissoute ou partiellement dissoute, par voie percutanee ou perungueale et dispositif correspondant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9523597A1 *

Also Published As

Publication number Publication date
JPH09509676A (ja) 1997-09-30
WO1995023597A1 (fr) 1995-09-08
NO963674D0 (no) 1996-09-03
NZ281304A (en) 1999-09-29
AU1820495A (en) 1995-09-18
GB9404293D0 (en) 1994-04-20
CN1146721A (zh) 1997-04-02
NO963674L (no) 1996-09-03
CA2184075A1 (fr) 1995-09-08

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