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WO2017005375A1 - Procédé permettant d'améliorer l'administration de médicaments à travers la peau - Google Patents

Procédé permettant d'améliorer l'administration de médicaments à travers la peau Download PDF

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Publication number
WO2017005375A1
WO2017005375A1 PCT/EP2016/025069 EP2016025069W WO2017005375A1 WO 2017005375 A1 WO2017005375 A1 WO 2017005375A1 EP 2016025069 W EP2016025069 W EP 2016025069W WO 2017005375 A1 WO2017005375 A1 WO 2017005375A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
strokes
microcrystals
fractured
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2016/025069
Other languages
English (en)
Inventor
Johan Selmer
Torsten SKOV
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.)
Leo Laboratories Ltd
Original Assignee
Leo Laboratories 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 Leo Laboratories Ltd filed Critical Leo Laboratories Ltd
Publication of WO2017005375A1 publication Critical patent/WO2017005375A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents

Definitions

  • the invention relates to a pre-treatment of human skin, which improves the delivery of topical administered compounds through the skin outer barrier.
  • the present invention demonstrates how only a few strokes with fractured microcrystals on a solid support of the correct constitution can provide increased penetration of for example pharmaceutically active compounds through the skin with minimal or no microscopic changes to the stratum corneum.
  • the method is particularly relevant for skin diseases and disorders, which would benefit from drug delivery to the dermis and epidermis of the skin.
  • Figure 1 shows the concentration of compound 2 in dermis and epidermis.
  • Figure 2 shows skin histology with and without pretreatment.
  • Figure 4 shows results of skin penetration of compound 4
  • Figure 5 shows results of skin penetration of clobetasol propionate
  • Figure 6 shows results of skin penetration of betamethasone valerate
  • Figure 7 shows results of skin penetration of ibuprofen
  • the invention provides the following :
  • a method for increasing drug penetration by pretreating the skin by applying 1-20 strokes of fractured microcrystals on a solid support followed by application of the pharmaceutical is a method for increasing drug penetration by pretreating the skin by applying 1-20 strokes of fractured microcrystals on a solid support followed by application of the pharmaceutical.
  • the application also discloses a kit of parts characterized by a kit having the fractured microcrystals on a solid support and the topical formulation of a pharmaceutical. Detailed description of the invention
  • the present invention For characterization of the fractured microcrystals on solid support, the present invention has used the well-established system for sandpaper. This characterizes the size of the microcrystals by well-known means by a standardized and generally accepted method . For the sake of quantification of the fractured microcrystals, the invention uses the characterisations systems as used for commercial available sandpaper. In the present invention, the sandpaper used was characterized by the P-coding.
  • the P-coding is the FEPA (Federation Europeenne des Fabricants de Produits Abrasifs) Federation of European Producers of Abrasives coding system .
  • the FEPA distinguishes between grain for sanding paper (FEPA P) is only used for sanding paper.
  • the definition of the P numbers is publicly available information .
  • the present invention has also applied test procedures using commercially available sandpaper to test the invention.
  • the present invention provides increased delivery of compound to the dermis and epidermis following pre-treatment of the skin by the method of the invention .
  • Initial experiments indicate that the stratum corneum of test samples is virtually intact with respect to thickness. This distinguishes the present method from other disclosed methods where the stratum corneum is either removed or reduced in thickness by excessive abrasion procedures.
  • the present invention discloses that the thickness of the stratum corneum is virtually intact, which in the context of the present invention means that the method is not dermabrasion because the method does not compromise the thickness of the stratum corneum, but instead some minor incisions are observed.
  • the invention provides an increased skin penetration as demonstrated by increased
  • the present invention has demonstrated the general applicability of the present invention by applying different known topical administered pharmaceuticals. The experiments show that regardless of the topical drug applied, the concentration in the skin is at least doubled. Some test compounds show up to 20 fold increase in the concentration following application of this method .
  • the invention provides increased drug delivery of topical applied drugs by skin barrier disruption following a limited number of strokes of fractured microcrystals on a solid support within a range of certain grit sizes.
  • the method is robust in that the number of strokes applied only has little impact on the increase in drug penetration.
  • the number of strokes is for the purpose of the present invention defined as for example 1-20 strokes.
  • Experiments indicate lack of overall disruption of destruction of the stratum corneum as it is seen with other abrasive procedures.
  • the limited number of strokes and the correct choice of grit size of the fractured microcrystals on a solid support, is considered the key to increase drug delivery in a robust and reproducible manner.
  • the method of the present invention does not destroy, remove or diminish the stratum corneum to a significant extent. Some local or minimal disruption of the stratum corneum is likely present, due to the procedure, and apparently, this is enough to ensure drug delivery in a significantly increased volume.
  • the invention provides increased penetration of topical applied drugs by skin barrier disruption following a number of strokes of fractured microcrystals on a solid support as represented by sandpaper grit size P220 and below.
  • the range of sandpaper applied is P40- P220.
  • the number of strokes is between 1-20 strokes. In an embodiment the number of strokes is 3-20. In other embodiments the number of strokes is between 1 and 10. In other embodiments the number of strokes is between 1 and 5. In other embodiments the number of strokes used is between 3 and 5. In embodiments the number of strokes used is 3.
  • the experiments conducted have applied a range of pressures on the solid support.
  • the force applied was described in experiments below.
  • the force used has been described as a light pressure applied by the fingers on the sandpaper.
  • Some grit sizes of the fractures microcrystals show no significant influence by the force applied in the method, while the smaller grit sizes show some influence by the force applied .
  • the present invention provides the application of the method as described wherein the force applied to fractured microcrystals on the solid support is between about 0.2 N/cm 2 - 1.0 N/cm 2 . In embodiments of the invention the force applied is about 0.3 N/cm 2 - 0.8 N/cm 2 .
  • the force applied is about 0.5 N/cm 2 - 0.7 N/cm 2 .
  • the strokes are all performed in the same direction. In embodiments of the invention the strokes are applied as half in one direction, and the other half in perpendicular direction .
  • the invention provides a method for achieving an up to 20 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin. In embodiments the invention provides up to 15 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin . In embodiments the invention provides up to 10 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin . In embodiments the invention provides up to 5 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin. In embodiments the invention provides up to 2 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin .
  • the invention provides more than 5 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin. In an embodiment the invention provides a 5-20 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin . In an embodiment the invention provides a 5-15 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin . In an embodiment the invention provides a 5-10 fold increased delivery of the drug in the dermis and epidermis compared to untreated skin .
  • the invention thus provides a method for treating diseases, which is otherwise difficult to treat due to for example lack of penetration of the pharmaceutical into the skin .
  • the invention also provides a method for reducing the amount of active compound applied in the treatment a certain disease.
  • a method for increasing drug penetration through to the stratum corneum characterized by pretreating the skin by applying 1-20 strokes of fractured microcrystals on a solid support followed by application of the pharmaceutical .
  • a method for increasing drug penetration to the dermis and epidermis characterized by pretreating the skin by applying 1-20 strokes of fractured microcrystals on a solid support followed by application of the pharmaceutical .
  • a method for increasing drug penetration through the skin characterized by pretreating the skin by applying about 1-20 strokes of fractured microcrystals on solid support within the ranges of P40 to P220 to the skin, followed by application of topical formulation of a pharmaceutical .
  • a method for increasing drug penetration to the dermis and epidermis characterized by pretreating the skin by applying about 1-20 strokes of fractured microcrystals on solid support within the ranges of P40 to P220 to the skin, followed by application of topical formulation of a pharmaceutical .
  • a method for increasing drug penetration to the dermis and epidermis by at least 2 fold compared to untreated skin characterized by pretreating the skin by applying about 1-20 strokes of fractured microcrystals on solid support within the ranges of P40 to P220 to the skin, followed by application of topical formulation of a pharmaceutical.
  • the skin disease is actinic keratosis or non-melanoma skin cancer.
  • the invention provides a method for improving drug penetration into the dermis and epidermis by applying 1-20 strokes with fractured microcrystals on a solid support with a grit size between P40 and P220 and by applying a force of 0.2 N/cm 2 - l .ON/cm 2
  • the present invention has demonstrated the general utility of the method by applying a number of different model compounds.
  • the effect for the compounds 1-4 has been documented through clinical testing. Therefore, their effect has been well understood, and established analytical methods to detect presence and concentration have been described. .
  • the present invention has used an estimate of the side effects, the local skin reaction, as a measure of penetration into the skin of these compounds.
  • the local skin reactions have been carefully qualified and characterized in a series of clinical trials concerning model compounds. Therefore, the measurement of local skin reaction is an acknowledged in vivo method for estimating the amount of compound that has penetrated the skin without taking out samples of live skin . Also in-vitro data have been generated to show the drug concentration in dermis and epidermis of model compounds.
  • the enclosed experiments show effect through in-vitro and in- vivo experiments not only on the 2 established products, but across 3 different molecules.
  • the model compounds used are all formulated in a hydroalcoholic gel formulation for comparison.
  • commercially available topical pharmaceuticals have been tested according to the present invention. The experiments show that the present invention is general applicable to any of the compounds used.
  • the experiment used explant skin 8 mm in 3 replicates.
  • the Compound 2 in 0.05% is applied in 5 ⁇ per well .
  • the experiment included the following pre-treatments:
  • skin biopsies (3 mm) were taken from a freshly sanded area on the upper arm close to previous sanding.
  • the freshly sanded area was sanded exactly like the initial sanding : i.e. a total of 8 strokes parallel to the upper arm.
  • a biopsy was taken from a non-sanded area close to the sanded area .
  • Section 1 was sanded with 1 stroke
  • Section 2 was sanded with 3 strokes
  • Section 3 was sanded with 6 strokes
  • Section 4 was pretreated with 9 strokes. All sanding were performed parallel to the upper arm . All sections on the one arm were treated with Compound 1, 0.0075% in a volume of approximately 10 microliter/cm 2 .
  • an area "Section 0" not pretreated with sanding, were also treated with Compound 1, 0.0075% in a volume of approximately 10 microliter/cm 2 .
  • Section 0 to Section 4 were treated with methylene blue 1 mg/ml vehicle gel in a volume of approximately 10 microliter/cm 2 .
  • Methylene blue was used as a marker of stratum corneum integrity.
  • the Compound 1 treated sections were inspected and photographed after 24 hours.
  • Sanding with sandpaper P150 increased the effect of a low concentration of Compound 1.
  • a concentration of Compound 1 of 0.0075% gave rise to stronger skin reaction and importantly more uniform skin reactions as compared to treatment with Compound 1, 0.05% used for two consecutive days.
  • test fields were tape stripped 60X prior to application of Compound 1.
  • the day of first dosing was designated day 1.
  • the dosing day 7 was performed 24 hours prior to termination of the animals.
  • Sandpapering was done by applying a slight pressure using fingers on sandpaper with grit size P150. Sandpapering was done 6 or 12 times on each relevant test field . The first halves of the strokes were done in one direction . The following halves of the strokes were done perpendicular to the initial strokes. A piece of sandpaper was only used three times and then exchanged with new sandpaper before continuing the procedure. Tape stripping was performed by applying and removing tape to/from the skin test field for 60 consecutive times. The tape used is 3M Transpore. The application was performed by two persons. One person holding a tape strip above the skin while the other person presses the tape strip onto the test field with the fingers. The applied pressure should be firm yet not too hard. An area of tape was only used to tape strip once.
  • Compound 1 was applied immediately after pretreatment of the test fields. 20ul formulation was applied with a positive dispensing pipette. The concentration of Compound 1 dosed were 0.015%, 0.05% or 0.1% .
  • the test fields were observed at 6h, 24h (day 2), 48h (day 3), and 72h (day 4), 96h (day 5), 120h (day 6), 144h (day 7), 168h (day 8) after dosing .
  • the Local Skin Response was scored defined as erythema, necrosis, oedema, ulceration, vesiculation, crusting/flaking and telangiectasia each on a scale from 0 to 3. At each time point, pictures were taken of the test fields.
  • the optimal grit size of the sandpaper was investigated in a pig skin model .
  • Sandpaper of different P-numbers were tested in grit size P40, P60, P80, P120, P150, P180, P220, P320, P600, P800 and P1000.
  • Control test fields was treated with Compound 1, 0.05% and 0.1%
  • Control test fields was treated with Compound 2, 0.05% and 0.1%
  • Sandpapering was done by applying a slight pressure using fingers on sandpaper with varying grit size (P40, P60, P80, P120, P150, P180, P220, P320, P600, P800 and P1000). Sandpapering was done 12 times on each relevant test field . The first halves of the strokes were done in one direction . The following halves of the strokes were done perpendicular to the initial strokes. A piece of sandpaper was only used six times and then exchanged with new sandpaper before continuing the procedure.
  • Tape stripping was performed by applying and removing tape to/from the skin test field for 60 consecutive times (table 2).
  • the tape used was 3M Transpore.
  • the application was performed by two persons. One person held a tape strip above the skin while the other person pressed the tape strip onto the test field with the fingers. The applied pressure should be firm yet not too hard. An area of tape was only used to tape strip once.
  • Compound 1, 2 or 3 were applied immediately after pre-treatment of the test fields. 20ul formulation was applied with a positive dispensing pipette. The concentration of compound dosed on each test field was 0.1% or 0.05%.
  • the test fields were observed at 6h, 24h (day 2), 48h (day 3), and 72h (day 4), 96h (day 5), 120h (day 6), 144h (day 7), 168h (day 8) after dosing.
  • the LSR scored was defined as erythema, necrosis, oedema, ulceration, vesiculation, crusting/flaking and telangiectasia each on a scale from 0 to 3.
  • the aim of the study is to provide in vivo data supporting the hypothesis that a skin preparation with fractured microcrystals will enhance skin penetration of pharmaceuticals.
  • the pharmaceuticals tested were :topical applied compounds 3 and 4, and other classes of drugs (NSAID, steroids)
  • the treated fields were gently washed with a surgical scrub (Hibiscrub®), tape stripped twice, and the skin was cut out from treated areas. Biopsies for drug concentration were taken inside-out from the cut-out skin and flash frozen .
  • test fields were 3x3 cm test fields, and the amount of formulation applied was 90 ⁇ for formulation containing ingeol derivatives and 45 ⁇ steroid and NSAID formulations.
  • the skin preparation procedure employed was either three strokes with sandpaper grit size P80 or six strokes with sandpaper P150.
  • the strokes were performed at three different forces : approximately 8N, 15N and 29N, equivalent to 800g, 1.5 kg and 3 kg.
  • the skin preparation procedure employed was either three strokes with sandpaper grit size P80 or three strokes with sandpaper P150.
  • the strokes were performed at three different forces: approximately 4N, 8N and 15N, equivalent to 400g, 0.8 kg and 1.5 kg applied on an approximately 15 cm 2 area by using weight applied support designed to control the preparation procedure in terms of the applied pressure.
  • fields were prepared by using handheld sandpaper.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé permettant d'augmenter la pénétration de produits pharmaceutiques par application cutanée.
PCT/EP2016/025069 2015-07-08 2016-06-30 Procédé permettant d'améliorer l'administration de médicaments à travers la peau Ceased WO2017005375A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15175876 2015-07-08
EP15175876.0 2015-07-08

Publications (1)

Publication Number Publication Date
WO2017005375A1 true WO2017005375A1 (fr) 2017-01-12

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/025069 Ceased WO2017005375A1 (fr) 2015-07-08 2016-06-30 Procédé permettant d'améliorer l'administration de médicaments à travers la peau

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WO (1) WO2017005375A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060047242A1 (en) * 2004-08-25 2006-03-02 Becton, Dickinson And Company Method and device for the delivery of a substance including a covering
US20090232580A1 (en) * 2008-03-17 2009-09-17 Castel John C Multi-Functional Applicator
WO2010040271A1 (fr) * 2008-10-07 2010-04-15 Tuo Jin Micro-aiguilles polymères à transition de phase
US20130226107A1 (en) * 2012-02-27 2013-08-29 Lexington Pharmaceuticals Laboratories, Llc Medicinal roller ball applicators, associated pharmaceutical compositions, and their use to treat afflicted skin tissues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060047242A1 (en) * 2004-08-25 2006-03-02 Becton, Dickinson And Company Method and device for the delivery of a substance including a covering
US20090232580A1 (en) * 2008-03-17 2009-09-17 Castel John C Multi-Functional Applicator
WO2010040271A1 (fr) * 2008-10-07 2010-04-15 Tuo Jin Micro-aiguilles polymères à transition de phase
US20130226107A1 (en) * 2012-02-27 2013-08-29 Lexington Pharmaceuticals Laboratories, Llc Medicinal roller ball applicators, associated pharmaceutical compositions, and their use to treat afflicted skin tissues

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