WO2019105890A1 - Procédé d'analyse d'absorption percutanée d'un agent - Google Patents

Procédé d'analyse d'absorption percutanée d'un agent Download PDF

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Publication number
WO2019105890A1
WO2019105890A1 PCT/EP2018/082552 EP2018082552W WO2019105890A1 WO 2019105890 A1 WO2019105890 A1 WO 2019105890A1 EP 2018082552 W EP2018082552 W EP 2018082552W WO 2019105890 A1 WO2019105890 A1 WO 2019105890A1
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WO
WIPO (PCT)
Prior art keywords
agent
skin
interstitial fluid
percutaneous absorption
determining
Prior art date
Application number
PCT/EP2018/082552
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English (en)
Inventor
Markus Renlund
Pelle Rangsten
Original Assignee
Ascilion Ab
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 Ascilion Ab filed Critical Ascilion Ab
Priority to EP18814803.5A priority Critical patent/EP3758605A1/fr
Publication of WO2019105890A1 publication Critical patent/WO2019105890A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/44—Detecting, measuring or recording for evaluating the integumentary system, e.g. skin, hair or nails
    • A61B5/441—Skin evaluation, e.g. for skin disorder diagnosis
    • 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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A61B2010/008—Interstitial fluid

Definitions

  • the present invention relates to a method of analysis of skin permeability, and in particular a method of measurement of local percutaneous absorption of an exogenous agent.
  • measurement of skin absorption of an agent include measuring a concentration of the agent in blood, taking skin samples for analysis, in addition to various in vitro methods using skin. It is also known to calculate permeability coefficients ( K P ) for chemical compounds based on their size (molecular weight or molecular volume) and octanol/water partition coefficient (Potts, R.O. & Guy, R.H. Pharm Res (1992) 9: 663). The mass of chemical absorbed through the skin can then be calculated
  • Usk is the mass of chemical absorbed through the skin (mg)
  • K P is the permeability coefficient (cm-lr 1 )
  • C is the concentration on the skin (mg -cm 3 )
  • A is the area exposed (cm 2 ), and t is the duration of exposure (h).
  • Using a blood sample for analysis entails drawing blood from the subject, which may be more or less of an uncomfortable procedure for the subject, and normally requires a medically qualified person to perform it. Furthermore, measuring blood levels of an agent, after exposure of subject to the agent, gives a system-wide average concentration of the blood, as the agent, if present in the blood, will be instantly diluted throughout the circulatory system. This may make it difficult to relate the absorbed levels to the amount of exposure of the agent on a localized area of skin.
  • Taking a skin sample after exposure to an agent is an invasive procedure, which may be anything from uncomfortable to painful for the subject, and runs the risk of infection at the sample site.
  • US 2011/0112121 A1 discloses methods of analyzing skin penetration.
  • the analytical method involves isolating the epidermis of sacrificed animals by heating the skin samples, taking biopsies and analyzing the content of the biopsies by LC/MS.
  • Skin permeability may actively be influenced by human interference in different manners.
  • One example of external manipulation of skin permeability is ultrasound treatment, as shown in US 6,190,315 B1 , wherein is disclosed a method using ultrasound to enhance transdermal transport of drugs.
  • microneedles in devices for sampling of bodily fluid. See e.g. WO2015/027093, WO2016/164208, WO2011/116388,
  • Such devices may be used to sample interstitial fluid or blood, and analyzing various endogenous agents, e.g. glucose levels or levels of various biomarkers.
  • a microneedle within such an array is provided with a capillary bore for withdrawing the interstitial fluid.
  • a number of microneedles are provided on a substrate, and by capillary action, and/or an applied suction or sub-atmospheric pressure, a sample is extracted from the skin and into a collection or analysis chamber.
  • microneedles With hollow microneedles a new type of pain-free general extraction method of bodily fluids can be used.
  • the skin penetration with microneedles is perceived as minimally invasive and causes no pain, with needles too short to reach sensory nerves in the skin. It can utilize interstitial fluid, instead of blood, as measurement media, extracted through a matrix of sub-millimeter long silicon microneedles at a skin depth where no blood capillaries exist.
  • An example of such a microneedle is disclosed in WO 2017/095321.
  • a microneedle having a capillary bore extending in the longitudinal direction and having an opening close to the distal end. The proximal end is connected to a substrate on which the microneedle is provided.
  • the distal end is configured with a bevel.
  • An object of the present invention is to provide a method for analyzing agents applied to the skin.
  • a further object of the present invention is to provide a method for determining whether a person has been exposed to an agent capable of penetrating the skin.
  • Another object of the present invention is to provide a method of measurement of local percutaneous absorption of an agent with minimal effect on the absorption process itself.
  • Yet another object is to provide a method of measurement of local percutaneous absorption of an agent with minimal effect on the metabolism and effect of the absorbed agent.
  • the present disclosure relates to a method of analyzing local percutaneous absorption of an agent, characterized by the steps a) applying the agent to the skin of a subject b) extracting interstitial fluid from the skin using at least one hollow microneedle; c) determining a presence of the agent in the extracted interstitial fluid, wherein the presence of the agent in the extracted interstitial fluid indicates local percutaneous absorption of the agent.
  • the determination of the presence of the agent in the extracted interstitial fluid further comprises determining a concentration of the agent in the extracted interstitial fluid.
  • the method further comprises a step of calculating a ratio of the amount of agent in the interstitial fluid in relation to the amount of agent applied to the skin surface.
  • a skin surface area through which the extraction is performed is essentially within a skin surface area where the agent is applied.
  • the invention relates to a method of analyzing the ability of a helper agent to modify local percutaneous absorption of an agent comprising performing the method according to the above in the presence and absence of said helper agent, respectively, and comparing the results.
  • a method for determining whether a person has been exposed to an agent capable of penetrating the skin comprising steps of extracting interstitial fluid from the skin of a subject with at least one hollow microneedle, and determining a presence of the agent in the interstitial fluid is disclosed.
  • the invention relates to the use of at least one microneedle in a method according to the invention.
  • known methods of analyzing concentration of agents in interstitial fluid focus on analysis of endogenous agents, or substances transported to the interstitial fluid via the bloodstream.
  • Known methods for analyzing local percutaneous absorption of agents are commonly invasive, painful and/or require time-consuming steps and resources.
  • a method of analyzing the ability of an agent to penetrate a skin's outer layer comprising the steps of a) applying an agent to the skin of a subject b) extracting interstitial fluid from the skin using at least one hollow
  • microneedle c) determining a presence of the agent in the interstitial fluid. This method is based on the realization that the presence and/or amount of an exogenous agent in the interstitial fluid will directly correlate to the amount absorbed by the skin after application of, or direct exposure to, the agent on a skin surface.
  • An agent to be determined in the present invention may be a chemical compound that is capable of being absorbed through the human or animal skin.
  • the use of the above method, and in particular the use of at least one hollow microneedle to extract interstitial fluid from the skin has minimal effect on the absorption process itself.
  • the extremely small size of the needles barely affects the skin surface, and the small amount of interstitial fluid extracted is a very small volume compared to the total volume of the interstitial fluid in the sample area of the skin.
  • the step of determining a presence of the agent in the interstitial fluid may comprise determining a concentration of the agent in the interstitial fluid. Depending on the nature of the agent, various methods of detection and measurement may be used.
  • a ratio of the amount of agent in the interstitial fluid in relation to the amount of agent applied to the skin surface may be calculated.
  • the extraction of the interstitial fluid is performed within a skin surface area that is essentially within a skin surface area where the agent is applied.
  • Such a method may have many applicable uses.
  • One example is within drug discovery or the cosmetics industry, wherein an active, or passive, substance’s ability to penetrate skin needs to be quickly and easily assessed.
  • any known means of application of, or exposure to, an agent on a skin surface may be used.
  • Non-limiting examples may be applying a powder, solid, patch, paste, cream, emulsion, solution, suspension, gel, gas, aerosol or spray comprising the agent, or immersion in a fluid comprising the agent.
  • the method above may also be used for analyzing the ability of a helper agent to modify the ability of an agent to penetrate a skin's outer layer. This may be performed by executing the method as described above in the presence and absence of said helper agent, respectively, and comparing the results.
  • a method for determining whether a subject has been exposed to an agent capable of penetrating the skin comprising the steps a) extracting interstitial fluid from the skin of a subject with at least one hollow microneedle; b) determining a presence of the agent in the interstitial fluid.
  • This method is based on the same realization as previously described, i.e. that the presence of an exogenous agent in the interstitial fluid will directly correlate to the amount absorbed by the skin after exposure of the skin surface to the agent.
  • a ratio of the amount of agent in the interstitial fluid in relation to the amount of agent applied to the skin surface may be calculated.
  • a measurement of the agent’s presence will indicate the subject’s exposure to the agent known to penetrate the skin’s outer layers.
  • Such a method would be useful in e.g. environments where it is essential to test subjects who have been exposed to e.g. airborne toxic substances.
  • hollow microneedles may be used for extraction of interstitial fluid. While a single hollow microneedle may suffice or even be desirable in a number of embodiments of the invention, it is also contemplated to use a plurality of
  • microneedles The plurality of microneedles may be arranged in an array.
  • Non- limiting examples of arrangements of microneedles may be those disclosed in WO2015/187066, WO2014/088493, or WO 2017/095321.
  • an array of hollow microneedles may be arranged in a regular pattern on a miniature chip.
  • the microneedles may comprise an elongated body extending from a distal end with a bevel to a proximal end on the substrate along a longitudinal axis; the elongated body comprising a capillary bore extending in a longitudinal direction thereof and defining a fluid path, the proximal end being integrally connected with the substrate and the capillary bore being in fluid communication with a fluid channel of the substrate, as taught in WO2017/095321.
  • a microneedle or plurality of microneedles may be pressed against the skin of a subject and the tips of the microneedles will penetrate into the outer layers of the skin by only a minimal depth, such that interstitial fluid may be sampled, but not deep enough to reach blood vessels or even sensory nerves. Interstitial fluid may be drawn into the microneedles by capillary suction, and/or applied suction, and may be collected for sampling in an underlying collection chamber.
  • a skin site of interest with a specific surface area is cleaned using water and soap and allowed to dry.
  • a dose of diclofenac 1.16% topical gel (Voltaren ® , comprising 11.6 mg diclofenac diethylamine per gram gel) is measured and applied on the chosen skin site according to the manufacturer’s instructions.
  • the topical gel is left in place for a specific time, e.g. one hour, before the excess gel is removed and the skin site is again cleaned with water and soap.
  • One or more microneedles are applied to the skin site for extraction of interstitial fluid through microneedles onto a filter paper
  • Molecules are extracted from filter paper via elution in e.g. acetonitrile in a test vial (i.e. the filter paper is immersed into a solvent suitable for sample preparation of the molecules of interest for LC-MS analysis, e.g. combinations of acetic acid,
  • the purified liquid is injected into an LC-MS according to a suitable analysis protocol, e.g. as a second mobile phase carrying the sample, preceded by a washing step and a first mobile phase containing water.
  • a suitable analysis protocol e.g. as a second mobile phase carrying the sample, preceded by a washing step and a first mobile phase containing water.
  • the separation column should be chosen according to the separation required.
  • a reverse-phase Thermo Fisher Accucore RP-MS 2.6 pm, 50 x 2.1 mm could provide appropriate separation (Jones, 2012, ThermoFisher Scientific Application Note 20569).
  • the amount of diclofenac in the analysed interstitial fluid is compared to the total dose diclofenac applied to the skin to assess diclofenac’s ability to penetrate the skin.
  • the present invention is not limited to the above-described preferred embodiments. Various alternatives, modifications and equivalents may be used as encompassed by the appended claims. Therefore, the above embodiments should not be taken as limiting the scope of the invention, which is defined by the appending claims.
  • Prior art disclosures cited herein are incorporated by reference in their entirety.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Medical Informatics (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Optics & Photonics (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

La présente invention concerne un procédé d'analyse d'absorption percutanée locale d'un agent, comprenant les étapes consistant à appliquer l'agent sur la peau d'un sujet, extraire un fluide interstitiel à partir de la peau à l'aide d'au moins une micro-aiguille creuse, et déterminer la présence de l'agent dans le fluide interstitiel extrait, la présence de l'agent dans le fluide interstitiel extrait indiquant une absorption percutanée locale d'un agent. En outre, l'invention concerne un procédé pour déterminer si une personne a été exposée à un agent capable de pénétrer dans la peau, comprenant les étapes consistant à extraire un fluide interstitiel à partir de la peau d'un sujet avec au moins une micro-aiguille creuse, et déterminer la présence de l'agent dans le fluide interstitiel.
PCT/EP2018/082552 2017-11-28 2018-11-26 Procédé d'analyse d'absorption percutanée d'un agent WO2019105890A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18814803.5A EP3758605A1 (fr) 2017-11-28 2018-11-26 Procédé d'analyse d'absorption percutanée d'un agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE1751461A SE1751461A1 (en) 2017-11-28 2017-11-28 Method of detecting an exogenous agent in interstitial fluid
SE1751461-3 2017-11-28

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WO2019105890A1 true WO2019105890A1 (fr) 2019-06-06

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Citations (9)

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Publication number Priority date Publication date Assignee Title
US6190315B1 (en) 1998-01-08 2001-02-20 Sontra Medical, Inc. Sonophoretic enhanced transdermal transport
US20110112121A1 (en) 2009-07-06 2011-05-12 Joerg Berghausen Pharmaceutical Compositions and Solid Forms
WO2011116388A1 (fr) 2010-03-19 2011-09-22 Nanostar Health Corporation Dispositif d'échantillonnage de fluides corporels/d'administration de fluides
WO2014088493A1 (fr) 2012-12-07 2014-06-12 Ascilion Ab Capteur microfabriqué et procédé de détection du niveau d'un constituant dans un fluide corporel
WO2015027093A1 (fr) 2013-08-22 2015-02-26 The Regents Of The University Of California Dispositif de collecte d'analyte sanguin et méthodes d'utilisation associées
WO2015187066A1 (fr) 2014-06-07 2015-12-10 Ascilion Ab Capteur micro-fabriqué, et procédé de détection de composant dans un liquide corporel
US20160029937A1 (en) * 2013-03-26 2016-02-04 The Trustees Of Columbia University In The City Of New York Fluid extraction and drug delivery system and methods using microneedles
WO2016164208A1 (fr) 2015-04-08 2016-10-13 Sandia Corporation Extraction in vivo de fluide interstitiel à l'aide de micro-aiguilles creuses
WO2017095321A1 (fr) 2015-12-04 2017-06-08 Ascilion Ab Micro-aiguille et puce

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US20040171980A1 (en) * 1998-12-18 2004-09-02 Sontra Medical, Inc. Method and apparatus for enhancement of transdermal transport
US20060246020A1 (en) * 2005-04-29 2006-11-02 Cole Curtis A Topical composition detection
US8147466B2 (en) * 2008-01-25 2012-04-03 The Procter And Gamble Company Method of determining a skin agent transferred to skin
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US20110112121A1 (en) 2009-07-06 2011-05-12 Joerg Berghausen Pharmaceutical Compositions and Solid Forms
WO2011116388A1 (fr) 2010-03-19 2011-09-22 Nanostar Health Corporation Dispositif d'échantillonnage de fluides corporels/d'administration de fluides
WO2014088493A1 (fr) 2012-12-07 2014-06-12 Ascilion Ab Capteur microfabriqué et procédé de détection du niveau d'un constituant dans un fluide corporel
US20160029937A1 (en) * 2013-03-26 2016-02-04 The Trustees Of Columbia University In The City Of New York Fluid extraction and drug delivery system and methods using microneedles
WO2015027093A1 (fr) 2013-08-22 2015-02-26 The Regents Of The University Of California Dispositif de collecte d'analyte sanguin et méthodes d'utilisation associées
WO2015187066A1 (fr) 2014-06-07 2015-12-10 Ascilion Ab Capteur micro-fabriqué, et procédé de détection de composant dans un liquide corporel
WO2016164208A1 (fr) 2015-04-08 2016-10-13 Sandia Corporation Extraction in vivo de fluide interstitiel à l'aide de micro-aiguilles creuses
WO2017095321A1 (fr) 2015-12-04 2017-06-08 Ascilion Ab Micro-aiguille et puce

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SE1751461A1 (en) 2019-05-29

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