WO2019068288A1 - Produit contenant un principe actif et une matrice de principe actif pour administrer par voie transdermique le principe actif, sa fabrication et son utilisation et matrice de principe actif, sa fabrication et son utilisation - Google Patents

Produit contenant un principe actif et une matrice de principe actif pour administrer par voie transdermique le principe actif, sa fabrication et son utilisation et matrice de principe actif, sa fabrication et son utilisation Download PDF

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Publication number
WO2019068288A1
WO2019068288A1 PCT/DE2018/100826 DE2018100826W WO2019068288A1 WO 2019068288 A1 WO2019068288 A1 WO 2019068288A1 DE 2018100826 W DE2018100826 W DE 2018100826W WO 2019068288 A1 WO2019068288 A1 WO 2019068288A1
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WIPO (PCT)
Prior art keywords
matrix
drug
active substance
product
skin
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PCT/DE2018/100826
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German (de)
English (en)
Inventor
Michael LUCKOW
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Berlimed International Research Gmbh
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Publication of WO2019068288A1 publication Critical patent/WO2019068288A1/fr

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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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy

Definitions

  • the invention relates to a product containing an active substance and a drug matrix for transdermal drug delivery.
  • the invention also relates to the preparation of this product and its use as well as the active ingredient matrix, their preparation and use.
  • topical retinoid preparations are known as creams or ointments or lotions.
  • topical retinoid preparations are known as creams or ointments or lotions.
  • certain retinoids or retinoid degradation inhibitors are used systemically (oral or intravenous).
  • iontophoresis is also known in connection with vitamin A or retinoic acid, with retinoic acid being subject to prescription and the use of electrical stimulation in the context of iontophoresis treatment always used by the practitioner and never the person treated and in combination with creams / ointments to be applied becomes.
  • the retinoids used, for example, to combat skin aging or in acne therapy are highly lipophilic molecules and very sensitive to oxidative influences from atmospheric oxygen and moisture as well as short-wave light.
  • the necessary for a biological effect diffusion into deeper skin layers is adversely affected by factors such as pH, oxidation by atmospheric oxygen (non-enzymatic), chemical properties of ointment or cream components.
  • an enzymatic degradation takes place in the skin.
  • EP 0 781 551 A1 shows a matrix in which retinoids are stabilized in pores of polymer particles such as acrylate particles and incorporated by impregnation of the particles with alcoholic retinoid solution.
  • Systems for transdermal drug delivery from a matrix of acrylic-based polymers are e.g. known from JP 2013-82727 A, JP 2012-56958 A, US 2004/0071764 A1 and the MX PA04001677 A.
  • release of the ionophoresis systems from a matrix are e.g. from JP H08-80354 A, and CA 2,026,885 B teaches a patch for transdermal drug delivery with ionophoresis.
  • Products containing galenic form for retinoids and / or retinoid compounds show: US 2006/0264804 A1 active substances encapsulated in vesicles for electrophoresis, EP 0 781 551 A1 emulsions in which retinoids are incorporated stabilized in pores of acrylate matrix particles, US 2001/0008644 A1 mixing a retinoid suspension with colloidal polymer such as gelatin with heating, WO 02/053123 A2 discloses a product with an air-excluded compartment for a retinoid-containing composition and a compartment for a composition with effect enhancers such as enzymes and coenzymes, EP 2 208 509 A1 emulsions with retinoid and hyaluronate and WO 2016 / No.
  • retinoids used in cosmetic as well as medical-dermatological applications (eg retinol or retinaldehyde, but also second and third generation synthetic retinoids) as effectively as possible and with the aid of a method which can be applied by the end user without any problem into deeper skin layers.
  • the invention is based on the object of specifying at least one new galenic form for products containing retinoids and / or retinoid compounds, in particular for the transdermal release of active ingredient.
  • the invention is also based on the object, a simple application for retinoids and / or retinoid compounds containing products, in particular with little effort for the qualification of persons who bring the retinoids and / or retinoid containing products for use. It is a further object of the invention to provide the handling and / or preparation of retinoids and / or retinoid compounds
  • the invention proposes in the claims defined products, drug matrices, methods and uses.
  • the drug is selected from retinoids and / or retinoid compounds.
  • Retinoidverbindun- These are in particular the compounds mentioned in EP 0781 551 A1 under the term "retinoid compound".
  • the active ingredient is selected from vitamin A derivatives such as retinol, retinaldehyde, retinoic acid retinaldehyde, preferably from retinaldehyde and retinol.
  • Corresponding products for transdermal drug delivery can be designed as an electrophoretic drug delivery system in the form of self-applicable by the end user masks, patches, gel patches.
  • the product may be part of a combination with a stimulation module such as an electrophoretic current output device for connecting anode and cathode for effective drug delivery of various retinoids into the skin.
  • the active ingredient matrix is loaded with the active substance by loading solid material of the active substance matrix, for example into pores of the solid material of the active ingredient matrix.
  • a combination of this drug matrix and a substance polymerizable with addition of a solvent to form a mass for application to the skin after polymerization may also be used alone as a self-adjusting personal mask after activation.
  • an addition of, for example, monomeric alginic acid, or other after polymerization with water-polymerizing substances may be provided to provide an application or dosage form as an individually moldable mask.
  • the product can be used in particular to combat skin aging, blemishes and / or acne.
  • the product can be designed as a patch or retinoid patch with or without an electrode.
  • a development of the active substance matrix by polymerization used for the invention represents a technical method of how the active substance can get into the polyelectrolyte matrix.
  • the active ingredient may be dissolved in solvent, associated with the already polymerized matrix. Carrying out a polymerization and adding the active substance during the polymerization process are steps known to the person skilled in the art with which it is known for the polymerization required chemicals, which is why it is possible to dispense with a detailed description of these known steps.
  • heat-soluble polymers such as agarose are largely cooled before the active ingredient is added in concentrated form.
  • agarose-based matrix after heating an aqueous buffer solution, the agarose is dissolved and the active ingredient dissolved in, for example, methanol is slowly concentrated and the still liquid agarose is between 50 and 80 ° C., preferably between 55 and 70 ° C., in particular at 60 ° C. added.
  • the solidified agarose can then be subjected to a drying process such as vacuum freeze-drying and pulverized, for example, with the completion of oxygen.
  • retinoids in particular retinol, are massively degraded under light and oxygen.
  • a retinoid solution stored only in aqueous solution and at room temperature suffers extreme degradation.
  • biocompatible electrolytes the use of biocompatible, already polymerized polyelectrolytes and liquefaction of the latter for introduction of the active substance, finally removing the solvent under protective gas / vacuum, or exposure of a dry polymerized matrix with dissolved in solvent Active substance, wherein the solvent is finally evaporated under inert gas.
  • the active ingredient matrix consists of polymer electrolyte.
  • it comprises by particles and / or one or more layers, wherein preferably the particle diameter of the particles below 2000 ⁇ , advantageously below 1000 ⁇ , preferably below 500 ⁇ are, in particular below 100 ⁇ (nanoparticles).
  • the active substance matrix is retinoid-compatible and can be formed in particular from polymerized polyelectrolyte, mineral, in particular fibrous material, synthetic fibers or substances which can be impregnated with a solution of the active ingredient, polyacrylic acid polymers, alginic acid polymers, pectins, carrageenan polymers, agarose, deoxyribonucleic acids, (Bis) acrylamide polymers, blends or copolymers.
  • the active ingredient matrix can be combined with parts of the abovementioned substances in their unpolymerized or mono- or oligomeric form, ie the active substance matrix can be used in combination with a polymerisable substance to form a mass for application to the skin after initiated or completed polymerisation - sation be provided.
  • biocompatible polyelectrolytes are used which are well known to the person skilled in the art. Suitable biocompatible polyelectrolytes are in particular all polyelectrolytes customarily used as adhesives / adhesives (eg patches).
  • the product according to the invention may be a powder mixture with the active substance matrix and at least one further substance, such as alginic acid, to form the preparation with moistening, wherein e.g. - Abolish the transdermal drug with resting the preparation of the product, the further substance for forming the preparation with humidification is a monomeric or oligomeric under moistening polymerizing substance and the powder mixture may also be a powder mixture to form a spreadable mask after moistening.
  • the powder mixture may also be a powder mixture to form a spreadable mask after moistening.
  • active ingredient matrix e.g. one or more of the pore-forming matrices disclosed in EP 0 781 551 A1, the technical disclosure of which is incorporated herein by reference.
  • Non-pore-forming matrices also allow drug stabilization and can be used.
  • the active substance matrix makes it possible, if appropriate in conjunction with other constituents of the product or with its packaging, to considerably improve the storage life of the product according to the invention and its protection against oxygen, moisture and light.
  • the drug matrix may be a polyacrylate-based or agarose-based drug matrix.
  • the active substance matrix may consist of an active substance matrix of any other biocompatible polymers, in particular such as agaroses, pectins, hyaloronates, and / or collagens.
  • a moistened state of the matrix When using the products of the invention for transdermal drug delivery, a moistened state of the matrix is provided.
  • a pure solid mixture by mixing the active ingredient in powder form with the likewise powdery active substance matrix is possible in order to moisturize these to the transdermal active ingredient and thus to form the moistened state of the matrix.
  • a moistened state of the drug matrix promotes transdermal drug delivery.
  • the drug matrix is loaded, preferably impregnated, with the drug (s), wherein a skin bearing surface of the product is formed by a surface of the drug matrix or by a surface of a permeable layer for the drug (s).
  • a tissue or a tissue with an adhesive layer for adhering the product to the skin may be provided between the active ingredient matrix, wherein
  • Paving known tissues and / or adhesive layers can be used.
  • skin-friendly tissue and possibly adhesive layers are chosen.
  • the active ingredient concentration of the matrix is advantageously between 0.005 and 0.05% by weight.
  • concentration of the active ingredient (s) in the matrix is between 0.005 and 0.04% by weight or between 0.04 and 0.5% by weight by weight for a therapeutic application. These concentrations are based on the total weight of the matrix, preferably the unhumidified matrix.
  • the solvent may even be water, with only one of the water solubility of
  • the solvent comprises at least one organic, preferably alcoholic, solvent, e.g. Ethanol.
  • concentration of the active ingredient (s) in the solvent during impregnation is advantageously 0.0005 to 0.05% (w / v), preferably 0.001 to 0.01% (w / v), advantageously 0.002 to 0.008%. (w / v).
  • the drug loading with low concentration of the (the) drug (s) results surprisingly a stabilization of the active ingredient (s). With water as the solvent can be worked inexpensively and with little risk of skin drying or damage by the drug-loaded matrix.
  • the active substance matrix for storing the active ingredient (s) is hereby also disclosed.
  • the active ingredient matrix is mixed with the active ingredient (s). loaded substance (s) in the drug concentrations shown above. This may benefit from the drug loading with low concentration of the drug (s) for surprisingly good stabilization of the drug (s). Thus, an advantageous preservation of the drug (s) is allowed.
  • the drug matrix is contacted with an anode, for example, layered on an electrode surface, and / or made accessible for moistening with water. It may be impregnated with the active agent (s) in solvent and subjected to evaporation of the solvent.
  • the anode may e.g. consist of silver, in particular a silver chloride layer.
  • the solvent may be water or, preferably, an organic solvent.
  • the drug matrix is contacted with the anode and the product is applied to transdermal drug delivery to the skin.
  • a patch with a cathode is applied to an area of the skin adjacent to the contact area of the product.
  • the cathode can also be made of silver.
  • the cathode and the anode are preferably arranged such that there is a distance of more than 0.5 cm, in particular 1 to 15 cm, between the skin contact areas of the cathode and the skin areas of the anode, with a DC voltage between the anode and the anode the cathode is adapted to alter the pH of the skin in the skin contact area of the product between the skin and the anode for a period of at least 3 minutes, preferably 5 minutes, advantageously at least 10 minutes.
  • the plaster is also formed like the product of the invention used on the anode side, but is used on the cathode side, so that the active agent matrix of this plaster is contacted with a cathode.
  • the drug matrix of the invention is available for water wetting. Transdermal drug delivery then takes place on the skin of the moistened product.
  • the moistening can be provided, in particular, by the side intended for contact with the skin and / or the side not intended to rest on the skin, advantageously only from the side not intended for resting on the skin.
  • the active ingredient matrix is loaded with the active ingredient (s) in the active substance concentrations shown above. This will benefit from low concentration drug loading of the drug (s) for surprisingly good stabilization of the drug (s), even in the air. Thus, an advantageous preservation and easy handling of the drug (s) is allowed.
  • anode for example, layered on an electrode surface, and / or made available for a moistening with water. It has been impregnated with the active ingredient (s) in solvent and subjected to evaporation of the solvent.
  • the anode may e.g. consist of silver, in particular a silver chloride layer.
  • the solvent may be water or, preferably, an organic solvent.
  • the active substance lies in the matrix for the transdermal active substance so that the
  • Drug release is activated.
  • an activation of the active substance delivery by means of a weak direct current or an activation by moistening, without electrical stimulation or moistening by moisture in the skin with moisture transport by capillary action in the drug matrix in predictable, eg for either therapeutic or cosmetic uses, especially for a fast and deep penetration of the active substance into the skin, and thus significantly higher concentrations of the active ingredients such as retinol, retinaldehyde at the relevant target site such as stratum granulosum or spinosum basale.
  • the drug matrix is accessible for moistening with water and a by the (the) drug (s) in solvent, in particular organic solvent impregnated and then subjected to evaporation of the solvent drug matrix.
  • the transdermal active substance is then applied to the surface of the moistened product on the skin.
  • the moistening can be provided, in particular, by the side intended for contact with the skin and / or the side not intended to rest on the skin, advantageously only from the side not intended for resting on the skin.
  • the active substance matrix can be provided for this purpose by a monomer which polymerizes after contact with water, so that, after activation with water, an active substance-containing, spreadable, rapidly polymerizing mass, for example a mask, in particular a face mask, is produced.
  • a monomer which polymerizes after contact with water
  • an active substance-containing, spreadable, rapidly polymerizing mass for example a mask, in particular a face mask
  • This is also a product for application to the skin and can be used in particular for electrophoresis with an electrode.
  • the active substance matrix can also be combined with the water-contact-polymerizing monomer so that, after activation with water, an active substance-containing, spreadable composition rapidly polymerizing the monomer, for example a mask, in particular a face mask, is produced.
  • the active ingredient in the transdermal drug delivery matrix is such that the drug delivery is activatable.
  • an activation of the active substance delivery by means of a weak direct current is provided, and in the second-mentioned use, an activation by moistening, without electrical stimulation.
  • Moisturizing by moisture in the skin with moisture transport by capillary action into the active ingredient matrix can also be provided.
  • the above uses may be either therapeutic or cosmetic uses.
  • a method according to the use with an electrophoretic active substance is the application of a DC voltage between the active substance-containing mask (main electrode, anode) and a counter electrode (cathode), which may be drug-free.
  • an integral product may be provided, which comprises an area with the product according to the invention and a region with the cathode-side plaster, which are interconnected.
  • the invention allows the use of a preserved drug, i.e., galenic forms such as creams or ointments.
  • a preserved drug i.e., galenic forms such as creams or ointments.
  • an active substance stored with protection against oxygen and / or light and / or moisture, in particular in local patches / patches or other local administration forms which can passively release the active substance after activation / mobilization by rehydration.
  • An example is a polymerizable substance that, combined with the active ingredient, can form a polymerized face mask.
  • high concentrations of retinol / retinaldehyde can be avoided, which can lead to problems such as discoloration or irritation of the skin.
  • retinoids such as retinol or retinaldehyde are very hygroscopic and stabilized in suitably packaged products according to the invention (dry and under protective gas or under vacuum). This eliminates the diffusion barrier of the active ingredients required in conventional creams, ointments and lotions. Also, unlike the application of conventional ointments, unwanted smearing and possibly contamination of areas which are not to come into contact with the active ingredients can be prevented.
  • the activation of products according to the invention advantageously takes place only immediately before use, specifically when they are taken out of the packaging or after their sticking to the skin area to be treated.
  • the activation takes place, for example, by a brief moistening with ordinary tap water, whereby, for example, a drug-containing polyelectrolyte of the matrix begins to swell within a few seconds, so that the retinoid particles of the impregnated matrix can go into solution.
  • Inventive products therefore have a significantly improved durability.
  • a larger reservoir of active ingredient can also be provided. Contamination risks can occur with firmly adhering patches or patches of the invention and directed release of the active ingredient (skin direction) are greatly reduced.
  • the invention also makes it possible to use products according to the invention overnight, in contrast to the naturally strongly colored retinoid-containing creams according to the prior art.
  • the invention also makes it possible to design a hitherto complicated electrophoretic drug delivery method (the so-called iontophoresis) in such a way that it can be carried out by the consumer himself.
  • each step of the process from impregnation of the drug matrix by suspension of the dry drug matrix in the active substance-containing solvent under protective gas for protection against oxygen and moisture and exclusion of light with wavelengths below 450 nm, preferably below 500 nm, in particular below 550 nm.
  • the solvent may be an organic solvent and advantageously comprises at least one alcohol, and is in particular methanol and / or ethanol.
  • the organic solvent may also be hexane.
  • the method may comprise filling a shell provided with the drug matrix with the drug matrix, or laminating the drug matrix between two sheets forming such a shell and adhered together at an edge around the drug matrix.
  • a correspondingly packaged product according to the invention can be used with the following steps: 1. opening the packaging,
  • steps 2. and 3. moistening the product with tap water (steps 2. and 3. can also be carried out in reverse order depending on the water permeability of the product), and
  • the active ingredient matrix offers better compatibility by better preservation of the active ingredients, as a result of which the total amount of retinoids can be significantly reduced without endangering the effectiveness.
  • it allows the Invention advantageous to ensure a larger drug reservoir by suppressing drug degradation and a simpler, more skin-friendly application waiving additives while improving the drug shelf life.
  • the invention also has a better ratio of active ingredient to degradation products compared to conventional moisture and oxygenated preparations.
  • Fig. 1A is a schematic sectional view of a Wirkstoffpfl asters of the invention.
  • Fig. 1 B is a plan view of another active ingredient plaster of the invention.
  • Fig. 1C is a schematic sectional view of the active substance patch shown in Fig. 1B along the line A-A shown in Fig. 1B.
  • Figures 2A and 2B show HPLC elution spectra obtained from retinoid-containing products of ionophore-treated skin samples.
  • Figures 3A, 3B and 3C show HPLC elution spectra obtained from retinoid-containing formulations.
  • FIGS. 4A and 4B show evaluations with retinoid quantities determined from HPLC elution spectra as shown in FIGS. 2A, 2B.
  • FIG. 5 shows an evaluation with quantities of retinoids and amounts of retinoid degradation determined from HPLC elution spectra as shown in FIG. 3.
  • DESCRIPTION OF PREFERRED EMBODIMENTS a) Plaster FIG. 1A shows in a highly schematic manner a reference numeral 10 in its entirety
  • Active substance plaster in which a drug-loaded polyelectrolyte matrix 12 is sandwiched between an outer membrane 14 and an inner membrane 16.
  • the outer membrane 14 may be coated on one side with adhesive for better adhesion of the drug-loaded polyelectrolyte matrix 12.
  • the inner membrane 16 may be adhesive-coated on both sides, namely towards the skin and the polyelectrolyte matrix 12.
  • the outer membrane 14 preferably consists of a tissue similar to that of ordinary wound plasters.
  • the inner membrane 16 is active and moisture-permeable.
  • the outer membrane 2 is preferably moisture-permeable.
  • Products according to the invention in particular the product according to FIG. 1, can be prepared and packaged as follows: Retinoid is taken up in a suitable solvent and combined with dry polyelectrolyte and uniformly mixed. Subsequently, the solvent is removed, e.g. by evaporation. The drug-containing matrix material thus obtained is measured for the concentration of retinoids, and the desired concentration is adjusted by dilution with dry polyelectrolyte. The filling of the electrode or of the local patch with active substance-containing carrier material then takes place. Subsequently, biocompatible polyacrylate adhesive is applied, and the products are in the desired
  • FIGS. 1B and 1C show a variant in which a layer of the active substance-laden polyelectrolyte 12 is provided with an active-material-permeable adhesive layer 18 directly on one side and the outer membrane 14 is glued directly on the other side, with one on each side Edge 20 of the drug-loaded polyelectrolyte 12 remains free. Likewise, an end of the outer membrane 14 is over, at the the patch 10 can be handled for handling, in particular during placement. b) Measurement methods ba) Skin sample preparation
  • filtrates from skin samples after electrophoresis were obtained as follows: The skin samples were subjected to three flushes of the surfaces in drug-free PBS solution for 5 minutes each. 10 mm x 10 mm epidermis / dermis skin samples were excised and subjected to comminution by means of a rotating stainless steel knife in acetonitrile (1 ml) followed by homogenization in the glass Teflon homogenizer. The protein precipitation was carried out from the homogenates at an intermediate storage for 24 h at -80 ° C.
  • HPLC elution spectra shown in this unitary chromatography protocol show retention times in minutes on the abscissa and light absorption units on the ordinate measured photometrically with a light source of 350 nm and 325 nm wavelength. These light absorption units are mAU (milli absorption units), ie a relative unit of the photocell of the UV / VIS detector used, or of the diode array of the diode array detector.
  • the (vertical) axis labeling indicates values for an integral of peaks of elution spectra with the unit mAU * s.
  • Retinoid concentrations can be demonstrated by detection of the retinoids and the primary oxidation products of the retinoids such as 4-hydroxy- and 4-keto-retinoid oxidation products (4-OH- or 4-OXO-retinol, 4-OH- or 4- OXO-retinal or 4-OH- or 4-OXO-retinoic acid). These decomposition products are detectable at retention times of less than 4 minutes. Degradation products after further oxidation are finally no longer detectable because of loss of the absorption properties at 325 or 350 nm. c) Electrode Example 1
  • Example 1 electrophoresis with retinaldehyde
  • the gel side of electrodes of electrode example 1 was impregnated for 30 minutes with a pH 7.35 PBS impregnation solution containing 0.005% (w / v) (176 ⁇ ) retinaldehyde. After impregnation, three washes were made over 5 minutes in drug-free PBS solution.
  • the thus impregnated polyacrylate-coated electrodes were placed at least 50 mm apart on the pigskin preparations and a voltage of between 6 - 8 V applied so that a constant current of 2 mA over 120 minutes resulted.
  • Figure 2A shows HPLC elution spectra of the uniform chromatography protocol with retention times on the abscissa and light absorption units on the ordinate measured photometrically with a light source of 350 nm and 325 nm wavelength.
  • Three elution spectra or three lines, respectively, of an anodal elution spectrum obtained from the skin sample stimulated with an electrophoresed patch anode from a cathodal elution spectrum obtained from the skin sample stimulated with an electrophoresed patch cathode are discernible.
  • a control elution spectrum that shows the conditions that occur without application of electricity. Under the condition corresponding to the control elution spectrum, under which a sample stored only in water for a longer time and at room temperature is applied, there is no elevated retinoid level (for the most sensitive retinoid retinol).
  • the elution spectra show absorption maxima at ca. 1, 5, 2.9 and 4.8 minutes retention time, which are assigned to the individual spectra as follows:
  • 4A shows the mean values with standard error bars of the control elution (left), as well as the anodal elution (in the middle) and the cathodal elution (right), by evaluating the spectra, in particular by integration of the peaks at 4.8 minutes elution time were obtained.
  • Ten measurements were taken for the mean value of the control elution and five measurements for the mean value of the anodal elution and five measurements for the mean value of the cathodal elutions.
  • Example 2 electrophoresis with retinol and beta-carotene
  • Electrodes from electrode example 1 were impregnated at their gel side for 30 minutes with a PBS impregnation solution of pH 7.35 containing 0.005% retinol (175 ⁇ ) and beta-carotene (500 ⁇ ). After impregnation, three washes were made over 5 minutes in drug-free PBS solution.
  • the polyacrylate-coated electrodes so impregnated were placed on the pigskin preparations at a distance of at least 50 mm, and a voltage of between 6 and 8 V was applied so that a constant current of 2 mA resulted over 120 minutes.
  • the elution spectra shown in Fig. 2B were obtained.
  • Figure 2B shows HPLC elution spectra of the uniform chromatography protocol with retention times on the abscissa and light absorption units on the ordinate measured photometrically with a light source of 350 nm and 325 nm wavelength. Three lines can be seen corresponding to the three elution spectra, namely
  • Fig. 2B illustrates by boundary lines among the peaks and dividing lines between the peaks.
  • Fig. 4B shows the mean values of control elution (left) and anodal elution
  • Electrodes from electrode example 1 were impregnated on their gel side for 30 minutes with a PBS impregnation solution of pH 7.35, which contains 0.005% (w / v).
  • the thus impregnated polyacrylate-coated electrodes were placed at least 50 mm apart on the pigskin preparations and a voltage of between 6 - 8 V applied so that a constant current of 2 mA over 120 minutes resulted.
  • Example 2 Using the methodology of Example 1, elution spectra were recorded and evaluated for absorption peaks for retinoic acid and the following mean values with standard control elimination error bars, anodal elution and cathodal elution from each of three measurements for each mean: Control elution anodal elution cathodal elution
  • Matrix - dry polyelectrolyte particles pure, polymerized
  • Example of pensions 1 In the case of reconstitution, after storage, the volume was adjusted prior to storage with the solvent. The following dilutions of the stock solution were respectively adjusted in the above comparative examples and examples with the solvent, each of Examples 4 to 6 being carried out twice:
  • the integrals of the peaks obtained in each of the examples were each divided by the integral of the peak of the control elution spectrum of the respective dilution to determine retinol concentration ratios of the respective dilutions.
  • the following values were obtained: Dilution / retinol concentration ratio of the evaluated reconstituted solutions evaluated (according to EinSpektren peaks vaporizing with matrix) / (after evaporation without matrix)
  • the data show that the lower the drug concentration in the starting solution, the greater the preservation effect of the matrix.
  • the HPLC elution spectra shown in FIGS. 3A to 3C were further evaluated by integrating the peaks at 4.7 minutes and the peaks at ⁇ 4 minutes, integrating the light absorption units mAU (milli-absorption units) of the diode array detector used and the multiplied by ten times the respective dilution factor (ie, 2 in the spectra of Fig. 3A, 10 in the spectra of Fig. 3B, and 20 in the spectra of Fig. 3C) to obtain relative integrals.
  • mAU milli-absorption units
  • Mean values with standard error limits were then formed from i) those from the elution spectra of Comparative Examples 1-3, ii) those from the elution spectra of Comparative Examples 4-6 and iii) from the elution spectra of Examples 4-6.

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Abstract

La présente invention concerne un produit (10) contenant au moins un principe actif et une matrice de principe actif (12) en électrolyte polymère pour administrer par voie transdermique le principe actif en appliquant le produit ou une préparation de celui-ci sur la peau. Elle concerne également son procédé de fabrication et son utilisation, le principe actif étant choisi parmi les rétinoïdes et/ou les composés des rétinoïdes, la matrice de principe actif (12) étant formée par des particules et/ou une ou plusieurs couches d'électrolyte polymère avec une surface de la matrice de principe actif (12) ou une surface d'une couche (18) perméable au(x) principe(s) actif(s) en tant que surface du produit en contact avec la peau ou le produit est un mélange pulvérulent humidifié avec la matrice de principe actif (12) et une autre substance pour former la préparation, et la matrice de principe actif (12) étant mise en contact avec une anode et/ou adaptée pour être humidifiée avec de l'eau.
PCT/DE2018/100826 2017-10-04 2018-10-04 Produit contenant un principe actif et une matrice de principe actif pour administrer par voie transdermique le principe actif, sa fabrication et son utilisation et matrice de principe actif, sa fabrication et son utilisation WO2019068288A1 (fr)

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182765A2 (fr) * 1984-11-19 1986-05-28 The Regents Of The University Of Minnesota Système de libération de médicaments à contrôle électro-chimique
CA2026885A1 (fr) 1989-02-06 1990-08-07 Keiichirou Okabe Interface pour l'iontophorese
JPH0880354A (ja) 1994-09-14 1996-03-26 Poritoronikusu:Kk 経皮投薬素子
EP0781551A1 (fr) 1995-12-29 1997-07-02 Advanced Polymer Systems, Inc. Formulations de rétinoides dans des microsphères poreuses à l'irritation réduite et stabilité améliorée
US20010008644A1 (en) 1998-02-23 2001-07-19 Hermann Stein Process for preparing a finely divided pulverous carotenoid retinoid or natural colournt preparation
WO2002053123A2 (fr) 2000-12-28 2002-07-11 Unilever Plc Produit de soin cutane stable contenant un retinoide et un systeme activateur de retinoide dans un emballage a deux compartiments
US20040071764A1 (en) 2001-01-30 2004-04-15 Stefan Bracht Transdermal therapeutic system for administering non-steroidal antiphlogistic agents containing carboxyl groups, and a method for the production of the same
MXPA04001677A (es) 2001-08-24 2004-05-31 Lts Lohmann Therapie Systems A Sistema terapeutico transdermico con base en adhesivos de poliacrilato de union por contacto sin grupos funcionales.
US20060264804A1 (en) 2005-04-07 2006-11-23 Yoram Karmon Device and kit for delivery of encapsulated substances and methods of use thereof
WO2009096822A1 (fr) * 2008-01-30 2009-08-06 Micromuscle Ab Dispositifs et procédés d'administration de médicament et leurs applications
EP2208509A2 (fr) 2004-01-29 2010-07-21 Pierre Fabre Dermo-Cosmetique Compositions topiques associant des fragments de hyaluronate de sodium et un retinoïde
JP2012056958A (ja) 2000-03-16 2012-03-22 Lts Lohmann Therapie-Systeme Ag 安定化した過飽和経皮治療吸収基材システム
JP2013082727A (ja) 1999-04-22 2013-05-09 Lts Lohmann Therapie-Systeme Ag 中和されたアクリル性粘着パッチを備えた経皮治療システム
DE202012013167U1 (de) * 2012-12-19 2015-03-18 Krystyna Komender-Spira Zusammensetzung für die kosmetische oder therapeutische Behandlung der Haut
WO2016135340A1 (fr) 2015-02-27 2016-09-01 Pierre Fabre Dermo-Cosmetique Combinaison d'un rétinoïde et d'un diol et d'un ester d'acide gras polyinsaturé

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182765A2 (fr) * 1984-11-19 1986-05-28 The Regents Of The University Of Minnesota Système de libération de médicaments à contrôle électro-chimique
CA2026885A1 (fr) 1989-02-06 1990-08-07 Keiichirou Okabe Interface pour l'iontophorese
JPH0880354A (ja) 1994-09-14 1996-03-26 Poritoronikusu:Kk 経皮投薬素子
EP0781551A1 (fr) 1995-12-29 1997-07-02 Advanced Polymer Systems, Inc. Formulations de rétinoides dans des microsphères poreuses à l'irritation réduite et stabilité améliorée
US20010008644A1 (en) 1998-02-23 2001-07-19 Hermann Stein Process for preparing a finely divided pulverous carotenoid retinoid or natural colournt preparation
JP2013082727A (ja) 1999-04-22 2013-05-09 Lts Lohmann Therapie-Systeme Ag 中和されたアクリル性粘着パッチを備えた経皮治療システム
JP2012056958A (ja) 2000-03-16 2012-03-22 Lts Lohmann Therapie-Systeme Ag 安定化した過飽和経皮治療吸収基材システム
WO2002053123A2 (fr) 2000-12-28 2002-07-11 Unilever Plc Produit de soin cutane stable contenant un retinoide et un systeme activateur de retinoide dans un emballage a deux compartiments
US20040071764A1 (en) 2001-01-30 2004-04-15 Stefan Bracht Transdermal therapeutic system for administering non-steroidal antiphlogistic agents containing carboxyl groups, and a method for the production of the same
MXPA04001677A (es) 2001-08-24 2004-05-31 Lts Lohmann Therapie Systems A Sistema terapeutico transdermico con base en adhesivos de poliacrilato de union por contacto sin grupos funcionales.
EP2208509A2 (fr) 2004-01-29 2010-07-21 Pierre Fabre Dermo-Cosmetique Compositions topiques associant des fragments de hyaluronate de sodium et un retinoïde
US20060264804A1 (en) 2005-04-07 2006-11-23 Yoram Karmon Device and kit for delivery of encapsulated substances and methods of use thereof
WO2009096822A1 (fr) * 2008-01-30 2009-08-06 Micromuscle Ab Dispositifs et procédés d'administration de médicament et leurs applications
DE202012013167U1 (de) * 2012-12-19 2015-03-18 Krystyna Komender-Spira Zusammensetzung für die kosmetische oder therapeutische Behandlung der Haut
WO2016135340A1 (fr) 2015-02-27 2016-09-01 Pierre Fabre Dermo-Cosmetique Combinaison d'un rétinoïde et d'un diol et d'un ester d'acide gras polyinsaturé

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