Medical patch comprising capsaicin or a capsaicin analog

Abstract

The present invention relates to a medical patch for the administration of capsaicin or a capsaicin analog comprising an active agent-containing self-adhesive layer structure comprising capsaicin or a capsaicin analog, such a medical patch for use in a method of treatment as well as processes of manufacture of such a medical patch.

Description

MEDICAL PATCH COMPRISING CAPSAICIN OR A CAPSAICIN ANALOGTECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a medical patch for the administration of capsaicin or a capsaicin analog, wherein the medical patch comprises an active agent-containing self-adhesive layer comprising a polymer matrix based on natural or synthetic rubbers and capsaicin or a capsaicin analog in an amount of at least 1% by weight. Further, the present invention relates to processes of manufacture as well as methods of treatment and uses of the medical patch.BACKGROUND OF THE INVENTION

[0002] Capsaicin ((6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), the major bioactive component of chili peppers, is an alkaloid found in the Capsicum family. It is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), better known as vanilloid receptor. By binding to the TRPV1 receptor, the capsaicin molecule produces similar sensations to those of excessive heat or abrasive damage.

[0003] The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons expressing TRPV1. This receptor is a nonselective cation channel that allows the transient influx of Ca2+when activated during the detection and transduction of nociceptive stimuli. As calcium in the cell is one of the most versatile second messengers in numerous intracellular signaling pathways and TRPV1 permits cations to pass through the cell membrane and into the cell when activated, the resulting depolarization of the neurons stimulates it to signal the brain. Thus, TRPV1 plays a critical role in pain signaling.

[0004] Capsaicin has a role as a non-narcotic analgesic and is currently used for the treatment of several pain syndromes such as neuropathic pain. Such pain is believed to result from sensitization reactions in the peripheral and central nervous system and can occur as a result of peripheral injuries, or as a result of systemic diseases such as HIV, herpes zoster syphilis, autoimmune diseases and diabetes. Furthermore, capsaicin has also demonstrated beneficial effect on osteoarthritis pain relief due to its high capacity to inhibit P substance release, a powerful neuropeptide pain neuromodulator from the sensory nerves to the central nervous system. In addition, capsaicin is suggested to be able to kill cancer cells by causing them to undergo apoptosis.

[0005] Capsaicin is most often used as a topical analgesic and exists in many formulations of cream, liquid and patch preparations of various strengths. For example, an 8% capsaicin patch dermal delivery system is administered under the brand name QUTENZA® (Griinenthal). The topical system is indicated in adults for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) as well as for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet, and is currently approved for use in adults in the treatment of post- surgical neuropathic pain (PSNP). QUTENZA® delivers prescription-strength capsaicin directly to the skin for reversibly desensitizing and defunctionalizing the TRPV1 receptor, and can thus provide sustained pain relief that lasts for up to three months.

[0006] In view of the success of and demand for such capsaicin patches, it would be desirable to develop further capsaicin patch formulations providing further advantages, e.g., in view of cost. However, when substantive changes such as using different adhesives are made, ensuring an appropriate release of the active in terms of released amount and the release profile over time is challenging. No such capsaicin patches with an alternative formulation are commercially available to date.

[0007] There is thus a need for a different formulation for a medical patch for the topical and / or transdermal delivery of capsaicin or capsaicin analogs.OBJECTS AND SUMMARY OF THE INVENTION

[0008] It is an object of the present invention to provide a medical patch for the administration of capsaicin or a capsaicin analog providing advantages over the current capsaicin patches such as reduced cost or improved performance, e.g. in terms of patient compliance.

[0009] It is an object of the present invention to provide a medical patch for the administration of capsaicin or a capsaicin analog based on a different formulation, in particular relying on alternative adhesives, in comparison to the patches described in the prior art, which allow the use of alternative, fluorine-free release liners.

[0010] It is a further object of the present invention to provide a medical patch for the administration of capsaicin or a capsaicin analog based on a different formulation, in particular relying on alternative adhesives, in comparison to the patches described in the prior art, which achieves topical and / or transdermal delivery of the active at a level which is sufficient in terms of the active amount for achieving a therapeutically effective dose of the active agent, which in particular is of the same or similar strength when compared to the current QUTENZA® patch.

[0011] It is also an object of the present invention to provide a medical patch for the administration of capsaicin or a capsaicin analog based on a different formulation in comparison to the patches described in the prior art, and comprising the active agent capsaicin or a capsaicin analog at a high concentration, to allow for the same or similar strength when compared to the current QUTENZA® patch, which is stable, also over time, and is not at risk of e.g. the active agent precipitating from the matrix formulation.

[0012] It is a yet further object of the present invention to provide a medical patch for the administration of capsaicin or a capsaicin analog based on a different formulation in comparison to the patches described in the prior art, and which achieves topical and / or transdermal delivery of the active with a release profile over time that is favorable for a short term administration of the active agent and is characterized, e.g., by a fast onset of action.

[0013] One or more of the above and other objects are accomplished by the present invention, which according to one aspect relates to a medical patch for the administration of capsaicin comprising an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising:A) a backing layer;B) an active agent-containing matrix layer comprising1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.

[0014] It has been surprisingly found that medical patches with the active agent capsaicin or a capsaicin analog formulated in an active agent- containing matrix layer comprising a natural or synthetic rubber polymer show a favorable release behavior, i.e., a high release after a short period of time, which is particularly advantageous for a short-term administration of the active.

[0015] According to certain embodiments of the present invention, the medical patch according to the invention is for use in a method of treating neuropathic pain, in particular chronic neuropathic pain. In certain embodiments, the medical patch is for use in a method of treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands and feet, post-surgical neuropathic pain, joint pain, or cancer pain.

[0016] According to certain embodiments of the invention, the present invention also relates to the use of a medical patch according to the invention for the manufacture of a medicament for treating neuropathic pain, in particular chronic neuropathic pain, and in certain embodiments, for the manufacture of a medicament for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, post- surgical neuropathic pain, joint pain, or cancer pain.

[0017] According to other embodiments of the invention, the present invention relates to a method of treating neuropathic pain, in particular chronic neuropathic pain, and in certain embodiments peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, post-surgical neuropathic pain, joint pain, or cancer pain including applying a medical patch according to the invention to the skin of a patient.

[0018] Moreover, the invention relates to a method of manufacturing an active agent-containing matrix layer for use in a medical patch according to the invention comprising the steps of:1) combining at least the components1. capsaicin or capsaicin analog, and2. polymer based on natural or synthetic rubbers, to obtain a coating composition;2) coating the coating composition onto a backing layer or a release liner or any intermediate liner; and3) drying the coated coating composition to form the active agent-containing matrix layer.DEFINITIONS

[0019] Within the meaning of this invention, the term “medical patch” refers to a dermal delivery system by which the active agent (capsaicin or a capsaicin analog) is administered to a patient and refers to the entire individual dosing unit that is applied, after removing an optionally present release liner, to the skin of the patient, and which comprises a therapeutically effective amount of capsaicin or a capsaicin analog in an active agent-containing self-adhesive layer structure. The active agent-containing self-adhesive layer structure may be located on a release liner (a detachable protective layer), thus, the medical patch may further comprise a release liner. Suitable release liners may be siliconized in order to avoid permanent adhesion of the active agent-containing matrix layer to the release liner.

[0020] In this context, the term “medical patch” is understood to mean an adhesive patch which can be a topical medical patch or a transdermal therapeutic system (TTS). Even if the topicalmedical patch as well as the TTS are topically applied in the sense that they are attached to the skin of the patient, the term “topical” or “topical administration” refers to the administration of capsaicin or a capsaicin analog relying on passive diffusion into the skin itself, which creates a local effect at a point of action. In contrast, the term “TTS” refers to a system by which capsaicin or a capsaicin analog is administered to the systemic circulation via transdermal delivery. Topical capsaicin administration may be preferable to capsaicin transdermal delivery systems regarding systemic side effects, drug interactions, contraindications and development of tolerance.

[0021] Within the meaning of this invention, the term “active agent-containing self-adhesive layer structure” refers to the capsaicin-containing structure or the capsaicin analog-containing structure, respectively, providing the area of release for capsaicin or a capsaicin analog during administration. An adhesive overlay adds to the overall size of the medical patch but does not add to the area of release. The active agent-containing self-adhesive layer structure comprises a backing layer and at least one active agent-containing matrix layer. In this context, the term “active agent-containing” covers both the term “capsaicin-containing” and the term “capsaicin analog-containing”. The active agent-containing self-adhesive layer structure thus comprises a therapeutically effective amount of capsaicin and / or a capsaicin analog.

[0022] Within the meaning of this invention, the term “therapeutically effective amount” refers to a quantity of capsaicin or a capsaicin analog in the medical patch sufficient to provide, if administered by the medical patch to a patient, the desired therapeutic effect such as pain relief / reduction. A TTS usually contains more capsaicin (analog) in the system than is in fact provided to the skin and the systemic circulation, which is usually necessary to provide enough driving force for the delivery from the TTS to the systemic circulation.

[0023] Within the meaning of this invention, the terms “active agent” as well as “capsaicin” and “capsaicin analog” refer to capsaicin or a capsaicin analog in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include without limitation capsaicin or a capsaicin analog in its free form, cocrystals, solvates, hydrates, clathrates, complexes and so on, as well as the capsaicin or capsaicin analog in the form of particles, which may be micronized, crystalline and / or amorphous, and any mixtures of the aforementioned forms.

[0024] Within the meaning of this invention, the term “capsaicin analog” refers to a chemical compound that provides a similar pharmacological effect as capsaicin, in particular in view of the TRPV1 receptor. Preferably, a capsaicin analog is a natural or synthetic molecule that preserves all or a part of the aromatic catechol ring in its chemical structure and / or that is clearly demonstrated to be TRPV1 receptor agonist.

[0025] The capsaicin or capsaicin analog, where contained in a medium such as a solvent, may be dissolved or dispersed or in part dissolved and in part dispersed.

[0026] When the capsaicin or capsaicin analog is mentioned to be used in a particular form in the manufacture of the medical patch, this does not exclude interactions between this form of the capsaicin or capsaicin analog and other ingredients of the active agent-containing self-adhesive layer structure, e.g. salt formation or complexation, in the final medical patch. This means that, even if the capsaicin or capsaicin analog is included in one specific form, it may be present in the final medical patch in another form. Unless otherwise indicated, in particular the amount of the capsaicin or capsaicin analog in the self-adhesive layer structure relates to the amount of the capsaicin or capsaicin analog included in the medical patch during manufacture of the medicalpatch and is calculated based on the capsaicin or capsaicin analog itself, but not on other forms thereof. The capsaicin or capsaicin analog starting material included in the medical patch during manufacture of the medical patch may be in the form of particles. The capsaicin or capsaicin analog may e.g. be present in the active agent-containing self-adhesive layer structure in the form of particles and / or dissolved.

[0027] In this context, the term “particles” refers to a solid, particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, the particles are solid, including plastic / deformable solids, including amorphous and crystalline materials. The term “dispersing” refers to a step or a combination of steps wherein a starting material (e.g. capsaicin (analog)) is not totally dissolved. Dispersing in the sense of the invention comprises the dissolution of a part of the starting material (e.g. capsaicin (analog) particles), depending on the solubility of the starting material (e.g. the solubility of the capsaicin (analog) in the coating composition).

[0028] There are two main types of medical patches using (passive) active agent delivery, i.e. matrix-type medical patches and reservoir-type medical patches. In matrix-type medical patches the active agent is included in a matrix, while in a reservoir-type medical patch the active agent is included in a liquid or semi-liquid reservoir. The release of the active agent in a matrix-type medical patch is mainly controlled by the matrix including the active agent itself. In contrast thereto, a reservoir-type medical patch typically needs a rate-controlling membrane controlling the release of the active agent. In principle, also a matrix-type medical patch may contain a ratecontrolling membrane. However, matrix-type medical patches are advantageous in that, compared to reservoir-type medical patches, usually no rate determining membranes are necessary and no dose dumping can occur due to membrane rupture. In summary, matrix-type medical patches are less complex in manufacture and easy and convenient to be used.

[0029] In this context, a “matrix-type medical patch” is understood to mean a system or structure wherein capsaicin or a capsaicin analog is homogeneously dissolved and / or dispersed within a polymeric carrier, i.e. the matrix, which forms with the capsaicin or capsaicin analog and optionally remaining ingredients a matrix layer. In such a system, the matrix layer controls the release of the capsaicin or capsaicin analog from the medical patch. A matrix-type medical patch may also include a rate controlling membrane. Matrix-type medical patches may in particular be in the form of a “drug-in-adhesive”-type medical patch referring to a system wherein the active is homogeneously dissolved and / or dispersed within a pressure-sensitive adhesive matrix.

[0030] Medical patches with a rate-controlling membrane and a liquid or semi-liquid active agentcontaining reservoir, wherein the release of the active agent from the medical patch is controlled by the rate-controlling membrane, are referred to by the term “reservoir-type medical patch”. Reservoir-type medical patches are not to be understood as being of matrix-type within the meaning of the invention. In particular, within the meaning of this invention, microreservoir-systems (biphasic systems having an inner active-containing phase in an outer matrix-phase), considered in the art to be a mixture between a matrix-type medical patch and a reservoir-type medical patch, are considered to be of matrix-type within the meaning of the invention.

[0031] Within the meaning of this invention, the term “active agent-containing matrix layer” or “matrix layer” refers to any layer containing the active homogeneously dissolved and / or dispersed within a polymeric carrier. Typically, a matrix layer is present in a matrix-type medical patch as theactive agent-containing layer. A reservoir-type medical patch may comprise, in addition to a reservoir layer and a rate-controlling membrane, an additional adhesive layer which serves as a skin contact layer. In such a reservoir-type medical patch, the additional adhesive layer often is manufactured as an active agent-free layer. However, due to the concentration gradient, the active agent will migrate from the reservoir to the additional adhesive layer over time, until an equilibrium is reached. Therefore, in such a reservoir-type medical patch, after some time of equilibration, the additional adhesive layer contains the active agent and is to be regarded as a matrix layer in the sense of the present invention.

[0032] The matrix layer is the final, solidified layer e.g. obtained after coating and drying the solvent-containing coating composition. The matrix layer may also be manufactured by laminating two or more such solidified layers (e.g. dried layers) of the same composition to provide the desired area weight. The matrix layer may be self-adhesive (in the form of a pressure sensitive adhesive matrix) or the medical patch may comprise an additional skin contact layer of a pressure sensitive adhesive for providing sufficient tack. In particular, the matrix layer is a pressure sensitive adhesive matrix.

[0033] Within the meaning of this invention, the term “skin contact layer” refers to a layer included in the active agent-containing self-adhesive layer structure to be in direct contact with the skin of the patient during administration. When the medical patch comprises a skin contact layer, the other layers of the active agent-containing self-adhesive layer structure do not contact the skin and do not necessarily have self-adhesive properties. As outlined above, the skin contact layer may over time absorb parts of the active agent and then may be regarded as a matrix layer. The area of release is provided by the area of the matrix layer. A skin contact layer may be used to enhance adherence. The sizes of an additional skin contact layer and the matrix layer are usually coextensive and correspond to the area of release.

[0034] Within the meaning of the invention, the term “backing layer” refers to a layer which supports the active agent-containing matrix layer. At least one backing layer in the medical patch and usually the backing layer of the active agent-containing matrix layer is substantially impermeable to the capsaicin or capsaicin analog, as well as optionally any additive, contained in the layer during the period of storage and administration and thus prevents active loss or crosscontamination in accordance with regulatory requirements. The backing layer may also be occlusive, meaning substantially impermeable to water and water-vapor, or non-occlusive. Suitable materials for a backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate-copolymer (EVA), polyesters, polyurethanes, and mixtures thereof. Suitable backing layers may be non-siliconized in order to improve the adhesion of the active agent-containing matrix layer to the backing layer.

[0035] Furthermore, an adhesive overlay may be present. In this context, the term “adhesive overlay” is understood to mean a self-adhesive layer structure that is free of the capsaicin or capsaicin analog and larger in area than the active agent-containing self-adhesive layer structure and provides additional area adhering to the skin, but no area of release of the capsaicin or capsaicin analog. It enhances thereby the overall adhesive properties of the medical patch. The area of said adhesive overlay adds to the overall size of the medical patch but does not add to the area of release. The adhesive overlay may comprise a self-adhesive polymer or a self-adhesive polymer mixture selected from the group of acrylic polymers, polyisobutylenes, styrene-isoprene- styrenecopolymers, polysiloxanes, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure. The adhesive overlay comprises a backing layer that may provide occlusive or non-occlusive properties and an adhesive layer. In certain embodiments, the backing layer of the adhesive overlay provides non-occlusive properties.

[0036] Within the meaning of this invention, the term “area weight” refers to the dry weight of a specific layer, e.g. of the active agent-containing matrix layer, provided in g / m2. The area weight values are subject to a tolerance of ± 10 %, or ± 7.5 %, due to manufacturing variability.

[0037] If not indicated otherwise “%” refers to wt.% (% by weight).

[0038] Within the meaning of this invention, the term “polymer” refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers which consist of one type of monomer and copolymers which consist of two or more types of monomers. Polymers may be of any architecture such as linear polymers, star polymer, comb polymers, brush polymers, of any monomer arrangements in case of copolymers, e.g. alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the polymer type and is known to the skilled person. Polymers may e.g. have a molecular weight above 2000, above 5000 or even above 10,000 Dalton. Correspondingly, compounds with a molecular weight below 2000, below 5000 or below 10,000 Dalton are usually referred to as oligomers.

[0039] Within the meaning of the invention, the term “natural or synthetic rubbers” refers to a homopolymer or copolymer obtainable by polymerization or copolymerization of unsaturated hydrocarbon monomers. In particular, the term describes an elastomer which is obtainable by polymerizing an unsaturated hydrocarbon, such as isoprene (2- methyl -1,3 -butadiene), or by copolymerizing such hydrocarbons with styrene, butadiene, or the like. In certain embodiments, natural or synthetic rubbers may be styrenic triblock copolymers or polyisobutylenes.

[0040] Within the meaning of this invention, the term “pressure sensitive adhesive” refers to a material that in particular adheres with finger pressure, is permanently tacky, exerts a strong holding force and should be removable from smooth surfaces without leaving a residue. It is obtainable from a solvent-containing adhesive coating composition after coating on a film and evaporating the solvents (e.g. n-heptane or ethyl acetate). In this context, the term “solvent” is understood to mean any liquid substance, and may be a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, or mixture thereof.

[0041] Within the meaning of this invention, the term “solubilizer” refers to an agent that increases the solubility of the capsaicin or capsaicin analog in the active agent-containing matrix layer.

[0042] It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. The skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. For examples, the solubilizer as defined above may also act as e.g., permeation enhancer. On the other hand, a permeationenhancer as used within the meaning of this invention does not necessarily increases the solubility of the capsaicin or capsaicin analog in the active agent-containing matrix layer.

[0043] The medical patch according to the present invention can be characterized by certain parameters as measured in an in vitro skin permeation test.

[0044] The in vitro permeation test can be performed with human or animal skin, e.g., with dermatomed split-thickness human skin with a thickness of 500 pm and an intact epidermis, and with 0.9 % sodium chloride solution as receptor medium (32 °C with 0.1 % saline azide) with or without addition of a maximum of 40 vol-% organic solvent e.g. ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400 so that a receptor medium may e.g. contain 60 vol-% of 0.9% sodium chloride, 30 vol-% dipropylene glycol and 10 vol-% acetonitrile. The in vitro permeation test may be performed in a Franz diffusion cell with heat separated human epidermis, and with 0.9 % sodium chloride solution as receptor medium (32 °C with 0.1 % saline azide). The amount of the capsaicin or capsaicin analog permeated into the receptor medium is determined in regular intervals using a partial validated HPLC method (column: stainless steel column 150 mm x 4.6 mm internal diameter with C18 base and acid deactivated stationary phase, 3.5 pm particle size, e.g. Zorbax SB C18 (Agilent); column temperature: 25 °C; mobile phase: acetonitrile / water / TEA = 20:80:0.35 (v / v / v) with a UV photometric detector by taking a sample volume. The receptor medium is completely or in part replaced by fresh medium when taking the sample volume, and the measured amount of the capsaicin or capsaicin analog permeated relates to the amount permeated between the two last sampling points and not the total amount permeated so far.

[0045] Thus, within the meaning of this invention, the parameter “permeated amount” is provided in pg / cm2and relates to the amount of the capsaicin or capsaicin analog permeated in a sample interval at certain elapsed time. E.g., in an in vitro permeation test as described above, wherein the amount of the capsaicin or capsaicin analog permeated into the receptor medium has been e.g. measured at minutes 0, 30, 60, 90, 120, 180 and 240, the “permeated amount” of the capsaicin or capsaicin analog can be given e.g. for the sample interval from minute 90 to minute 120 and corresponds to the measurement at minute 120, wherein the receptor medium has been exchanged completely at minute 90. The permeated amount can also be given as a “cumulative permeated amount”, corresponding to the cumulated amount of the capsaicin or capsaicin analog permeated at a certain point in time. E.g., in an in vitro permeation test as described above, wherein the amount of the capsaicin or capsaicin analog permeated into the receptor medium has been e.g. measured at minutes 0, 30, 60, 90, 120, 180 and 240, the “cumulative permeated amount” of the capsaicin or capsaicin analog at minute 120 corresponds to the sum of the permeated amounts from minute 0 to minute 30, minute 30 to minute 60, minute 60 to minute 90 and minute 90 to minute 120.

[0046] Within the meaning of this invention, the parameter “skin permeation rate”, also referred to as „A flux rate”, for a certain sample interval at certain elapsed time is provided in pg / (cm2*min) and is calculated from the permeated amount in said sample interval as measured by in vitro permeation test as described above in pg / cm2, divided by the minutes of said sample interval. E.g. the skin permeation rate in an in vitro permeation test as described above, wherein the amount of the capsaicin or capsaicin analog permeated into the receptor medium has been e.g. measured at minutes 0, 30, 60, 90, 120, 180 and 240, the “skin permeation rate” at Atime point 105 is calculated as the permeated amount in the sample interval from minute 90 to minute 120 divided by 30minutes. A “cumulative skin permeation rate” can be calculated from the respective cumulative permeated amount by dividing the cumulative permeated amount by the elapsed time.

[0047] Within the meaning of this invention, the above parameters “permeated amount” and “skin permeation rate” (as well as “cumulative permeated amount” and “cumulative skin permeation rate”) refer to mean values calculated from at least 6 in vitro permeation test experiments. Where not otherwise indicated, the standard deviation (SD) of these mean values refer to a corrected sample standard deviation, calculated using the formula:wherein n is the sample size, {xltx2, ... xn} are the observed values and x is the mean value of the observed values.

[0048] Within the meaning of this invention, the term “room temperature” refers to the unmodified temperature found indoors in the laboratory where the experiments are conducted and usually lies within 15 to 35 °C, or about 18 to 25 °C.

[0049] Within the meaning of this invention, the term “patient” refers to a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. In certain embodiments, the patient suffers from neuropathic pain or mixed neuropathic and / or nociceptive pain such as joint pain or cancer pain.

[0050] Within the meaning of this invention, the term “neuropathic pain” refers to pain caused by a lesion or disease of the somatosensory nervous system. In this context, the term “chronic neuropathic pain” is understood to mean neuropathic pain lasting for at least three months. When suffering from neuropathic pain, most patients complain of an ongoing or intermittent spontaneous pain of, e.g., burning, pricking, squeezing quality, which may be accompanied by evoked pain, particular to light touch and cold. Ectopic activity in, e.g., nerve-end neuroma, compressed nerves or nerve roots, dorsal root ganglia, and the thalamus may in different conditions underlie the spontaneous pain. Neuropathic pain includes peripheral neuropathic pain that particularly affects the peripheral nerves, meaning the nerves located outside the brain and spinal cord. In particular, neuropathic pain within the meaning of this invention relates to post-surgical neuropathic pain, as well as neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy of the hands or feet.

[0051] In this context, the term “post-surgical neuropathic pain” is understood to mean chronic pain that develops after a surgical procedure and persists beyond the healing process, i.e. at least three months after the surgery. The pain is either localized to the surgical field or area of injury, projected to the innervation territory of a nerve situated in this area, or referred to a dermatome (after surgery / injury to deep somatic or visceral tissues). Chronic post-surgical pain is the result of nerve damage and can be due to the surgery itself or other causes of pain including infection, malignancy, etc.

[0052] In this context, the term “postherpetic neuralgia”, also referred to as post-shingles nerve pain, is understood to mean pain occurring if nerves are damaged due to a previous herpes zoster infection, commonly referred to as shingles. Symptoms of post-shingles nerve pain are often limitedor localized to the area of the skin where the shingles outbreak first occurred, in the band around the trunk, usually on one side of the body. Less common symptoms of post-shingles nerve pain include itching, numbness, or feeling "pins and needles."

[0053] In this context, the term “diabetic peripheral neuropathy”, also referred to as diabetic nerve pain”, is understood to mean pain occurring if nerves are damaged as a result of diabetes. Although diabetic nerve pain can affect any nerve, it is most often felt in extremities, such as the hands or feet.

[0054] Within the meaning of this invention, the term “joint pain” refers to an articular condition, such as discomfort, aches or soreness in any of the body’s joints of a patient, including spine, shoulders, hips, elbows and knees. This includes in particular joint pain caused by arthritis, such as osteoarthritis. In this context, the term “osteoarthritis” is understood to mean a degenerative disease characterized by cartilage erosion, bony hypertrophy, subchondral sclerosis, and synovial and capsular changes. It is clinically characterized by joint pain, stiffness, and functional limitation. Although the pain of osteoarthritis is traditionally considered to be nociceptive, some patients also have neuropathic pain. The joint pain may be in particular knee pain, elbow pain, hip pain, shoulder pain, pain of the hands or feet, or pain of the (lower) back.

[0055] Within the meaning of this invention, the term “cancer pain” relates to neuropathic cancer pain caused by nerve damage attributable to the cancer per se, and / or treatments including chemotherapy, radiotherapy, and surgery. Cancer pain caused by the tumor per se usually involves both nociceptive and neuropathic components, and mixed pain is more common than neuropathic cancer pain caused by cancer treatments. Most cancer pain caused by chemotherapy is purely neuropathic in nature. Neuropathic cancer pain is nerve-related (typically neuron-related) pain characterized as a burning or electrical sensation; however, it sometimes manifests as decreased sensation or actual muscle weakness.

[0056] According to the invention, the medical patch as described herein is suitable for use in a method of treatment, in which the medical patch is applied for a short period of time (application time), but provides for the desired effect of pain relief for an extended period of time (effect time). Within the application time, the medical patch may release almost the total amount of the capsaicin or capsaicin analog contained in the active agent-containing matrix layer of the medical patch. The capsaicin or capsaicin analog is believed to be able to desensitize and defunctionalize the TRPV1 receptor within the application time, so that it can provide sustained pain relief that lasts during the effect time.

[0057] Within the meaning of this invention, the term “short period of time”, i.e., the application time, or “short-term application” relates to a period of less than or about 240 minutes, less than or about 180 minutes, less than or about 120 minutes, less than or about 90 minutes, less than or about 60 minutes, less than or about 45 minutes, less than or about 30 minutes, less than or about 15 minutes, or 30 to 90 minutes.

[0058] Within the meaning of this invention, the term “extended period of time”, i.e., the effect time, relates to a period of at least or about 1 week, at least or about 2 weeks, at least or about 1 month, at least or about 1.5 months, at least or about 2 months, at least or about 3 month, or 1 to 3 months.

[0059] The interval between two dosage form administrations, also called dosing interval, needs to be adapted accordingly. Within the meaning of the present invention, the term „dosing interval“refers to the period of time between two consecutive medical patch administrations, i.e. the interval between two consecutive points in time a medical patch is applied to the skin of the patient. Once applied, the medical patch is only maintained on the skin of the patient for the application time and subsequently removed. However, the dosing interval lasts until a new medical patch is applied to the skin.

[0060] Within the meaning of this invention, the term “coating composition” refers to a composition comprising all components of the active agent-containing matrix layer which may be coated onto the backing layer or release liner to form the active agent-containing matrix layer upon drying.

[0061] Within the meaning of this invention, the term “dissolve” refers to the process of obtaining a solution, which is clear and does not contain any particles, as visible to the naked eye.

[0062] Within the meaning of this invention, and unless otherwise specified, the term “about” refers to an amount that is ± 10 % of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ± 5 % of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ± 2 % of the disclosed amount.DETAILED DESCRIPTIONMEDICAL PATCH STRUCTURE

[0063] The present invention relates to a medical patch for the administration of capsaicin or a capsaicin analog. The medical patch can be either a topical medical patch or a transdermal therapeutic system. In certain embodiments, the patch is a topical medical patch, and in particular for the topical administration of capsaicin or a capsaicin analog.

[0064] The medical patch according to the present invention comprises an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising:A) a backing layer;B) an active agent-containing matrix layer comprising1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.In certain embodiments, the active agent-containing matrix layer is a capsaicin-containing matrix layer, which comprises1. capsaicin in an amount of at least 1 % by weight, based on the total weight of the capsaicin-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.Alternatively, the active agent-containing matrix layer is a capsaicin analog-containing matrix layer, which comprises1. a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the capsaicin analog-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.

[0065] In accordance with the invention, the medical patch comprises capsaicin or a capsaicin analog, in particular in a therapeutically effective amount. Thus, in certain embodiments, the medical patch comprises the capsaicin or capsaicin analog in an amount of from 0.5 to 250 mg. In ayet further embodiment, the medical patch comprises the capsaicin or capsaicin analog in an amount of about 179 mg.

[0066] The backing layer is in particular substantially impermeable to the capsaicin or capsaicin analog. In certain embodiments, the backing layer is non-siliconized. A backing layer which is nonsiliconized provides close adhesion with the active agent-containing matrix layer, in particular does not peel off from the active agent-containing matrix layer.

[0067] In specific embodiments, the active agent-containing self-adhesive layer structure according to the invention may comprise an additional skin contact layer. The additional skin contact layer is self-adhesive and provides for adhesion between the active agent-containing self- adhesive layer structure and the skin of the patient during administration. In such embodiments, the self-adhesive layer structure may or may not comprise a membrane which is located between the active agent-containing matrix layer and the additional skin contact layer.

[0068] In another embodiment, the self-adhesive layer structure according to the invention does not comprise an additional skin contact layer. Sufficient adhesion between the self-adhesive layer structure and the skin of the patient during administration is then provided for by other means, e.g., the active agent-containing matrix layer and / or an adhesive overlay.

[0069] Thus, according to certain embodiments, the medical patch according to the invention may further comprise an adhesive overlay or does not comprise an adhesive overlay. This adhesive overlay is in particular larger than the active agent-containing self-adhesive layer structure and is attached thereto for enhancing the adhesive properties of the overall medical patch. Said adhesive overlay comprises also a backing layer. The area of said adhesive overlay adds to the overall size of the medical patch but does not add to the area of release. The adhesive overlay may comprise a self- adhesive polymer or a self-adhesive polymer mixture selected from the group of acrylic polymers, polyisobutylenes, styrene-isoprene-styrene block copolymers, polysiloxanes, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the active agent-containing self-adhesive layer structure.

[0070] The active agent-containing self-adhesive layer structure according to the invention is normally located on a detachable protective layer (release liner) from which it is removed immediately before application to the surface of the patient’s skin. Thus, according to certain embodiments, the medical patch further comprises a release liner. This release liner may be fluorine-free, e.g., may have a silicone coating, i.e., the release liner is siliconized. A release liner having a silicone coating can be easily peeled off from the active agent-containing matrix layer.

[0071] In certain embodiments, the release liner consists of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane. In certain preferred embodiments, the release liner consists of siliconized polyethylene or siliconized polyethylene terephthalate. In yet further embodiments, the release liner is not fluoropolymerized.

[0072] A medical patch protected this way can be stored in a seam-sealed pouch. The packaging may be child resistant and / or senior friendly.ACTIVE AGENT-CONTAINING MATRIX LAYER

[0073] As outlined in more detail above, the medical patch according to the present invention comprises an active agent-containing self-adhesive layer structure comprising inter alia an active agent-containing matrix layer, which comprises1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.

[0074] In certain embodiments, the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of at least 2 % by weight, based on the total weight of the active agent-containing matrix layer. In certain embodiments, the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of at least 5 % by weight, based on the total weight of the active agent-containing matrix layer. In these or other embodiments, the active agent-containing matrix layer may comprise the capsaicin or capsaicin analog in an amount of up to 20 % by weight, based on the total weight of the active agent-containing matrix layer. Thus, according to certain embodiments, the active-agent-containing matrix layer contains the capsaicin or capsaicin analog in an amount of from 2 to 20 % by weight, based on the total weight of the active-agent containing matrix layer.

[0075] In certain embodiments of the medical patch according to the present invention, the active agent-containing matrix layer further comprises a tackifier. In particular, according to certain embodiments, the active agent-containing matrix layer comprises1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer,2. a polymer based on natural or synthetic rubbers, and3. a tackifier.

[0076] In these or other embodiments of the medical patch according to the present invention, the active agent-containing matrix layer further comprises a solubilizer. In particular, according to certain embodiments, the active agent-containing matrix layer comprises1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer,2. a polymer based on natural or synthetic rubbers,3. a tackifier, and / or4. a solubilizer.

[0077] In certain embodiments, the active agent-containing matrix layer further comprises a permeation enhancer. The permeation enhancer may be selected from the group consisting of monoterpenes and / or methyl salicylate. The active agent-containing matrix layer may comprise the permeation enhancer in an amount of from 0.1 to 10 % by weight, based on the total weight of the active agent-containing matrix layer.

[0078] In one embodiment, the active agent-containing matrix layer contains at least 0.40 mg / cm2, capsaicin or capsaicin analog per area of release.

[0079] In certain embodiments, the capsaicin or capsaicin analog is homogeneously distributed within the active agent-containing matrix layer. As used herein, an active agent-containing matrix layer is a layer containing the capsaicin or capsaicin analog, which may be dissolved or dispersed in the polymer. In further embodiments, the active agent-containing matrix layer comprises the capsaicin or capsaicin analog and a solubilizer dissolved in the polymer.

[0080] According to certain embodiments, the active agent-containing matrix layer is obtainable by a solvent-based coating process, i.e. the active agent-containing matrix layer is manufactured by combining at least the capsaicin or capsaicin analog and the polymer, or at least the capsaicin orcapsaicin analog, the polymer, the tackifier and / or the solubilizer, in a solvent to obtain a coating composition and coating the coating composition onto a backing layer or a release liner or any intermediate liner. In accordance with such embodiments, the active agent-containing matrix layer is not manufactured using a hot-melt coating or an electrospinning process, the latter resulting in a fibrous web characterized by a porous structure. Thus, in certain embodiments, the active agentcontaining matrix layer is not an electrospun fibrous web, i.e., the active agent-containing matrix layer is non-porous. Such a porous structure can be determined by various methods as known to the skilled person, and can, e.g., be made visible in a scanning electron microscope.

[0081] Further, in a certain embodiment, the area weight of the active agent-containing matrix layer ranges from 30 to 200 g / m2POLYMER

[0082] According to the invention, the medical patch comprises an active agent-containing self- adhesive layer structure comprising an active agent-containing matrix layer, which comprises a polymer. This polymer may provide for sufficient cohesion and / or adhesion of the active agentcontaining matrix layer.

[0083] Polymers which are suitable as the polymer in accordance with the invention are polymers based on natural or synthetic rubbers. It has been surprisingly found that formulations based on such polymers allow for a favorable delivery of the capsaicin or capsaicin analog compared to formulations based on e.g., acrylic polymers, characterized by a high and fast release. In particular, these polymers are advantageous in terms of providing a medical patch suitable for short-term applications and in terms of the compatibility with certain fluorine-free release liners (detachable protective layer). The polymers can in particular be used in combination with a tackifier as defined below.

[0084] In certain embodiments, the polymer is a styrenic triblock copolymers or a polyisobutylene. The polymer may be a styrenic triblock copolymer selected from the group consisting of styrene-ethylene-styrene (SES) block copolymers, styrene-butadiene-styrene (SBS) block copolymers, styrene-isoprene-styrene (SIS) block copolymers, styrene-ethylene / butylene- styrene (S-EB-S) block copolymers, styrene-ethylene / butylene / propylene-styrene (s-EBS-S) block copolymers, styrene-isoprene / butadiene-styrene (S-IB-S) block copolymers, and mixtures thereof.

[0085] In certain embodiments, the polymer is at least one SIS block copolymer. The at least one SIS block copolymer consists of three blocks of polystyrene, polyisoprene and polystyrene and in particular has a molecular weight of from about 100,000 to 200,000.

[0086] In certain embodiments of the invention, the at least one SIS block copolymer comprises blocks of polystyrene and of polyisoprene in a ratio of from about 10:90 (%) to about 30:70 (%), or in a ratio of about 15:85 (%) or about 22:78 (%).

[0087] Suitable SIS block copolymers according to the invention are commercially available e.g. under the brand names JSR-SIS. Specific SIS block copolymer-based pressure-sensitive adhesives are available under the tradenames JSR-SIS5229 and JSR-SIS5002.

[0088] Suitable polyisobutylenes according to the invention are commercially available under the tradename Oppanol®.

[0089] Additional polymers may also be added, e.g., to enhance cohesion and / or adhesion.

[0090] According to certain embodiments, the amount of the polymer in the active agentcontaining matrix layer ranges from 10 to 90 % by weight, based on the total weight of the active agent-containing matrix layer.TACKIFIER

[0091] The medical patch according to the invention, and in particular the active agent-containing matrix layer may further comprise a tackifier. Such tackifier may be added to improve or adjust self-adhesive properties of the active agent-containing matrix layer, e.g., in case polymer(s) is / are selected which does / do not provide sufficient self-adhesive properties for a desired purpose.

[0092] In certain embodiments, the at least one tackifier is an alicyclic saturated hydrocarbon resin, a hydrogenated rosin glycerol ester, a mineral oil, or a mixture thereof. The at least one tackifier may be a mixture comprising an alicyclic saturated hydrocarbon resin and a mineral oil, or a mixture comprising a hydrogenated rosin glycerol ester and a mineral oil.

[0093] Alicyclic saturated hydrocarbon resins are described in detail in the respective monograph in the Japanese pharmacopeia. In certain embodiments of the invention, the alicyclic saturated hydrocarbon resin is obtainable from polymerization of an unsaturated hydrocarbon obtainable prepared by the decomposition of petroleum naphtha at elevated temperatures.

[0094] A specific alicyclic saturated hydrocarbon resin is available from Arakawa Europe under the tradename Arkon P-100 and has the chemical structure as detailed below.

[0095] Other alicyclic saturated hydrocarbon resins, in particular supplied by Arakawa Europe, may also be suitable to be used in the medical patch according to the invention.

[0096] Hydrogenated rosin glycerol esters are described in detail in the respective monograph in the Japanese pharmacopeia. In certain embodiments of the invention, the hydrogenated rosin glycerol ester is a solid resin obtainable from the hydrogenation of rosin, followed by esterification with glycerin.

[0097] A specific hydrogenated rosin glycerol ester is available from Arakawa Europe under the tradename Pinecrystal KE-100 and has the chemical structure as detailed below.

[0098] Other hydrogenated rosin glycerol esters, in particular supplied by Arakawa Europe, may also be suitable to be used in the medical patch according to the invention.

[0099] Suitable mineral oils include any pharmaceutically acceptable distillation product of petroleum, such as e.g. paraffinum liquidum. Paraffinum liquidum is a refined mixture of liquid, saturated hydrocarbons as defined in the European Pharmacopeia (Ph.Eur.).

[0100] Further examples of commercially available products to be used as tackifier in the active agent-containing matrix layer according to the invention include YS Resin PX or YS Resin PXN manufactured by Yasuhara Chemical Co., Ltd.

[0101] According to certain embodiments of the invention, the amount of the mineral oil, such as paraffinum liquidum, contained in the active agent-containing matrix layer ranges from 30 to 80 % by weight, based on the amount of SIS block copolymer(s) contained in the active agent-containing matrix layer.

[0102] In certain embodiments, the ratio of the amount of SIS block copolymer(s) to the amount of tackifier(s) is between 60:40 (w / w) and 20:80 (w / w), or between 50:50 (w / w) and 25:75 (w / w), based on the total weight of the active agent-containing matrix layer.

[0103] Further, in certain embodiments, the amount of the tackifier contained in the active agentcontaining matrix layer ranges from 20 to 80 % by weight, based on the total weight of the active agent-containing matrix layer. The at least one SIS block copolymer and the at least one tackifier may also be present in the active agent-containing matrix layer in an overall amount of at least 70 % by weight, based on the total weight of the active agent-containing matrix layer.SOLUBILIZER

[0104] The medical patch according to the invention, and in particular the active agent-containing matrix layer advantageously may comprise a solubilizer.

[0105] As outlined above, a solubilizer is an agent that increases the solubility of the capsaicin or capsaicin analog in the active agent-containing matrix layer. This can be achieved by a substance or a mixture of substances having a relatively high solubility for capsaicin or capsaicin analog. Thus, the solubilizer may be a substance or a mixture of substances in which the capsaicin or capsaicin analog has a solubility of at least 40 % by weight, or of at least 45 % by weight.

[0106] The solubilizer may also be released along with the capsaicin or capsaicin analog to further act as penetration enhancer. It has been surprisingly found that formulations including a solubilizer appear to provide for improved delivery of the capsaicin or capsaicin analog characterized by a high and fast release. Without wishing to be bound by theory, it is believed that a solubilizer may also have a limited or reduced affinity to the synthetic or natural rubber polymer, and that this way, the driving force of the active agent dissolved in the solubilizer out of the patch is kept high.

[0107] Suitable solubilizers are, e.g., dipropylene glycol, di ethylene glycol monoethyl ether, or dimethyl isosorbide. Diethylene glycol monoethyl ether and dimethyl isosorbide are, e.g., available under the trade names transcutol® and dottisol®, respectively. While any of the above-mentioned solubilizers can be used in the present medical patch, dipropylene glycol and in particular dimethyl isosorbide appear to be most advantageous, as will be shown in the Examples.

[0108] Further, in certain embodiments, the active agent-containing matrix layer comprises the solubilizer in an amount of from 1 to 40 % by weight, based on the total weight of the active agentcontaining matrix layer.RELEASE CHARACTERISTICS

[0109] The medical patch according to the present invention is designed for topically administering capsaicin or a capsaicin analog to create a local effect at a point of action, or for transdermally administering capsaicin or a capsaicin analog to the systemic circulation, for a predefined period of time. While topically administering capsaicin or a capsaicin analog relies on diffusion into the skin itself and does not necessitate transdermal release into the systemic circulation, in vitro skin permeation experiments still provide a good indication as to whether there is an effective topical release.

[0110] According to certain embodiments, the medical patch provides a cumulative permeated amount of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of from 0.1 to 1.0 pg / cm2or of about 0.3 pg / cm2over a time period of about 60 minutes, and / or a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of 0.06 pg / (cm2h) to 0.3 pg / (cm2h), or of 0.2 pg / (cm2h) to 1.2 pg / (cm2h), or of about 0.6 pg / (cm2h) after 60 minutes.[oni] In a specific embodiment of the invention, the medical patch according to the invention as described above provides a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of0 pg / (cm2h) to 0.9 pg / (cm2h) in the first 60 minutes,0.6 pg / (cm2h) to 1.2 pg / (cm2h) from minute 60 to minute 90,0.8 pg / (cm2h) to 1.4 pg / (cm2h) from minute 90 to minute 120,0.9 pg / (cm2h) to 1.6 pg / (cm2h) from minute 120 to minute 240.

[0112] In certain embodiments, the medical patch provides therapeutically effective skin permeation of the capsaicin or capsaicin analog, within less than 90 minutes, or even within less than 60 minutes after application of the medical patch to the skin, and in particular, the medical patch provides the maximum of the skin permeation rate of the capsaicin or capsaicin analog within a time period of 90 minutes, or within a time period of 60 minutes. Thus, medical patches according to the present invention are particularly suitable for short-term applications.METHOD OF TREATMENT / MEDICAL USE

[0113] The medical patch according to the present invention is suitable for use in a method of treatment, and in particular in a method of treating a human patient.

[0114] In certain embodiments, the medical patch according to the invention is for use in a method of treatment, wherein the medical patch is applied to the skin of the patient, e.g., for less than 90 minutes, less than 60 minutes, or even less than 30 minutes. In certain embodiments, the medical patch according to the invention is for use in a method of treatment with a dosing interval of at least or about 1.5 months, at least or about 2 months, or at least or about 3 months. Thus, it is preferred for a medical patch to be only applied after a break of, e.g., at least 90 days after removal of a preceding medical patch.

[0115] In one embodiment, the medical patch according to the invention is for use in a method of treating neuropathic pain, in particular chronic neuropathic pain, including postherpetic neuralgia, post-surgical neuralgia such as, e.g., post-herniotomy pain, post-thoracotomy pain or postmastectomy pain, post-traumatic neuropathy, polyneuropathy such as, e.g., painful diabeticneuropathy, ch emotherapy -induced neuropathy, neuropathy caused by tumors, HIV-associated neuropathy, alcohol-related neuropathy, small-fiber neuropathy or complex regional pain syndrome, radiculopathy, or compression syndromes such as carpal tunnel syndrome.

[0116] The medical patch according to the invention may also be for use in a method of treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands and feet, post-surgical neuropathic pain, joint pain, or cancer pain.

[0117] In certain embodiments, the medical patch according to the invention is for use in a method of treating neuropathic pain associated with postherpetic neuralgia, or neuropathic pain associated with diabetic peripheral neuropathy of the hands or feet in a human patient, in particular an adult. In certain embodiments, the medical patch according to the invention is for use in a method of treating post-surgical neuropathic pain in a human patient, in particular an adult.

[0118] In connection with the above, the medical patch according to the invention is preferably applied to at least one body surface on the patient, which may be, e.g., selected from the back, the bottom, the legs, the feet, or the hands. The application time of a medical patch according to the invention may be in particular less than or about 60 minutes on the back, bottom or legs, and less than or about 30 minutes on the feet or hands.

[0119] According to a specific aspect, the present invention is also related to a method of treating neuropathic pain, in particular chronic neuropathic pain, peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, post-surgical neuropathic pain, joint pain, or cancer pain including applying a medical patch as described herein to the skin of a patient.PROCESS OF MANUFACTURE

[0120] The invention further relates to a process of manufacture of an active agent-containing matrix layer for use in a medical patch and a corresponding active agent-containing self-adhesive layer structure and a corresponding medical patch.

[0121] In accordance with the invention, the process of manufacture of a self-adhesive matrix layer for use in a medical patch according to the present invention, in particular of a medical patch according to the present invention, comprises the steps of1) combining at least the components1. capsaicin or capsaicin analog, and2. polymer based on natural or synthetic rubbers, to obtain a coating composition;2) coating the coating composition onto the backing layer or a release liner or any intermediate liner; and3) drying the coated coating composition to form the active agent-containing matrix layer.

[0122] In this process of manufacture, in step 1) the components are preferably combined in a solvent to obtain the coating composition. The solvent may be selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, n-propyl acetate, hexane, n-heptane, petroleum ether, toluene, and mixtures thereof.

[0123] The capsaicin or capsaicin analog is preferably homogeneously dissolved or dispersed in the coating composition.

[0124] The coated coating composition is solidified by drying in step 3). Drying is preferably performed at a temperature of from 20 to 90 °C.

[0125] According to certain embodiments, the active agent-containing matrix layer is manufactured in a solvent-based coating process. In particular, the active agent-containing matrix layer is manufacturing without using a hot-melt coating process or an electrospinning process.EXAMPLES

[0126] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Numerical values provided in the examples regarding the amount of ingredients in the composition or the area weight may vary slightly due to manufacturing variability.EXAMPLES 1A - 1C AND REFERENCE EXAMPLE ID

[0127] Medical patches comprising 0.03-0.04% Capsaicin in an SIS block copolymer adhesive were prepared. After having obtained very promising preliminary results in an in vitro permeation (i.e., a high permeation rate and a favorable permeation profile with a fast onset of release, reaching maximum permeation rate within a few hours), for a patch formulation comprising inter alia about 0.03% capsaicin in an adhesive mixture based on an SIS block copolymer, terpene resin and paraffin, it was decided that further excipients are investigated in formulations with low capsaicin concentration, to enable sensory testing of the prepared patches, before testing high concentration formulations. In view of a potential high concentration formulation, however, solubilizers with a high solubility for capsaicin were selected. The solubility of capsaicin was tested by way of gravimetric analysis and determined to be in the range of 46-48 % (w / w) for transcutol® and 42-45 % (w / w) for dottisol® at 21 °C. These solubilities are sufficient to ensure proper formulation of high-concentration capsaicin compositions.

[0128] The low-concentration formulation of the capsaicin-containing coating compositions according to Examples la to 1c and according to Reference Example Id (solubilizer-free control) are summarized in Table 1.1 below. The solids %-values refer to the amounts (Amt) in % by weight.

[0129] Table 1.1Preparation of the capsaicin-containing coating composition

[0130] For all four patches, the capsaicin solution, the polymer SIS 5229P, the paraffin, the terpene resin PX1150N, the mineral filler, the fumed silica filler and the two solvents n- propylacetate and n-heptane were mixed under stirring. As applicable, transcutol® (for Ex. la), dipropylene glycol (for Ex. lb) or dottisol® (for Ex. 1c) were added, respectively, and the mixture was then stirred until a homogeneous mixture was obtained.Coating of the capsaicin-containing coating composition

[0131] The resulting capsaicin-containing coating composition was coated on a siliconized PET film, which may function as release liner, and dried at 50 °C until the solvent was substantially removed.

[0132] The resulting capsaicin-containing layer was then laminated with a backing layer which was a non-occlusive fabric backing (Ex. la and lb) or an occlusive PET backing (Ex. 1c and Ref. Ex. Id), respectively. The capsaicin-containing layers were monolithic matrix layers for all patches (Ex. la, lb and 1c as well as Ref. Ex. Id), none of the patches showed any microreservoir structure.Sensory testing

[0133] The resulting medical patches were applied on the skin to evaluate the degree of topical release of capsaicin.

[0134] Samples of 10 cm2were applied to the inner side of the forearm for 13 / 4 hours. During this period, the tingling effect, and the evolution of skin reddening around the patch was documented. After removal of the patches, the skin appearance under the patches was assessed.Results of Sensory testing

[0135] The characteristic tingling effect of capsaicin indicating topical release did not occur for the patch of Ref. Ex. Id and was weak for the patch of Ex. la and stronger for Ex. lb. The patch of Ex. 1c provided the most pronounced tingling sensation, with a fast onset and a clear reddening of the skin. A comparable formulation based on acrylate adhesives resulted in no effect being perceivable during the sensory testing on skin at all.

[0136] In this set of experiments, it was shown, that dimethyl isosorbide showed best results in terms of Capsaicin penetration into the skin, because the onset of tingling effect was fast, and the reddening effect to the skin was strong. For patches with higher Capsaicin content (> 1 %), this effect will be correspondingly greater, as the thermodynamic driving force will push more Capsaicin into the skin. This effect should be observed 1 : 1 in the in-vitro skin permeation experiment.

[0137] It should be noted that the formulations included fillers to keep the tingling effect of Capsaicin (which some also perceive as an uncomfortable burning sensation) at a manageable level, and that it will be able to control and further increase the capsaicin release of the topical patch to meet the requirements of the desired treatment effects by increasing the capsaicin concentration, but also by omitting such fillers.The invention relates in particular to the following further items:1. Medical patch for the administration of capsaicin or a capsaicin analog comprising an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising:A) a backing layer;B) an active agent-containing matrix layer comprising1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer, and2. a polymer based on natural or synthetic rubbers.2. Medical patch according to item 1, wherein the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of at least 2 % by weight, or at least 5 % by weight, based on the total weight of the active agentcontaining matrix layer.3. Medical patch according to item 1 or 2, wherein the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of from 2 to 20 % by weight, based on the total weight of the active agent-containing matrix layer.4. Medical patch according to any one of items 1 to 3, wherein the amount of the polymer in the active agent-containing matrix layer ranges from 10 to 90 % by weight, based on the total weight of the active agent-containing matrix layer.5. Medical patch according to any one of items 1 to 4, wherein the polymer is a styrenic triblock copolymer or a poly isobutylene, or mixture thereof.6. Medical patch according to any one of items 1 to 5, wherein the polymer is a styrenic triblock copolymer selected from the group consisting of styrene-ethylene- styrene (SES) block copolymers, styrene-butadiene-styrene (SBS) block copolymers, styrene- isoprene-styrene (SIS) block copolymers, styrene-ethylene / butylene-styrene (S-EB-S) block copolymers, styrene-ethylene / butylene / propylene-styrene (S-EBP-S) block copolymers, styrene- isoprene / butadiene-styrene (S-IB-S) block copolymers, and mixtures thereof.7. Medical patch according to any one of items 1 to 6, wherein the polymer is an SIS block copolymer.8. Medical patch according to item 7, wherein the SIS block copolymer comprises blocks of polystyrene and of polyisoprene in a ratio of from 10:90 (%) to 30:70 (%).9. Medical patch according to item 7 or 8, wherein the at least one SIS block copolymer consists of three blocks of polystyrene, polyisoprene and polystyrene.10. Medical patch according to any one of items 1 to 9, wherein the active agent-containing matrix layer further comprises at least one tackifier.11. Medical patch according to item 10, wherein the at least one tackifier is an alicyclic saturated hydrocarbon resin, or a hydrogenated rosin glycerol ester, or a mineral oil, or mixture thereof.12. Medical patch according to item 10 or 11, wherein the at least one tackifier is a mixture comprising an alicyclic saturated hydrocarbon resin and a mineral oil.13. Medical patch according to item 11 or 12, wherein the alicyclic saturated hydrocarbon resin is obtainable from polymerization of an unsaturated hydrocarbon prepared by the decomposition of petroleum naphtha at elevated temperatures.14. Medical patch according to any one of items 10 to 13, wherein the at least one tackifier is a mixture comprising a hydrogenated rosin glycerol ester and a mineral oil.15. Medical patch according to item 14, wherein the hydrogenated rosin glycerol ester is a solid resin obtainable from the hydrogenation of rosin, followed by esterification with glycerin.16. Medical patch according to any one of items 10 to 15, wherein the amount of tackifier contained in the active agent-containing matrix layer ranges from 20 to 80 % by weight, based on the total weight of the active agent-containing matrix layer.17. Medical patch according to any one of items 11 to 16, wherein the amount of the mineral oil contained in the active agent-containing matrix layer ranges from 30 to 80 % by weight, based on the amount of SIS block copolymer(s) contained in the active agentcontaining matrix layer.18. Medical patch according to any one of items 10 to 17, wherein the ratio of the amount of SIS block copolymer(s) to the amount of tackifier(s) is between 60:40 (w / w) and 20:80 (w / w), based on the total weight of the active agent-containing matrix layer.19. Medical patch according to any one of items 10 to 18, wherein the at least one SIS block copolymer and the at least one tackifier are present in the active agentcontaining matrix layer in an overall amount of at least 70 % by weight, based on the total weight of the active agent-containing matrix layer.20. Medical patch according to any one of items 1 to 19, whereinthe active agent-containing matrix layer is non-porous.21. Medical patch according to any one of items 1 to 20, wherein the active agent-containing matrix layer further comprises a solubilizer.22. Medical patch according to item 21, wherein the solubilizer is a substance or mixture of substances in which the capsaicin or capsaicin analog has a solubility of at least 40 % by weight.23. Medical patch according to item 21 or 22, wherein the solubilizer is dipropylene glycol, diethylene glycol monoethyl ether, or dimethyl isosorbide.24. Medical patch according to any one of items 21 to 23, wherein the active agent-containing matrix layer comprises the solubilizer in an amount of from 1 to 40 % by weight, based on the total weight of the active agent-containing matrix layer.25. Medical patch according to any one of items 1 to 24, wherein the active agent-containing matrix layer further comprises a permeation enhancer.26. Medical patch according to item 25, wherein the permeation enhancer is selected from the group consisting of monoterpenes and / or methyl salicylate.27. Medical patch according to item 25 or 26, wherein the active agent-containing matrix layer comprises the permeation enhancer in an amount of from0.1 to 10 % by weight, based on the total weight of the active agent-containing matrix layer.28. Medical patch according to any one of items 1 to 27, wherein the active agent-containing matrix layer contains at least 0.40 mg / cm2capsaicin or capsaicin analog.29. Medical patch according to any one of items 1 to 28, wherein the medical patch comprises the capsaicin or capsaicin analog in an amount of from 0.5 to 250 mg.30. Medical patch according to any one of items 1 to 29, wherein the medical patch comprises the capsaicin or capsaicin analog in an amount of about 179 mg.31. Medical patch according to any one of item 1 to 30, wherein the area weight of the active agent-containing matrix layer ranges from 30 to 200 g / m232. Medical patch according to any one of items 1 to 31, wherein the active agent-containing matrix layer is obtainable by a solvent-based coating process.33. Medical patch according to any one of items 1 to 32, whereinthe backing layer is non-siliconized.34. Medical patch according to any one of items 1 to 33, wherein the medical patch further comprises a release liner.35. Medical patch according to item 34, wherein the release liner has a silicone coating.36. Medical patch according to item 34 or 35, wherein the release liner consists of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane.37. Medical patch according to any one of items 34 to 36, wherein the release liner consists of siliconized polyethylene or siliconized polyethylene terephthalate.38. Medical patch according to any one of items 1 to 37, wherein the medical patch is a topical medical patch.39. Medical patch according to any one of items 1 to 37, wherein the medical patch is a transdermal therapeutic system.40. Medical patch according to any one of items 1 to 39, wherein the medical patch provides a cumulative permeated amount of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of from 0.1 to 1.0 pg / cm2or of about 0.3 pg / cm2over a time period of about 60 minutes, and / or a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of 0.06 pg / (cm2h) to 0.3 pg / (cm2h), or of 0.2 pg / (cm2h) to 1.2 pg / (cm2h), or of about 0.6 pg / (cm2h) after 60 minutes.41. Medical patch according to any one of items 1 to 40, wherein the medical patch provides a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of0 pg / (cm2h) to 0.9 pg / (cm2h) in the first 60 minutes,0.6 pg / (cm2h) to 1.2 pg / (cm2h) from minute 60 to minute 90,0.8 pg / (cm2h) to 1.4 pg / (cm2h) from minute 90 to minute 120,0.9 pg / (cm2h) to 1.6 pg / (cm2h) from minute 120 to minute 240.42. Medical patch according to any one of items 1 to 41, for use in a method of treating neuropathic pain, in particular chronic neuropathic pain, such as in a method of treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands and feet, post-surgical neuropathic pain, joint pain, or cancer pain.43. Use of a medical patch according to any one of items 1 to 41, for the manufacture of a medicament for treating neuropathic pain, in particular chronic neuropathic pain, such as for the manufacture of a medicament for treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, post-surgical neuropathic pain, joint pain, or cancer pain.44. A method of treating neuropathic pain, in particular chronic neuropathic pain, such as peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands or feet, post-surgical neuropathic pain, joint pain, or cancer pain including applying a medical patch according to any one of items 1 to 41 to the skin of a patient.45. A method of manufacturing an active agent-containing matrix layer for use in a medical patch according to any one of items 1 to 41 comprising the steps of:1) combining at least the components1. capsaicin or capsaicin analog, and2. polymer based on natural or synthetic rubbers, to obtain a coating composition;2) coating the coating composition onto the backing layer or a release liner or any intermediate liner; and3) drying the coated coating composition to form the active agent-containing matrix layer.

Claims

CLAIMS1. Medical patch for the administration of capsaicin or a capsaicin analog comprising an active agent-containing self-adhesive layer structure, said active agent-containing self-adhesive layer structure comprising:A) a backing layer;B) an active agent-containing matrix layer comprising1. capsaicin or a capsaicin analog in an amount of at least 1 % by weight, based on the total weight of the active agent-containing matrix layer, and2. a polymer based on natural or synthetic rubbers, wherein said capsaicin analog is a TRPV1 receptor agonist preserving all or a part of an aromatic catechol ring in its chemical structure, and said polymer based on natural or synthetic rubbers is a styrenic triblock copolymer or a polyisobutylene, or mixture thereof.

2. Medical patch according to claim 1, wherein the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of at least 2 % by weight, or at least 5 % by weight, based on the total weight of the active agentcontaining matrix layer, and / or the active agent-containing matrix layer comprises the capsaicin or capsaicin analog in an amount of from 2 to 20 % by weight, based on the total weight of the active agent-containing matrix layer.

3. Medical patch according to claim 1 or 2, wherein the amount of the polymer in the active agent-containing matrix layer ranges from 10 to 90 % by weight, based on the total weight of the active agent-containing matrix layer.

4. Medical patch according to any one of claims 1 to 3, wherein the polymer is a styrenic triblock copolymer selected from the group consisting of styrene-ethylene- styrene (SES) block copolymers, styrene-butadiene-styrene (SBS) block copolymers, styrene- isoprene-styrene (SIS) block copolymers, styrene-ethylene / butylene-styrene (S-EB-S) block copolymers, styrene-ethylene / butylene / propylene-styrene (S-EBP-S) block copolymers, styrene- isoprene / butadiene-styrene (S-IB-S) block copolymers, and mixtures thereof.

5. Medical patch according to any one of claims 1 to 4, wherein the polymer is an SIS block copolymer, wherein preferably the SIS block copolymer comprises blocks of polystyrene and of polyisoprene in a ratio of from 10:90 (%) to 30:70 (%), and / or the SIS block copolymer consists of three blocks of polystyrene, polyisoprene and polystyrene.

6. Medical patch according to any one of claims 1 to 5, wherein the active agent-containing matrix layer further comprises at least one tackifier, wherein preferablythe at least one tackifier is an alicyclic saturated hydrocarbon resin, or a hydrogenated rosin glycerol ester, or a mineral oil, or mixture thereof, and / or the at least one tackifier is a mixture comprising an alicyclic saturated hydrocarbon resin and a mineral oil, and / or the at least one tackifier is a mixture comprising a hydrogenated rosin glycerol ester and a mineral oil.

7. Medical patch according to claim 6, wherein the alicyclic saturated hydrocarbon resin is obtainable from polymerization of an unsaturated hydrocarbon prepared by the decomposition of petroleum naphtha at elevated temperatures, and / or the hydrogenated rosin glycerol ester is a solid resin obtainable from the hydrogenation of rosin, followed by esterification with glycerin.

8. Medical patch according to claim 6 or 7, wherein the amount of tackifier contained in the active agent-containing matrix layer ranges from 20 to 80 % by weight, based on the total weight of the active agent-containing matrix layer, and / or the amount of the mineral oil contained in the active agent-containing matrix layer ranges from 30 to 80 % by weight, based on the amount of SIS block copolymer(s) contained in the active agentcontaining matrix layer, and / or the ratio of the amount of SIS block copolymer(s) to the amount of tackifier(s) is between 60:40 (w / w) and 20:80 (w / w), based on the total weight of the active agent-containing matrix layer, and / or the at least one SIS block copolymer and the at least one tackifier are present in the active agentcontaining matrix layer in an overall amount of at least 70 % by weight, based on the total weight of the active agent-containing matrix layer.

9. Medical patch according to any one of claims 1 to 8, wherein the active agent-containing matrix layer further comprises a solubilizer, wherein preferably the active agent-containing matrix layer comprises the solubilizer in an amount of from 1 to 40 % by weight, based on the total weight of the active agent-containing matrix layer, and / or the solubilizer is a substance or mixture of substances in which the capsaicin or capsaicin analog has a solubility of at least 40 % by weight, and / or the solubilizer is dipropylene glycol, diethylene glycol monoethyl ether, or dimethyl isosorbide.

10. Medical patch according to any one of claims 1 to 9, wherein the active agent-containing matrix layer further comprises a permeation enhancer, wherein preferably the active agent-containing matrix layer comprises the permeation enhancer in an amount of from 0.1 to 10 % by weight, based on the total weight of the active agent-containing matrix layer, and / or the permeation enhancer is selected from the group consisting of monoterpenes and / or methyl salicylate.

11. Medical patch according to any one of claims 1 to 10, wherein the medical patch further comprises a release liner, wherein preferablythe release liner has a silicone coating, and / or the release liner consists of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane, and / or the release liner consists of siliconized polyethylene or siliconized polyethylene terephthalate.

12. Medical patch according to any one of claims 1 to 11, wherein the medical patch is a topical medical patch or a transdermal therapeutic system.

13. Medical patch according to any one of claims 1 to 12, wherein the medical patch provides a cumulative permeated amount of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of from 0.1 to 1.0 pg / cm2or of about 0.3 pg / cm2over a time period of about 60 minutes, and / or a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of 0.06 pg / (cm2h) to 0.3 pg / (cm2h), or of 0.2 pg / (cm2h) to 1.2 pg / (cm2h), or of about 0.6 pg / (cm2h) after 60 minutes, and / or a skin permeation rate of the capsaicin or capsaicin analog as measured in a Franz diffusion cell with dermatomed human skin of0 pg / (cm2h) to 0.9 pg / (cm2h) in the first 60 minutes,0.6 pg / (cm2h) to 1.2 pg / (cm2h) from minute 60 to minute 90,0.8 pg / (cm2h) to 1.4 pg / (cm2h) from minute 90 to minute 120,0.9 pg / (cm2h) to 1.6 pg / (cm2h) from minute 120 to minute 240.

14. Medical patch according to any one of claims 1 to 13, for use in a method of treating neuropathic pain, in particular chronic neuropathic pain, such as for use in a method of treating peripheral neuropathic pain, neuropathic pain associated with postherpetic neuralgia or diabetic peripheral neuropathy (DPN) of the hands and feet, post-surgical neuropathic pain, joint pain, or cancer pain.

15. A method of manufacturing an active agent-containing matrix layer for use in a medical patch according to any one of claims 1 to 13 comprising the steps of:1) combining at least the components1. capsaicin or capsaicin analog, and2. polymer based on natural or synthetic rubbers, to obtain a coating composition;2) coating the coating composition onto the backing layer or a release liner or any intermediate liner; and3) drying the coated coating composition to form the active agent-containing matrix layer.

Images