WO2020093906A1 - 含有布洛芬或其结构类似物的多层经皮给药系统 - Google Patents

含有布洛芬或其结构类似物的多层经皮给药系统 Download PDF

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WO2020093906A1
WO2020093906A1 PCT/CN2019/113909 CN2019113909W WO2020093906A1 WO 2020093906 A1 WO2020093906 A1 WO 2020093906A1 CN 2019113909 W CN2019113909 W CN 2019113909W WO 2020093906 A1 WO2020093906 A1 WO 2020093906A1
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Prior art keywords
layer
polymer matrix
ibuprofen
transdermal
matrix layer
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PCT/CN2019/113909
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English (en)
French (fr)
Inventor
谢文委
律嵩
何双江
陈楠
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北京德默高科医药技术有限公司
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Application filed by 北京德默高科医药技术有限公司 filed Critical 北京德默高科医药技术有限公司
Priority to US17/292,387 priority Critical patent/US20220008351A1/en
Priority to JP2021525301A priority patent/JP7354242B2/ja
Priority to EP19881630.8A priority patent/EP3900710A4/en
Publication of WO2020093906A1 publication Critical patent/WO2020093906A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention belongs to the technical field of transdermal drug delivery, and in particular relates to a multi-layer transdermal drug delivery system containing ibuprofen or its structural analogs.
  • the system of the present invention contains highly loaded drug ibuprofen or its structural analogs, and can be evenly dispersed in a polymer matrix.
  • the system can continuously and stably deliver a dose of ibupro that achieves a therapeutic effect during 12-24 hours Fin or its structural analogues.
  • Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used to relieve pain, reduce fever and reduce inflammation.
  • This product can non-selectively and reversibly inhibit the activity of cyclooxygenase (COX) COX-1 and COX-2, and COX-1 and COX-2 are the key to the catalytic synthesis of prostaglandin (PG) in vivo Enzyme.
  • COX-1 and COX-2 are the key to the catalytic synthesis of prostaglandin (PG) in vivo Enzyme.
  • PG prostaglandin
  • Its structural analogues naproxen, fenoflofen, ketoprofen, flurbiprofen, loxoprofen all have similar pharmacology and efficacy.
  • ibuprofen Since ibuprofen was first marketed in the UK in 1969, there are currently many dosage forms, including oral dosage forms, such as ordinary solid oral tablets, sustained-release capsules, oral liquids, etc.
  • oral ibuprofen has many inconveniences and side effects, such as frequent administration due to short half-life, gastrointestinal irritation, gastrointestinal bleeding, etc.
  • surface preparations of ibuprofen on the market such as gel ointments and suppositories.
  • special operation and care are required when using gel ointment, which will contaminate clothing and local drug loss during use.
  • the ibuprofen dosage form also has injections, but it requires professional operation and is inconvenient to use, only used under special circumstances.
  • Transdermal administration is an ideal means to meet the requirements of ibuprofen administration.
  • Modern transdermal drug delivery system mainly refers to a method of administration where the drug is absorbed in the form of a patch through the skin or mucous membranes and exerts a pharmacological effect in a local treatment system or systemic system.
  • the transdermal method of administration has many advantages, such as comfort, convenience, long-acting sustained release, no gastrointestinal irritation and no first pass effect, no invasiveness, can reduce the fear of taking medication and the frequency of frequent medication, avoid oral absorption bands The volatility of the incoming blood drug concentration and higher safety.
  • Transdermal administration is more clinically significant for infants, young children, and elderly people who have difficulty taking oral drugs themselves. Since the first scopolamine patch (Transderm) in 1979 ) Since the market, people have made a lot of attempts to develop more transdermal drug delivery systems with therapeutic effects. So far, many products have been successfully marketed.
  • the patch can be generally classified into reservoir patches and drug-in-adhesives.
  • the mixed type of glue is to dissolve or disperse the active ingredients uniformly in a semi-solid composition composed of one or more polymer materials and other pharmaceutically acceptable auxiliary materials to form a uniform polymer matrix, if the polymer used
  • the material itself is pressure-sensitive adhesive, then the polymer material acts as a carrier for the drug and also has an adhesive effect with the skin at the application site.
  • the factors that need to be considered when designing a hybrid polymer matrix patch for adhesives are the nature of the active ingredient and its drug loading, the physical and chemical properties of each component in the polymer matrix, and the high formation of all components.
  • the polymer matrix patch mainly relies on the passive diffusion of the drug from the matrix through the stratum corneum into the human body, so the main factors that determine the diffusion rate are the concentration and saturation of the drug in the matrix, as well as the drug and other ingredients in the matrix
  • concentration and saturation of the drug in the matrix are also different.
  • concentration of the active ingredient in the matrix is low and the drug loading is small, it is difficult to achieve ideal drug delivery, especially difficult to achieve steady-state delivery.
  • the diffusion rate of the drug will be improved accordingly, but the overall adhesive properties of the matrix composition such as adhesion, peel strength and shear strength are affected or destroyed, which is more serious It is the undesired recrystallization problem that occurs in the active ingredient.
  • patent applications CN201410301673.0 and US20090161065A1 respectively disclose a surface composition of ibuprofen, which mainly uses natural polymer xanthan gum to improve the stability of ibuprofen, especially the stability at high temperature, of which ibuprofen or Its salt concentration is about 5.0%.
  • Patent application CN200910079489.5 discloses a transdermal patch of ibuprofen and its preparation method. The drug loading of ibuprofen is only between 5 and 15%.
  • Patent application CN200710151020.9 discloses an ibuprofen arginine gel, preferably with an active ingredient content of 9.25%.
  • Patent PCT / US2012 / 036366 discloses an ibuprofen gel, the ibuprofen content is below 15%, but a large amount of lower alcohol is used as a solvent, which has the potential risk of allergy and volatilization.
  • Patent application CN201510759804.4 discloses a long-acting adhesive-dispersed transdermal patch containing ibuprofen and its preparation process, using a penetration enhancer to achieve 12 to 48 hours of continuous release.
  • Patent application CN201510181823.3 discloses a compound ibuprofen patch and preparation method.
  • the used ibuprofen and traditional Chinese medicine compound are used for the treatment of periarthritis of shoulder.
  • the content of the active ingredient ibuprofen is about 1%.
  • Patent application CN201510379997.0 discloses a pharmaceutical composition containing ibuprofen, the Chinese medicine volatile oil clove oil is used as a penetration enhancer, wherein the content of the active ingredient ibuprofen is below 10%, and the dosage form is a gel And cream.
  • the literature Journal of Pharmaceuticals 103 (2014): 909–919) reported the use of PEG200 and oleic acid as penetration enhancers to comparatively study the effect of 5% ibuprofen content on transdermal absorption.
  • the content of ibuprofen disclosed in the above documents is relatively low.
  • the stability of ibuprofen in the patch is a challenge, and there is a risk of recrystallization during storage.
  • ibuprofen itself is a low-melting phenylpropionic acid derivative and has both hydrogen bond acceptors and donors. These properties cause it to interact with the polymer matrix composition, resulting in The fluidity in the matrix is hindered, which in turn affects the overall percutaneous penetration rate of ibuprofen.
  • ibuprofen's own tackifying properties will change the overall colloidal properties of the polymer matrix. For example, reducing the cohesive force leads to the residue of the patch on the skin. Changes in nature that occur during storage, etc.
  • the present invention provides a multi-layer transdermal drug delivery system containing ibuprofen or its structural analogues, which has high drug loading and high transdermal penetration efficiency, while being able to continuously and stably maintain at least 12 ⁇ 24 hours to achieve the therapeutic effect of blood concentration.
  • the system of the present invention can inhibit the crystallization of ibuprofen or its structural analogues under high drug loading, and keep the skin's transmission efficiency unchanged during long-term storage.
  • the system of the present invention has good colloidal performance and meets the wearing requirements during the use of the patch.
  • Transdermal administration The administration of active ingredients through the skin or mucous membranes into local or systemic systems.
  • Transdermal drug delivery system a system containing active ingredients for transdermal drug delivery, generally including a backing layer and a release film, and a drug delivery layer located between the two layers. According to the combination of active ingredients and other components in the drug delivery layer, it can be generally divided into depot type and glue mixed type.
  • the transdermal drug delivery system is also called a patch, and both can be used universally in the present invention.
  • composition Different components in the polymer matrix, including but not limited to active components, penetration enhancers, antioxidants, plasticizers, fillers and pressure-sensitive adhesives, etc. Through physical mixing, there is no mutual interaction between the components Chemical action or crosslinking.
  • Diffusion The drug passively passes through the skin or mucous membranes.
  • the driving force is the concentration difference of the active ingredients on both sides of the skin, which is directly related to the concentration gradient inside and outside the skin.
  • Polymer matrix refers to the water-insoluble materials in the transdermal drug delivery system, including any combination of polymer materials to which the active ingredient ibuprofen has been added, and also includes other pharmaceutically acceptable components, such as polyacrylic acid Polymers, silicone polymers and rubbers such as polyisobutylene, etc.
  • the ibuprofen in the polymer matrix of the present invention is uniformly dissolved therein.
  • the polymer matrix generally includes pressure-sensitive adhesive.
  • the polymer matrix serves as the drug delivery layer of the transdermal drug delivery system to form a mixed drug-type transdermal drug delivery system.
  • Pressure-sensitive adhesive refers to a type of viscoelastic polymer material. When contacting with the surface of most other materials, it can be adhered together with a very light force and can maintain long-term adhesion. There are two types of pressure-sensitive adhesives, one is the pressure-sensitive adhesive itself, and the other can achieve the function of pressure-sensitive adhesive by adding a tackifier or plasticizer.
  • the pressure-sensitive adhesive has satisfactory physical properties at room temperature, such as good skin adhesion, maintains adhesion for a certain period of time, and can peel off without damaging the skin. Generally including acrylic pressure sensitive adhesives, silicone pressure sensitive adhesives and rubber pressure sensitive adhesives.
  • the transdermal drug delivery system generally includes a drug-impermeable backing layer.
  • One side of the backing layer is directly connected to the polymer matrix layer.
  • the backing layer protects the matrix layer and the surrounding environment. Contact to prevent the loss of drugs.
  • the materials of the backing layer generally include polyester, polyethylene, polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil, non-woven fabric, etc.
  • the thickness is generally 2 to 1000 ⁇ m, such as ScotchPak TM 1109 from 3M or Cotran TM 9720 from 3M.
  • Release film also called protective layer. In the present invention, the two have the same meaning and can be used universally.
  • Transdermal drug delivery systems generally include a release membrane that is directly connected to the other side of the polymer matrix layer, such as Scotpak TM 9744 from 3M. Before the patch is used, the release film needs to be removed.
  • Single-layer structure transdermal drug delivery system refers to that between the backing layer and the release film in the transdermal drug delivery system, only one layer of drug-containing polymer matrix is contained, and the polymer matrix contains polymer pressure-sensitive adhesive.
  • the matrix layer not only plays the role of drug loading, but also plays a role of direct adhesion to the skin.
  • the active substance can deliver enough to achieve the required amount for local or systemic effect, so as to achieve a specific pharmacological effect, such as curing, reducing or controlling disease or symptoms.
  • Peel strength peel adhesion
  • Adhesion reflects the force between the pressure-sensitive adhesive and the skin at the application site. Decide whether the patch will come off during wearing.
  • Cohesion reflects the interaction force inside the polymer matrix. Too small cohesion will cause the polymer matrix to produce stringing and residual phenomena at the application site.
  • Shear strength (shear resistance) reflects the degree of slip of the patch on the skin surface of the application site. For softer parts of the skin, greater shear strength is required.
  • Viscosity-increasing effect When a substance is added to the polymer matrix containing the pressure-sensitive adhesive in the transdermal drug delivery system, the fluidity and viscosity of the polymer matrix are increased, thereby changing the overall performance of the pressure-sensitive agent. After added to the polymer matrix, ibuprofen will have a thickening effect.
  • Penetration enhancer A substance that can accelerate the diffusion of the active ingredients in the polymer matrix into the skin. Generally, it can be miscible with the polymer matrix and evenly dispersed in the polymer matrix.
  • Cold flow refers to the adhesive force of the polymer matrix layer is greater than the cohesive force, viscoelastic creep occurs, which leads to the instability and safety of the patch system. It may stick to the protective layer and packaging container during storage.
  • ibuprofen 2- (4-isobutylphenyl) propionic acid
  • the molecular formula is C 13 H 18 O 2
  • the molecular weight is 206.3
  • the melting point range is 74.5-77.5 ° C
  • white crystalline powder its chemical structure is as follows :
  • Ibuprofen is a chiral drug with two optical isomers, R and S. Although in vitro studies show that only the S isomer has the effect of inhibiting the synthesis of prostaglandins, another R isomer that has no activity in vitro can be found in Most of the organisms are converted to S isomers. Therefore, the ibuprofen used in the present invention may be the R isomer or the S isomer, a mixture of the two, or the racemate of ibuprofen. Since ibuprofen itself has a carboxyl group, which is both a hydrogen bond donor and a hydrogen bond acceptor, it can be expected to interact with related components in the polymer matrix.
  • One of the objectives of the present invention is to provide a transdermal drug delivery system in which a sufficient amount of ibuprofen is loaded and uniformly dispersed in a polymer matrix without recrystallization during long-term storage.
  • the compounds in the table below are similar in structure to ibuprofen, have properties and functions similar to ibuprofen, and can also achieve the purpose of the present invention.
  • the carboxyl group of ibuprofen or its structural analogue itself causes interaction between it and the polymer matrix component, which affects its diffusion rate in the polymer matrix, and also affects the skin especially
  • the stratum corneum has an interaction that affects the diffusion of ibuprofen or its structural analogs into the body, and the overall effect causes the diffusion rate of ibuprofen or its structural analogs to be hindered, not reaching the delivery within a given time range
  • An effective therapeutically effective dose of ibuprofen or its structural analogs An effective therapeutically effective dose of ibuprofen or its structural analogs.
  • the present invention has surprisingly discovered through a large number of experiments that adding a compound containing at least one amino group can keep ibuprofen continuously and controllably and stably released within a given time range.
  • the flow of ibuprofen partially salted with the amino compound in the polymer matrix increases, and the interaction with the skin surface decreases.
  • the salt formation of ibuprofen and amino compounds is reversible.
  • a high concentration of ibuprofen-amino salt releases ibuprofen, enters the stratum corneum by diffusion, and then enters the circulatory system.
  • the rate of diffusion is related to the concentration of the ibuprofen-amino compound salt. It can be expected that by controlling the content and molar ratio of ibuprofen and the amino compound, a continuous and controlled administration can be established within the desired use time range, and Reach the blood concentration with therapeutic effect.
  • the present invention further surprisingly found that after the active ingredient ibuprofen forms a salt with the compound containing at least one amino group (ie, forms an ibuprofen-amino compound salt), the melting point of the salt is greatly reduced compared to free ibuprofen It is liquid even at room temperature, so that it can be evenly dispersed in the polymer matrix and can not be recrystallized during long-term storage.
  • the present invention finds that the drug loading of the polymer matrix to ibuprofen and the degree of saturation of ibuprofen can be adjusted within a relatively large range to meet the requirements of high-dose ibuprofen.
  • the present invention first provides a transdermal patch containing ibuprofen or a structural analogue thereof, the patch includes a backing layer, a protective layer, and a polymer matrix located between the backing layer and the protective layer Floor.
  • the polymer matrix layer contains an active ingredient, a compound containing at least one amino group, and a pressure-sensitive adhesive.
  • the active ingredient is ibuprofen or its structural analogs; the structural ibuprofen analogs include Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen ( Flurbiprofen) and Loxoprofen can be selected from any one or more of them.
  • all or part of the active ingredient forms a salt with the compound containing at least one amino group; all or part of the formed active ingredient-amino compound salt (ie, ibuprofen-amino compound salt) , Or ibuprofen structural analogue-amino compound salt) and all or part of the free active ingredients remain homogeneously dissolved in the polymer matrix, and can be stably stored without recrystallization before use.
  • active ingredient-amino compound salt ie, ibuprofen-amino compound salt
  • ibuprofen structural analogue-amino compound salt ibuprofen structural analogue-amino compound salt
  • the melting point of the formed active ingredient-amino compound salt is lower than that of ibuprofen or its corresponding structural analog.
  • the molar ratio of the active ingredient in the polymer matrix layer to the amino group in the compound containing at least one amino group is about 12: 1 to about 1: 1, including about 10: 1 to about 1.5: 1, such as About 10: 1, about 9: 1, about 10: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, About 1.5: 1.
  • the transdermal permeation efficiency of ibuprofen or its structural analogues in the transdermal delivery system is reduced, and the delivery capacity is not To the requirement of therapeutic effect, it will also lead to a decrease in the drug-carrying capacity of the ibuprofen or its structural analogues in the polymer matrix; if the ratio is less than 1: 1, the melting point of the active ingredient-amino compound salt formed decreases or It is liquid at room temperature, which leads to the deterioration of the colloidal performance of the polymer matrix.
  • the reduction of the cohesive force of the colloid leads to serious problems such as stringing at the application site after the patch is applied and residual cream on the skin.
  • the weight content of the compound containing at least one amino group in the polymer matrix layer of the patch (referring to the ratio of the weight of the compound containing at least one amino group to the dry weight of the polymer matrix layer) is about 1% To about 15%, including about 2% to about 12%, such as about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% , About 11%, about 12%.
  • the compound containing at least one amino group is preferably an aliphatic amine, which may be a chain amine or a cyclic amine.
  • the compound containing at least one amino group may be a primary amine, a secondary amine or a tertiary amine.
  • the compound containing at least one amino group may contain 1-4 amino groups, such as one amino group, such as two amino groups, such as three amino groups, such as four amino groups.
  • the compounds containing at least one amino group include but are not limited to the following compounds: ethanolamine (Am_1), diethanolamine (Am_2), triethanolamine (Am_3), diethylamine (Am_4), triethylamine (Am_5), propylenediamine ( Am_6), N-ethylmorpholine (Am_7), N-ethylpiperidine (Am_8), N-ethylpiperazine (Am_9), N-hydroxyethylpiperidine (Am_10), N-hydroxyethylpyrrole (Am_11), dimethylpropanediamine (Am_12), tetramethylpropanediamine (Am_13), N-dodecylpyrrole (Am_14), trihexylamine (Am_15), N-dodecylhomopiperamine Pyridinium (Am_16), pyridin-2-yl-methanol (Am_17), ethylenediamine (Am_18), tetramethylethylenedi
  • the amount of the active ingredient added to the polymer matrix (i.e. ibuprofen or its structural analog) in the patch of the present invention varies according to the therapeutic effect required and the time range of the patch. Passive diffusion of active ingredients from the patch into the skin is a step in determining the speed of transdermal absorption, so the minimum dosage required in this way depends on the minimum effective concentration of the therapeutic effect achieved during patch application.
  • the patch of the invention is generally used for 12 to 24 hours, so in some embodiments, the invention can continuously and controllably deliver an amount that achieves a therapeutic effect within 12 to 24 hours.
  • the weight content of the active ingredient in the polymer matrix layer of the patch (referring to the ratio of the weight of the active ingredient to the dry weight of the polymer matrix layer) is about 15% to about 45%, including From about 20% to about 40%, such as from about 20% to about 35%, further preferably from about 25% to about 35%, in some special embodiments, the weight content of the active ingredient in the polymer matrix layer is 25%, in In some special embodiments, the weight content of the active ingredient in the polymer matrix layer is 30%, and in some special embodiments, the weight content of the active ingredient in the polymer matrix layer is 35%.
  • the polymer matrix layer of the patch of the present invention includes at least one pressure-sensitive adhesive that is pharmaceutically suitable for transdermal drug delivery systems, and can be specifically selected from acrylic-based polymer compounds or silicone polymer compounds. Or their composition, or their complex.
  • the polymer matrix includes acrylic polymer compounds.
  • the acrylic polymer is different according to the monomer selected during the polymerization.
  • the acrylic polymer may be any homopolymer, copolymer, terpolymer, and polymers of different acrylic acid. According to different functional groups, it can be non-functional acrylic pressure-sensitive adhesive and functional acrylic pressure-sensitive adhesive.
  • Non-functionalized acrylic pressure-sensitive adhesives include any acrylic polymer that contains no or substantially no functional groups, such as carboxyl groups, hydroxyl groups, amino groups, epoxy groups, etc., including polyacrylates and polyacrylamide or corresponding methyl groups Acrylic acid derivatives.
  • the functionalized acrylic pressure-sensitive adhesive includes chemically active groups, such as carboxyl groups, hydroxyl groups, amino groups, epoxy groups, and the like.
  • the types and amounts of acrylic polymers are different based on the amount of active ingredient added (i.e., ibuprofen or its structural analogs) and the amount of delivery needed to achieve a therapeutic effect.
  • the acrylic pressure-sensitive adhesive accounts for about 40% to about 80% of the dry weight of the polymer matrix, preferably about 45% to about 75%, such as about 45% to about 70%, including about 45%, about 50%, about 55%, about 60%, about 65%, about 70%.
  • functionalized acrylic pressure-sensitive adhesives can be selected, in some special embodiments, non-functionalized acrylics, or a combination of the two, the specific ratio can be determined according to the performance requirements of the patch, and can be based on conventional Experimental screening. Acrylic pressure-sensitive adhesives that do not contain functional groups are preferred, or when a composition using functionalized acrylic pressure-sensitive adhesives and non-functional acrylics is mixed, it is preferred that non-functional acrylics occupy a larger proportion.
  • polyacrylic acid pressure sensitive adhesives include Henkel's Duro-Tak products, such as Duro-Tak 87-900A, Duro-Tak 87-9900, Duro-Tak 87-9301 (non-crosslinked, not Contains vinyl acetate acrylic pressure-sensitive adhesive, no functional groups), Duro-Tak 87-4098 (non-crosslinked vinyl acetate acrylic pressure sensitive adhesive, no functional groups), Duro-Tak 87-2287 (non-crosslinked vinyl acetate acrylic pressure Sensitive adhesive with hydroxyl functional groups), Duro-Tak 87-2852 (crosslinked acrylic pressure sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2196 (crosslinked acrylic pressure sensitive adhesive with carboxyl functional groups), Duro -Tak 87-2296 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2194 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2516 (crosslinked acrylic pressure Sensitive adhesive with
  • the polymer matrix includes or includes a silicone-based polymer pressure-sensitive adhesive.
  • Silicone pressure-sensitive adhesive has a higher drug diffusion rate, but has less solubility to the active ingredient ibuprofen or its structural analogues, and is incompatible with acrylic pressure-sensitive adhesives, so it is in the first combination layer Not used alone.
  • it is used in combination with at least one polyacrylic pressure-sensitive adhesive.
  • the silicone pressure sensitive adhesive accounts for about 0% to about 10% of the dry weight ratio in the polymer matrix, preferably about 1% to about 5%, including about 1.5%, about 2 %, About 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%.
  • the polymer matrix includes a composite of silicone-based polymer pressure-sensitive adhesive and polyacrylic polymer pressure-sensitive adhesive.
  • Silicone polymer has a high drug diffusion rate, does not irritate the skin, and has good chemical stability.
  • Acrylic pressure-sensitive adhesive has a high dissolving ability, but because the properties of the two types of colloids are very different, ordinary physical mixing can only In the form of a suspension, the amount of silicone glue is limited.
  • a new silicone-polyacrylic composite polymer pressure-sensitive adhesive is formed by using chemical means to crosslink silicone-based pressure-sensitive adhesive and silicone pressure-sensitive adhesive together, and the composite pressure-sensitive adhesive is balanced Acrylic pressure sensitive adhesive and silicone pressure sensitive adhesive properties, and can form a homogeneous homogeneous phase.
  • the weight ratio of the polysiloxane-polyacrylic acid composite polymer in the polymer matrix is about 40% to 80%, preferably about 45% to 75%, including about 45%, about 50%, 55% , 60%.
  • silicone pressure sensitive adhesives are commercially available from Dow-Corning, such as Dow SilAc Hybrid PSA; Dow SilAc Hybrid PSA; and Bio-PSA products, such as Bio-PSA 7-4502, Bio-PSA 7-4602, Bio-PSA 7-4302 and Bio-PSA 7-4102.
  • polymer matrix layer of the transdermal patch containing ibuprofen or its structural analog may further contain pharmaceutically acceptable auxiliary materials.
  • both ibuprofen itself and the ibuprofen-amino compound salt have a viscosity-increasing effect on the polymer matrix, resulting in a decrease in the cohesion of the polymer matrix, and the patch has serious stringing and Residual, the colloidal performance of the patch can not meet the requirements of wearing, which brings another serious challenge when developing the present invention.
  • the present invention was surprisingly surprised to find that adding a pharmaceutically acceptable filler can improve or solve the problem of colloidal performance, and does not reduce the overall transdermal penetration rate of the active ingredient ibuprofen.
  • the present invention found that adding an appropriate amount of filler increases the overall cohesion of the polymer matrix, thereby reducing the problems such as stringing and residue of the polymer matrix on the skin surface after application; but when the cohesion is increased, it will cause adhesion The force and peel strength decrease.
  • the cohesion, adhesion, peel strength and shear strength of the pressure-sensitive adhesive are mutually dependent, changing one of the properties, the other properties will also change, it is difficult to achieve only to improve the cohesion or adhesion
  • the force does not affect other properties, or does not damage the mechanical properties of the pressure-sensitive adhesive's overall adhesive system.
  • the change of cohesion changes with the change of the corresponding adhesion.
  • the colloidal properties of the polymer matrix containing ibuprofen and amino compounds can be adjusted by adding fillers, so as to solve the problem of having appropriate cohesion. Keep the gel free from stringing and residue after application, as well as acceptable adhesion, peel strength and shear strength.
  • the polymer matrix layer contains a filler.
  • the average particle size of the filler is about 300 mesh to about 5000 mesh, including about 500 mesh to about 3000 mesh.
  • the filler is a surface area of about 1.5m 2 / g to about 15m 2 / g, including from about 3m 2 / g to about 10m 2 / g, about 4m 2 / g to about 7m 2 / g.
  • the filler includes but is not limited to any one or more of talc, bentonite, kaolin, colloidal silica, montmorillonite and the like.
  • the filler in the polymer matrix layer cannot be a metal oxide (such as titanium dioxide, zinc oxide, magnesium oxide, etc.) or an inorganic salt (such as sodium carbonate, magnesium carbonate, etc.). Because these fillers will cause the transmission rate of ibuprofen or its structural analogs to decrease seriously.
  • a metal oxide such as titanium dioxide, zinc oxide, magnesium oxide, etc.
  • an inorganic salt such as sodium carbonate, magnesium carbonate, etc.
  • the amount of filler contained in the polymer matrix accounts for about 0.5% to about 10% by weight of the total dry polymer matrix, preferably in the range of about 1% to about 10%, and still more preferably about 2% to about 8%, such as about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%.
  • the specific amount of filler to be added should be comprehensively determined according to the amount of the active ingredient and the amino-containing compound in the polymer matrix, as well as the type, nature and ratio of the pressure-sensitive adhesive used, so as to achieve the situation without affecting the diffusion rate of the active ingredient Next, precisely adjust the mechanical properties of the colloid to meet the wearing requirements.
  • the polymer matrix layer further includes an antioxidant.
  • the antioxidants include 2,6-di-tert-butyl-4-methylphenol (BHT), butylhydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), vitamin C, vitamin E, ascorbic acid Sodium, sodium metabisulfite, polyethylene glycol tocopheryl succinate (TPGS), L-ascorbyl palmitate and mixtures of these antioxidants.
  • the content of the antioxidant in the polymer matrix is about 0.1% to about 1% of the total weight of the dry matrix, preferably about 0.1% to about 0.5%.
  • the present invention unexpectedly found that the commonly used penetration enhancers in transdermal absorption systems did not have the expected effect of increasing the diffusion rate in this system.
  • the penetration rate in some special embodiments was basically No change, or in some special embodiments, it inhibits the permeation rate of ibuprofen or its structural analogs.
  • the penetration enhancers include, but are not limited to, different types of penetration enhancers with different mechanisms, such as propylene glycol, PEG600, olive oil, squalene, silicone oil, mineral oil, oleic acid, isopropyl myristate, palmitate palmitate, propylene glycol Monocaprylate, caprylic capric acid glyceride, ethyl oleate, oleic acid polyethylene glycol glyceride, urea, azone, N-methylpyrrolidone, dimethyl sulfoxide (DMSO), glycerin, etc.
  • the penetration enhancers are used alone or in combination in some embodiments.
  • the content of the penetration enhancer in the polymer matrix is about 0.5% to about 5%, preferably about 1% to about 5%, such as about 1%, about 2%, about 2.5%, about 3%. Since the penetration enhancer is basically liquid or oily substance, adding it to the polymer matrix of the present invention will further increase the fluidity of the matrix, and is not related to any theory, which may cause flow difficulties for some reason. Therefore, the penetration enhancer does not help the permeation efficiency of the ibuprofen or its structural analog transdermal delivery system described in the present invention. Therefore, the present invention does not require any penetration enhancer.
  • the patch of the present invention contains active ingredients (i.e. ibuprofen or its structural analogues) occupying about 15% to 45% of the dry weight of the polymer matrix, and an amino compound used to form part or all of the salt, which successfully solves the problem Problems of diffusion rate, high drug loading and stability of ibuprofen or its structural analogs.
  • active ingredients i.e. ibuprofen or its structural analogues
  • the weight content of the active ingredient is about 15% to about 45%, and the compound containing at least one amino group
  • the weight content of is about 1% to about 15%; the molar ratio of the active ingredient and the amino group in the compound containing at least one amino group is about 12: 1 to about 1: 1; the active ingredient and the at least Compounds containing one amino group form all or part of the salt.
  • the active ingredients are evenly dispersed or dissolved in a polymer matrix and can be stored stably for a long time. Ibuprofen or its structural analogues do not recrystallize, so that it can continuously and stably deliver a therapeutically effective amount in at least 12 to 24 hours .
  • the patch of the present invention can continuously increase the blood drug concentration within 8 hours, and then steadily decrease within the next 4 hours to achieve a stable clinical effect for 12 hours.
  • the cohesive effect of the active ingredient (i.e. ibuprofen or its structural analogues) and the active ingredient-amino compound salt on the polymer matrix reduces the overall cohesion of the polymer matrix, resulting in patch application Serious skin drawing and residual problems are formed on the back skin, which seriously affects the patient's compliance with the patch, and there is a risk of sliding or falling off when worn for a long time.
  • the present invention solves the problem of residual skin caused by the thickening effect of the active ingredient and the active ingredient-amino compound salt by adding a solid filler to control the cohesion of the polymer matrix. However, due to the addition of fillers, the cohesion is optimized along with the loss of adhesion.
  • the present invention also provides a multi-layer transdermal drug delivery system containing ibuprofen or its structural analog, including the above-mentioned transdermal patch containing ibuprofen or its structural analog A combined layer), which also includes a second combined layer.
  • the second combined layer includes a backing layer, a protective layer, and a polymer matrix layer located between the backing layer and the protective layer; the polymer matrix layer includes a pressure-sensitive adhesive.
  • the present invention has unexpectedly discovered that by adding the design of the multi-layer structure such as the second combination layer, the above-mentioned problems are greatly reduced or avoided, and a percutaneous drug delivery system of ibuprofen that meets the wearing requirements is provided.
  • the multi-layer transdermal drug delivery system of the present invention has good performance, meets the wearing requirements, and does not slip, remain, or damage the skin during peeling, the patch is safe during storage and use, and the patient wears well.
  • the second combination layer includes a polymer matrix layer between the two layers including pressure-sensitive adhesive, pharmaceutically acceptable auxiliary materials, and / or further including the activity Ingredients (ie ibuprofen or its structural analogues) or other active ingredients.
  • the polymer matrix layer of the second combined layer contains active ingredients such as ibuprofen has no substantial effect on solving the cold flow problem of the polymer matrix layer of the first combined layer.
  • active ingredients such as ibuprofen to the polymer matrix layer of the second combination layer can be determined according to actual needs.
  • the weight content of ibuprofen or its structural analog in the polymer matrix layer of the second combined layer may be ⁇ 15%, such as ⁇ 10%, ⁇ 8%, or ⁇ 5%.
  • the polymer matrix layer of the second combined layer includes at least any pharmaceutically acceptable polyacrylic acid pressure-sensitive adhesive, silicone pressure-sensitive adhesive, rubber, or two or more of them The above mixture.
  • the pressure-sensitive adhesive may be a styrene-isobutylene-styrene (SIS) polymer block.
  • the polymer matrix may further include other pharmaceutically acceptable auxiliary materials, such as antioxidants, plasticizers, fillers and the like.
  • the present invention finds that the use of the second combination layer can enable the transdermal drug delivery system of ibuprofen or its structural analogs to have satisfactory wearing performance, so that it can be achieved within 12 to 24 hours of use Satisfactory delivery dose.
  • the separate transdermal patch containing ibuprofen or its structural analog and the second combination layer are combined to form the multi-layer ibuprofen transdermal delivery system of the present invention.
  • the multi-layer transdermal drug delivery system containing ibuprofen or its structural analogs can be stripped of the protective layer of the second combination layer before use, and attached to the ibuprofen or its structural analogs
  • the protective layer of the transdermal patch is peeled off and applied to the site of administration (eg, patient's skin).
  • transdermal delivery system of ibuprofen or its structural analogs of the present invention can continuously and controllably deliver therapeutically effective amounts within 12 to 24 hours of use without the use of penetration enhancers to meet the needs of clinical use .
  • the patch of the present invention can continuously increase the blood drug concentration within 16 hours, and then steadily decrease within the next 8 hours to achieve a stable clinical effect of 24 hours. Therefore, without using a penetration enhancer, the present invention can deliver a therapeutically effective dose of ibuprofen or its structural analogs within 12 to 24 hours according to the requirements of the therapeutic effect.
  • the invention can be applied to fever reduction, such as fever reduction for children from 6 months to 36 months.
  • the invention can also be used for pain relief, such as for local pain relief.
  • the thickness of the dry polymer matrix layer in the transdermal patch containing ibuprofen or its structural analog and / or the second combination layer is about 10 ⁇ m to about 120 ⁇ m, preferably about 15 ⁇ m to About 80 ⁇ m.
  • the peripheral width of the second combination layer is slightly wider than the peripheral width of the transdermal patch containing ibuprofen or its structural analog, more preferably wider than about 0.5 cm to about 1.0 cm.
  • transdermal patch and / or the polymer matrix layer in the second combination layer are all single-layer structures.
  • both the transdermal patch and the second combination layer of the present invention include a separate backing layer and protective layer.
  • One side of the backing layer is directly connected to the polymer matrix layer.
  • the backing layer serves to protect the matrix layer and the surrounding environment from contact and prevent the loss of drugs.
  • the material of the backing layer generally includes polyester, polyester poly and vinyl acetate composite film, polyethylene and vinyl acetate conforming film, polyurethane, metal foil such as metal aluminum-lined polyester, non-woven fabric, etc.
  • the thickness is generally about 20 to 250 ⁇ m, preferably 20 to 100 ⁇ m, such as ScotchPak TM 1109, ScotchPak TM 9733 of 3M Company, or Cotran TM 9720, Cotran TM 9722 of 3M Company.
  • the release film is connected to the other side of the polymer matrix layer.
  • the material of the release film generally includes polyester, polypropylene, etc., and the surface is generally coated with fluoride.
  • the thickness is generally about 50 to 100 ⁇ m, preferably 60 to 80 ⁇ m, such as ScotchPak TM 9744 and ScotchPak TM 9755 from 3M Company.
  • the transdermal patch and the second combination layer of the present invention can be prepared separately.
  • the transdermal patch containing ibuprofen or its structural analogs first prepare the polymer matrix part of the transdermal drug delivery system, and formulate the calculated amount of the active ingredient, pressure-sensitive adhesive, amino compound, or Furthermore, auxiliary materials such as fillers and oxidants are added to a suitable organic solvent, stirred evenly, and then coated on a protective layer (release film) at room temperature, and then the coated polymer matrix is dried at a certain temperature to remove organic Solvent, and finally composite backing layer. Die-cut or cut to the required specifications as required.
  • the organic solvent is a solvent capable of dissolving ibuprofen or its structural analogs, pressure-sensitive adhesive, and amino compounds, including ethyl acetate, methanol, ethanol, isopropanol, toluene, acetonitrile, acetone, and the like.
  • a polymer matrix is coated on the release film, and then combined with the backing layer to form a transdermal drug delivery system, and finally different specifications are made according to the needs of use.
  • the general coating method is solution coating.
  • the polymer matrix is prepared after mixing all the components, and then the prepared polymer matrix is coated on the release film, placed at about 35-50 ° C to remove the solvent, and then compounded with the backing layer .
  • the active ingredients and solid fillers can be added at any stage as needed.
  • the polymer pressure-sensitive adhesive and the amino compound are dissolved in an organic solvent and stirred uniformly, then the active ingredient is added, stirred until all are dissolved, and finally a solid filler is added.
  • first dissolve ibuprofen or its structural analogues in an organic solvent then add the polymer pressure-sensitive adhesive and the amino compound successively, add the solid filler after stirring the above mixture, and then stir until dispersed .
  • the amount of the added components, the order of addition, and the stirring time can be determined by those skilled in the art through experiments. Exemplary preparation methods are as follows:
  • Step 1) First, weigh the calculated amount of polymer pressure-sensitive adhesive and add it to a suitable organic solvent. The stirring time is determined according to whether it is evenly mixed, generally about 15-30 minutes. Then, while maintaining stirring, add the amino compound and antioxidant and stir until all are dissolved. Subsequently, the active ingredients are added in batches, and gradually dissolved after stirring, and then the next batch of the active ingredients is added until all the addition is completed. Finally, add solid filler and stir until all are dispersed evenly.
  • Step 2) The mixed solution prepared in step 1) is coated on the release film, and the coating thickness is determined according to the final clinical use requirements.
  • Step 3 Dry through an oven with exhaust function at 35-50 ° C for 5-15 minutes to remove organic solvents.
  • Step 4) Compound the dried product with the selected suitable backing film.
  • Step 5 Punch or cut to the appropriate specifications according to the needs of use.
  • the second combination layer of the present invention can be prepared by referring to the preparation method of the transdermal patch described above.
  • the content of the active ingredient (i.e., ibuprofen or its structural analogue) contained in the patch polymer matrix of the present invention ranges from about 0.8 mg / cm 2 to about 4.0 mg / cm 2 , Including from about 1.2 mg / cm 2 to about 3.2 mg / cm 2 , from about 1.5 mg / cm 2 to about 2.9 mg / cm 2 , such as about 1.6 mg / cm 2 , about 1.9 mg / cm 2 , about 2.2 mg / cm 2 , about 2.3 mg / cm 2 , about 2.4 mg / cm 2 , about 2.6 mg / cm 2 , about 2.9 mg / cm 2 .
  • the administration area of the patch of the present invention is about 10cm 2 to about 150cm 2 , including from about 20cm 2 to about 120cm 2 , such as 20cm 2 , 30cm 2 , 40cm 2 , 50cm 2 , 60cm 2 , 70cm 2 , 80cm 2 .
  • the patch of the present invention can continuously increase the blood drug concentration within 8 hours, and then steadily decrease within the next 4 hours to achieve a stable clinical effect for 12 hours.
  • the patch of the present invention can continuously increase the blood drug concentration within 16 hours, and then steadily decrease within the next 8 hours to achieve a stable clinical effect of 24 hours. Therefore, the present invention can deliver a therapeutically effective dose of ibuprofen or its structural analogs within 12 to 24 hours according to the therapeutic effect requirements.
  • the present invention is applied to fever, such as fever in children from 6 months to 36 months.
  • the present invention is used for analgesia, such as analgesia for localized pain.
  • Figure 1 shows the experimental results of Experimental Example 1 stability
  • Figure 2 shows the results of in vitro release experiment of Experimental Example 2
  • Fig. 3 shows the results of the in vitro transdermal experiment of Experimental Example 3
  • Figure 4 shows the experimental results of human blood concentration in Experimental Example 4.
  • Fig. 5 shows the experimental results of fever-reducing fever in Experimental Example 5;
  • Fig. 6 shows a schematic structural view of the transdermal patch containing ibuprofen of the present invention (Fig. 6A) and a schematic structural view of the second combination layer (Fig. 6B).
  • Dow Corning Dow It is a composite of acrylic pressure-sensitive adhesive and silicone pressure-sensitive adhesive.
  • Duro-tack-4098 is acrylic and vinyl acetate copolymer pressure-sensitive adhesive, without functional groups and cross-linking agents.
  • Duro-tack-2074 is an acrylic pressure-sensitive adhesive with carboxyl and hydroxyl functional groups and a cross-linking agent.
  • Duro-tack-6908 is a polyisobutylene pressure-sensitive adhesive with no functional groups and no cross-linking agent.
  • Bio-PSA-7-4302 is a silicone pressure sensitive adhesive.
  • Tert-butyl-4-hydroxyanisole (BHA) is an antioxidant.
  • a transdermal patch containing ibuprofen includes a polymer matrix layer, the polymer matrix layer includes an active ingredient ibuprofen, a compound containing at least one amino group, and a pressure-sensitive adhesive; in the polymer matrix layer, All or part of ibuprofen forms a salt with the compound containing at least one amino group, so that all or part of the formed ibuprofen-amino compound salt and all or part of the free ibuprofen remain uniformly dissolved in the polymer matrix, and It can be stored stably without recrystallization before use.
  • the skin patch of this embodiment further includes a backing layer and a protective layer; the polymer matrix layer is located between the backing layer and the protective layer.
  • the weight content of ibuprofen in the polymer matrix layer is 35%; the weight content of the pressure-sensitive adhesive is 54% (in which the weight content of Duro-tack-4098 is 50%, the weight of Bio-PSA-7-4302 The content is 4%); the weight content of the compound containing one amino group (specifically Am_25) is 5%; it can also contain pharmaceutically acceptable auxiliary materials (such as talc, colloidal SiO 2 , montmorillonite, vitamin E, etc.) ).
  • pharmaceutically acceptable auxiliary materials such as talc, colloidal SiO 2 , montmorillonite, vitamin E, etc.
  • This embodiment also provides a preparation method of the transdermal patch, which includes: first weighing a calculated amount of polymer pressure-sensitive adhesive, adding an appropriate amount of ethyl acetate, and then adding an amino compound while maintaining stirring, or further adding For auxiliaries (such as vitamin E) and other auxiliary materials, the stirring time is determined according to whether they are evenly mixed, and is generally about 15 to 30 minutes. After stirring until all are dissolved, the active ingredient ibuprofen is then added in batches. After gradually dissolving under stirring, the next batch of ibuprofen is added until all the additives are dissolved. Finally, add solid filler and stir until all are uniformly dispersed.
  • auxiliaries such as vitamin E
  • the prepared polymer matrix is coated on the release film, and the coating thickness is determined according to the final clinical use requirements.
  • the coated polymer matrix is passed through an oven with an exhaust function and dried at 35-50 ° C for 5-15 minutes to remove the organic solvent.
  • the dried product is then compounded with a suitable backing film. Finally, according to the needs of use, cut into appropriate specifications and package into products.
  • Example 1 The typical formulation of the polymer matrix layer of the transdermal patch containing ibuprofen (Examples 1-10) is shown in Table 1 (for the preparation method, refer to Example 1).
  • Example 1 The transdermal patch containing ibuprofen, the formulation of the polymer matrix layer is shown in Table 1, and the preparation method refers to Example 1.
  • a multi-layer transdermal drug delivery system containing ibuprofen includes a transdermal patch containing ibuprofen (referred to as a first combination layer for short) and a second combination layer.
  • the second combined layer includes a backing layer, a protective layer, and a polymer matrix layer located between the backing layer and the protective layer.
  • the transdermal patch containing ibuprofen ie, the first combination layer
  • the transdermal patch containing ibuprofen may be selected from the transdermal patch containing ibuprofen in Examples 1-21.
  • the polymer matrix layer of the second combination layer includes pressure-sensitive adhesive and pharmaceutically acceptable auxiliary materials, and may also contain active ingredients such as ibuprofen.
  • active ingredients such as ibuprofen.
  • the polymer matrix layer of the second combination layer contains ibuprofen, its weight content is ⁇ 15%, such as ⁇ 10%, ⁇ 8%, or ⁇ 5%.
  • the second combination layer can be prepared according to the preparation method of the transdermal patch containing ibuprofen in Example 1.
  • the typical polymer matrix layer formulation of the second combined layer (ie Examples 22-26) is shown in Table 3.
  • Example 1 The structure of the transdermal patch containing ibuprofen is shown in Figure 6A.
  • Example 22 The schematic diagram of the structure of the second combined layer is shown in FIG. 6B, and the two constitute a multilayer transdermal drug delivery system 10 containing ibuprofen.
  • the transdermal patch 100 containing ibuprofen and the second combination layer 200 are independent before use, and each includes a backing layer, a protective layer, and a polymer matrix layer located between the two layers.
  • the inner surface 150 of the backing layer 110 is directly attached to one side of the polymer matrix layer 120, and the other side 140 of the backing layer 110 is exposed to the environment to protect the polymer matrix 120
  • the inner surface 160 of the protective layer 130 is bonded to the other surface of the polymer matrix layer 120.
  • the polymer matrix 120 is located between the protective layer 110 and the backing layer 130 before use.
  • the inner surface 250 of the backing layer 210 is directly attached to one side of the polymer matrix layer 220, and the other side 240 of the backing layer 210 is exposed to the environment to protect the polymer matrix 220.
  • the inner surface 260 is bonded to the other surface of the polymer matrix 220, and the polymer matrix layer 220 is located between the protective layer 210 and the backing layer 230 before use.
  • the second combination layer is 0.5 to 1.0 cm wider than the periphery of the transdermal patch containing ibuprofen.
  • Example 1 No changes were observed during the twelve-month observation period. Ibuprofen was evenly dispersed in the adhesive matrix. No crystals were observed under different magnifications, and no crystallization was observed, indicating that the patch has good stability. .
  • In vitro release is a basic performance indicator of the patch, reflecting the interaction of the active ingredient and other components in the polymer matrix.
  • In vitro release is the basis of transdermal absorption, and only a suitable release capacity can meet specific transdermal absorption requirements.
  • the release measurement method (Chinese Pharmacopoeia 2015 Edition Fourth General Principles 0931 Fourth Method-Paddle Method), using PBS as the dissolution medium, the temperature is 32 °C, 50 rpm, according to the law, respectively, 0.3h, 0.5h, 0.7h, 1.0h, 1.5h, 2.0h, 3.0h, 6.0h, 9.0h, 12.0h, 18.0h and 24.0h, sample 10ml and filter; another is precisely called the appropriate amount of ibuprofen reference substance, dissolved in the dissolution medium, Prepare a solution of appropriate concentration as a reference solution.
  • the in vitro transdermal experiment was measured by Franz vertical diffusion cell. Healthy adult pig ear skin, the skin used is in accordance with standard thermal separation methods to obtain the cuticle of the pig ear skin.
  • the receiving solution is a PBS solution with a pH of 7.4, the receiving cell volume is 7 mL, the set temperature is 32 ⁇ 0.1 ° C, and the stirring speed is 300 rpm. Samples were taken at 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h and 24h, sampling 3mL each time, and then supplemented with isothermal blank receiving solution. Six samples of each group were used in parallel, and a blank was used as a control. Calculate the cumulative transmission at each time point based on the results.
  • Fenbid As a control drug (400mg / ibuprofen sustained-release capsules, batch number: 17090198), the subjects took one capsule orally. Examples 3 and 6 were selected and applied to the lower abdomen of each person. Twelve subjects were randomly divided into three groups, with 4 people in each group. The first group of oral Fenbid The second group of application examples 3 and the third group of application examples 6.
  • Blood collection method upper limb vein blood collection; at 0h; 0.25h; 0.5h; 1h; 2h; 3h; 6h; 9h; 12h blood collection, 5mL each time.
  • Sample processing method protein precipitation method (0.2ml of serum added 0.2ml of acetonitrile, vortex to mix, centrifuge at 10000r / min, 15min, take supernatant).
  • the patch of the present invention can continuously increase the blood drug concentration within 8 hours, and then steadily decrease within the next 4 hours to achieve a stable clinical effect for 12 hours. At the same time, the blood drug concentration can continue to rise within 15 hours, and then decline steadily within the next 8 hours to achieve a stable clinical effect of 24 hours. Therefore, the patch of the present invention can deliver a therapeutically effective dose of ibuprofen within 12 to 24 hours according to the therapeutic effect.
  • Animals Wistar rats, male, weighing 300g ⁇ 20g, divided into 5 groups (four rats in each group). One group was used to apply the patch of Example 1, three groups were used for intragastric administration of different doses of Merrill TM (5 mg, 10 mg, and 20 mg, respectively), and one group was used as a blank control after fever.
  • Temperature measurement method anal depth of 3cm, electronic thermometer, two parallel determinations and taking the average value (the deviation between the two measurement results does not exceed ⁇ 0.1 °C)
  • Shaving method After anesthesia, first remove most of the hair with an electric shaver, then apply the hair removal cream evenly, and rinse with clean water after 3 minutes.
  • the patch of Example 1 was applied to the abdomen of a rat and fixed with gauze.
  • each group of animals was gavaged with Merrill Lynch TM (Johnson Johnson, concentration 20 mg / ml; production lot number: 171101428) 5 mg, 10 mg, and 20 mg.
  • Using a multi-layer transdermal drug delivery system containing ibuprofen using the transdermal patch containing ibuprofen as the first combination layer in Examples 2, 4 and 6, respectively, and using the second combination layer in combination (the matrix formula is the same Example 22).
  • Combined use method peel off the protective layer of the second combination layer, respectively stick it to the backing layer of the transdermal patch of Examples 2, 4, and 6 as the first combination layer, and then peel off the transdermal patch The protective layer is attached to the inside of the upper arm.
  • the patch of the present invention has substantially no residue.
  • a clear cold flow phenomenon was observed, as in Example 4 and Example 6, but after combined use, the cold flow phenomenon was eliminated.
  • the present invention provides a multi-layer transdermal drug delivery system containing ibuprofen or its structural analogs.
  • the multi-layer transdermal drug delivery system includes a transdermal patch containing ibuprofen or a structural analogue thereof and a second combination layer.
  • the transdermal patch includes a polymer matrix layer.
  • the polymer matrix layer includes an active ingredient, a compound containing at least one amino group, and a pressure-sensitive adhesive. All or part of the active ingredient-amino compound salt and all or part of the free active ingredient formed in the polymer matrix layer remain uniformly dissolved in the polymer matrix, and can be stably stored without recrystallization before use.
  • the invention also provides the preparation method and the use method of the transdermal drug delivery system.
  • the transdermal drug delivery system of the present invention can continuously and controllably deliver a therapeutically effective dose of ibuprofen or its structural analogs in the range of 12 to 24 hours without a penetration enhancer.
  • the transdermal drug delivery device of the invention has excellent wearing ability, avoids cold flow phenomenon, and has better economic value and application prospect.

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Abstract

一种含有布洛芬或其结构类似物的多层经皮给药系统，包括含有布洛芬或其结构类似物的透皮贴剂和第二组合层。所述透皮贴剂，包括高分子基质层，所述高分子基质层包含活性成份、至少含有一个氨基的化合物和压敏胶。所述高分子基质层中形成的全部或部分活性成份-氨基化合物盐及全部或部分游离活性成份在高分子基质中保持均匀溶解状态，并能在使用前能够稳定保存不重新结晶。所述经皮给药系统在没有促透剂的情况下能够在12～24小时范围内，连续可控地递送具有治疗效果剂量的布洛芬或其结构类似物，具有优异佩戴能力，避免了冷流现象。

Description

含有布洛芬或其结构类似物的多层经皮给药系统
交叉引用
本申请要求2018年11月9日提交的专利名称为“一种含有布洛芬或其结构类似物的多层经皮给药系统”的第201811332928.4号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明属于经皮给药技术领域，具体涉及一种含有布洛芬或其结构类似物的多层经皮给药系统。本发明系统含有高载药的布洛芬或其结构类似物，并能均匀分散在高分子基质中，所述系统能够在12-24小时期间能够保持连续稳定地递送达到治疗效果剂量的布洛芬或其结构类似物。
背景技术
布洛芬是一种非甾体抗炎药(NSAID)，用于止痛、退烧和消炎。本品能够非选择性地可逆地抑制环氧酶(cyclooxygenase，COX)COX-1和COX-2的活性，而COX-1和COX-2是生物体内催化合成前列腺素(prostaglandin，PG)的关键酶。通过抑制COX-1和COX-2的活性从而减少或消除由于前列腺素在体内产生导致的发热和疼痛症状。其结构类似物萘普生、非诺洛芬、酮洛芬、氟比洛芬、洛索洛芬都具有相似的药理和药效。
自从1969年布洛芬从英国首次上市以来，到目前有多种剂型，包括口服剂型，如普通固体口服片剂、缓释胶囊，口服液等。但布洛芬口服剂型存在着很多不便和副作用，如由于半衰期短导致的需要频繁给药，胃肠刺激，消化道出血等。市场上也有布洛芬的表面制剂，如凝胶膏、栓剂等。但在使用凝胶膏时需要特殊的操作和护理，在使用时会污染衣物、局部药物丢失等。同时布洛芬的剂型还有注射剂，但需要专业人员操作，使用不便，只是在特殊情况下使用。
因此目前仍然具有开发布洛芬其它剂型的强烈需求，来满足使用方便、快速起效、血药平稳，并期望每日给药一次。经皮给药是一种理想的满足布洛芬给药要求的手段。
现代经皮给药技术(transdermal drug delivery system，TDDS)主要是指药物以贴剂形式通过皮肤或粘膜吸收后在治疗局部部位或全身系统发挥药学作用的给药方式。经皮给药方式具有很多优点，如具有舒适、方便、长效缓释、无胃肠刺激和无首过效应、没有侵害性、能够减少服药的恐惧感及频繁服药的次数、避免口服吸收带来的血药浓度的波动性和更高的安全性。经皮给药对于自身口服药物困难的婴幼儿及老年群体更具有临床意义。自从1979年首个东莨菪碱贴剂(Transderm
Figure PCTCN2019113909-appb-000001
)上市以来，人们为了开发更多具有治疗效果的经皮给药系统做了大量的尝试，到目前为止已有多 个产品成功上市。
根据贴剂中活性成份和其它辅料的组合方式，贴剂一般可分类为储库型贴剂(reservoir systems)和胶药混合型贴剂(drug-in-adhesives)。其中胶药混合型是把活性成份均匀地溶解或分散在由一种或多种高分子材料以及其它药学上可用的辅料组成的半固体组合物中，形成均匀的高分子基质，如果所用高分子材料本身是压敏胶，那么高分子材料即起到药物的载体作用，又起到与贴敷部位皮肤的胶黏作用。在设计胶药混合型高分子基质贴剂时需要考虑的因素主要有活性成份本身的性质及其载药量，高分子基质中每个组分的物理和化学性质，以及所有组分形成的高分子基质的总体性能，贴剂生产和保存的外部环境条件，贴剂的使用部位及使用时间，需要达到的药物递送速度以及治疗效果，贴剂的佩戴能力等。
高分子基质型贴剂主要靠药物的被动扩散，从基质中穿过皮肤角质层进入人体，因此决定扩散速度的主要因素是药物在基质中的浓度和饱和程度，以及药物和基质中其它成份的相互作用的强弱，特别是组合物中的高分子和药物的相互作用。取决于活性成份的自身性质及所用高分子的不同，药物在高分子基质组合物中的浓度也不同。活性成份在基质中的浓度低并且载药量少的情况下很难达到理想的药物递送，特别是很难达到稳态递送。如果药物载药量高并且达到或接近饱和浓度，药物的扩散速度相应会得到改善，但是基质组合物的整体胶黏性能如粘力、剥离强度以及剪切强度受到影响或破坏，更为严重的是在活性成份会发生不期望的重新结晶问题。
为了尝试开发布洛芬经皮给药系统，文献公开报道了含有布洛芬的不同的经皮给药方法和组合物。比如专利申请CN201410301673.0及US20090161065A1分别披露了一种布洛芬表面组合物，主要是利用天然高分子黄原胶提高布洛芬的稳定性，特别是高温下的稳定性，其中布洛芬或其盐的浓度约为5.0％。专利申请CN200910079489.5披露了一种布洛芬经皮释放贴剂及其制备方法，布洛芬的载药量只是在5～15％之间。专利申请CN200710151020.9披露了一种布洛芬精氨酸凝胶剂，优选组分活性成份含量在9.25％。专利PCT/US2012/036366披露了一种布洛芬凝胶剂，所述布洛芬含量在15％以下，但用到大量的低级醇作为溶剂，有过敏和挥发的潜在风险。专利申请CN201510759804.4披露了一种含有布洛芬的一种长效黏胶分散型透皮贴剂及其制备工艺，利用促透剂达到12～48小时的连续释放。专利申请CN201510181823.3披露了一种复方布洛芬药贴及制备方法，所用布洛芬和中药复方，用于治疗肩周炎，其中活性成份布洛芬的含量在1％左右。专利申请CN201510379997.0披露了一种含有布洛芬药的药物组合物，所述用中药挥发油丁香油作为促透剂，其中活性成份布洛芬的含量在10％以下，所述剂型为凝胶和乳膏。文献(Journal of Pharmaceutical Sciences 103(2014):909–919)报道了利用PEG200和油酸作为促透剂，对比研究5％布洛芬含量在经皮吸收的效果。文献(Drug Dev Ind Pharm,2014，Early Online:1–9)报道了根据 ICH Q8来设计含有布洛芬贴剂的思路，只设定了胶体和油醇的简单情况，虽然布洛芬的含量达到20％，但都很容易结晶，没有实际使用意义。文献(European Journal of Pharmaceutics and Biopharmaceutics 60(2005)61–66)报道了3％含量的布洛芬在辅料丙二醇，聚乙二醇及氢化蓖麻油EL和高分子Eudragit E,RL情况下的稳定性研究。文献(Bangladesh Pharmaceutical Journal 15(1)(2012),17-21)报道了布洛芬载药量在5～8％下，使用Kollidon SR和Eudragut L两种高分子作为增溶剂。文献(Journal of Pharmaceutical Innovation 13(2018),48–57)报道了仅仅利用专利胶体开发用于疼痛的布洛芬贴剂。
但以上文献所公开的布洛芬含量相对较低。为了达到在12～24小时给药范围内达到递送具有药学意义的剂量，需要继续提高布洛芬贴剂的载药量和饱和浓度，从而提高活性成份在高分子基质中的热力学活性。在载药能力、饱和度、稳定性方面以及贴剂佩戴性如贴剂大小，胶体性能等方面找到一个合适的平衡。但高载药情况下，布洛芬在贴剂中的稳定是一个挑战，在保存期间有重新结晶的风险。但另一方面，布洛芬本身是一个低熔点的苯丙酸衍生物，同时具有氢键受体和供体，这些性质导致其会和高分子基质组合物具有相互作用，从而导致在高分子基质中的流动性收到阻碍，进而影响布洛芬的整体经皮透过速率。另外，布洛芬本身的增粘性质会改变高分子基质的整体胶体性能，如减小内聚力导致贴剂在皮肤的残留，冷流(cold flow)问题导致使用时贴剂四周形成的黑圈以及在保存期间发生的性质改变等。
发明内容
针对上述问题，本发明提供了含有布洛芬或其结构类似物的多层经皮给药系统，所述系统具有高载药和高的经皮透过效率，同时能够连续稳定地保持至少12～24小时达到治疗效果的血药浓度。同时，本发明所述系统能够抑制高载药下布洛芬或其结构类似物的结晶，在长期保存期内保持皮肤的透过效率不变。同时本发明所述系统具有良好的胶体性能，满足贴剂使用期间的佩戴要求。
以下为本发明涉及到的技术和科学专业术语，除非本发明上下文另有约定外，对本领域专业技术人员都具有下列相同的含义。
经皮给药：把活性成份通过皮肤或粘膜进入局部或全身系统的给药方式。
经皮给药系统：含有活性成份的用于经皮给药的系统，一般包括背衬层和离型膜，以及位于两层中间的给药层。根据给药层里面活性成份和其它组分的组合方式，一般可分为储库型和胶药混合型。经皮给药系统也叫贴剂，本发明中两者可以通用。
组合物：高分子基质中的不同组分，包括但不限于活性组分、促透剂、抗氧化剂、增塑剂、填充剂和压敏胶等，通过物理混合，各组分之间没有相互的化学作用或交联作用。
复合物：不同高分子之间通过化学作用交联在一起，形成性质稳定的高分子。
扩散：药物被动通过皮肤或粘膜，驱动力为皮肤两边活性成份的浓度差，和皮肤里外的浓度梯度直接相关。
高分子基质：指的是在经皮给药系统中的非水溶性材料，包括已加入活性成份布洛芬的任意高分子材料组合，同时也包括其它药学上可接受的组分，如聚丙烯酸高分子，聚硅酮高分子和橡胶如聚异丁烯等。本发明高分子基质中布洛芬均匀地溶解在其中。高分子基质一般包括压敏胶。高分子基质作为经皮给药系统的给药层，形成胶药混合型的经皮给药系统。
压敏胶：指的是一类粘弹性高分子材料，当和绝大多数其它材料表面接触时，只需用很轻的力量按压就可以粘附于一起并能保持长久的附着力。压敏胶包括两种类型，一种是本身即是压敏胶，另外一种可以通过加入增粘剂或增塑剂，可以达到压敏胶的功能。压敏胶在室温下具有令人满意的物理性质，如好的皮肤粘性，在一定时间内保持粘力，能够在不损伤皮肤的情况下能够剥离。一般包括丙烯酸类型压敏胶、聚硅酮类压敏胶和橡胶压敏胶。
背衬层：经皮给药系统一般包括药物不能透过的背衬层，背衬层的一个面直接和高分子基质层连接，在使用的时候背衬层起到保护基质层和周边环境的接触，防止药物的损失。背衬层的材料一般包括聚酯、聚乙烯聚醋酸乙烯脂复合膜、聚氯乙烯、聚氨酯、金属箔，无纺布等。厚度一般在2～1000μm，比如3M公司的ScotchPak TM 1109或3M公司Cotran TM 9720。
离型膜：也叫保护层，本发明中二者的意思相同，可以通用。经皮给药系统一般包括离型膜，直接和高分子基质层的另一面相连接，比如3M公司的Scotpak TM 9744。在贴剂使用前，需要将离型膜去掉。
单层结构经皮给药系统：指的是在经皮给药系统中背衬层和离型膜之间，只包括一层含药高分子基质，高分子基质中含有高分子压敏胶。该基质层不仅起到载药的作用，也起到直接和皮肤粘附的作用。
治疗有效剂量：当贴剂在使用期间，活性物质能够递送足够达到所需要的量，用于局部或系统起效，从而达到特定的药理作用，如治愈、减轻或控制疾病或症状。
剥离强度(peel adhesion)从皮肤上去除贴剂时用的力，反映的是舒适度，患者是否有痛感。
粘附力(adhesion)，反映的是压敏胶和贴敷部位皮肤之间的作用力。决定贴剂在佩戴过程中是否会脱落。
内聚力(cohesion)，反映的是高分子基质内部的互相作用力，过小的内聚力会导致高分子基质在贴敷部位产生拉丝和残留现象。
剪切强度(shear resistance)反映的是贴剂在贴敷部位皮肤表面滑动程度。对于皮肤较软部位，需要较大的剪切强度。
一般贴剂需要平衡胶体粘附力、内聚力、剥离强度和剪切强度等性质。对于用于医疗贴剂来说，需要足够大的内聚力，这样在撕掉胶带后不会有残留。提高胶体的剪切力同时，会导致粘附力和剥离强度减少。由于上面提到的压敏胶不同性质的平衡实际上是互相依耐，很困难达到只是提高内聚力或者粘附力而不影响其它性质，或者不破坏压敏胶的整体胶黏系统的性能。对于压敏胶来说，除了上面提到的四个方面性质外，还需要达到其本身的合适的透明度和抗氧化能力。
增粘作用：一种物质加入到经皮给药系统中的含有压敏胶的高分子基质后，增加了高分子基质的流动性和粘度，从而改变了压敏剂的整体性能。布洛芬在加入到高分子基质后会具有增粘作用。
促透剂：能够加快高分子基质中的活性成份扩散进入皮肤的物质。一般能够和高分子基质混溶，均匀地分散在高分子基质中。
冷流(cold flow)：是指高分子基质层的粘附力大于内聚力，发生粘弹性蠕变，从而导致贴剂系统的不稳定性及安全性，患者在佩戴过程中会产生黑圈，在存储过程中可能会和保护层及包装容器粘黏。
活性成份布洛芬或其结构类似物：
布洛芬的化学名称是2-(4-异丁基苯基)丙酸，分子式为C 13H 18O 2，分子量为206.3，熔点范围74.5～77.5℃，白色结晶性粉末，其化学结构如下：
Figure PCTCN2019113909-appb-000002
布洛芬是一个手性药物，具有R和S两个光学异构体，虽然体外研究显示只有S异构体具有抑制前列腺素合成的作用，但另外一个体外没有活性的R异构体可以在生物体内大部分转化为S异构体。因此本发明所用布洛芬可为R异构体或S异构体，也可为二者的混合物，或者为布洛芬的消旋体。由于布洛芬本身具有羧基，即是氢键的给体又是氢键的受体，因此可以预期会和高分子基质中的相关组分发生相互作用。另外，由于布洛芬本身药效较弱，为了达到具有治疗效果的血药浓度，需要递送较大的剂量，因此在经皮给药系统中需要较高的载药量；但受制于其自身性质，在一般贴剂高分子基质中，特别是压敏剂高分子基质体系的溶解度相对较小，因此布洛芬容易有较高的重新结晶风险，影响贴剂的保存和使用。本发明其中一个目标就是提供一种经皮给药系统，其中载入足够量的布洛芬，并且均匀分散在高分子基质中，在长期保存期间不重新结晶。
下表化合物与布洛芬结构类似，具有近似布洛芬的性质和功能，也能实现本发明目的。
Figure PCTCN2019113909-appb-000003
氨基化合物：
不与任何理论相关，布洛芬或其结构类似物本身具有的羧基导致它和高分子基质组分之间有相互作用，影响其在高分子基质中的扩散速度，同时也会和皮肤特别是角质层有相互作用，影响布洛芬或其结构类似物扩散进入体内，总体上的作用导致布洛芬或其结构类似物的扩散速度收到阻碍，达不到在给定使用时间范围内递送有效治疗效果剂量的布洛芬或其结构类似物。一般认为中性分子，不论是本身就是中性或者通过其它手段将其性质调控至中性，比如酸碱成盐的方法，减少活性成份与高分子基质及皮肤角质层的相互作用，从而可以达到增加活性成份被动扩散速率的目的。文献ACS Med.Chem.Lett.(2017),8:498-503和Drug Deliv.and Transl.Res.(2018)8:64–72报道了利用相反离子成盐的概念，通过相反离子的互相作用来增加极性化合物的经皮扩散透过能力。但相反离子的筛选和扩散能力的改变程度，目前并没有很好的理论支持，仍然需要大量实验筛选和验证。
本发明通过大量实验惊喜地发现加入至少含有一个氨基的化合物，能够保持布洛芬连续可控地在给定使用时间范围内稳定释放。不与任何理论相关，与氨基化合物部分成盐的布洛芬在高分子基质中的流动增加，与皮肤表面的相互作用减弱。布洛芬和氨基化合物成盐是可逆的，在皮肤表面存在浓度梯度的情况下，高浓度的布洛芬-氨 基盐释放布洛芬，通过扩散作用进入角质层，随后进入循环系统。扩散的速度和布洛芬-氨基化合物盐的浓度相关，可以预期通过控制布洛芬和氨基化合物的含量和摩尔比例，就可以达到在期望的使用时间范围内建立连续可控的给药，并能达到具有治疗效果的血药浓度。
本发明进一步惊喜地发现，活性成份布洛芬和所述至少含有一个氨基的化合物成盐后(即形成布洛芬-氨基化合物盐)，所述盐的熔点相比游离的布洛芬大大降低，甚至在室温下为液体，从而可以均匀地分散在高分子基质中，并能在长期保存期间不重新结晶。另一方面，本发明发现可以在较大范围内调控高分子基质对布洛芬的载药量以及布洛芬的饱和程度，满足布洛芬高剂量用药的要求。
基于上述研究，本发明首先提供一种含有布洛芬或其结构类似物的透皮贴剂，所述贴剂包括背衬层、保护层，以及位于背衬层和保护层中间的高分子基质层。所述高分子基质层包含活性成份、至少含有一个氨基的化合物和压敏胶。所述活性成份为布洛芬或其结构类似物；所述布洛芬结构类似物包括萘普生(Naproxen)、非诺洛芬(Fenoprofen)、酮洛芬(Ketoprofen)、氟比洛芬(Flurbiprofen)、洛索洛芬(Loxoprofen)，可选自其中任一种或几种。
进一步地，所述高分子基质层中，全部或部分活性成份与所述至少含有一个氨基的化合物形成盐；使所形成的全部或部分活性成份-氨基化合物盐(即布洛芬-氨基化合物盐，或布洛芬结构类似物-氨基化合物盐)及全部或部分游离活性成份在高分子基质中保持均匀溶解状态，并能在使用前能够稳定保存不重新结晶。
进一步地，所形成的所述活性成份-氨基化合物盐的熔点低于布洛芬或其相应结构类似物的熔点。
进一步地，高分子基质层中所述活性成份和所述至少含有一个氨基的化合物中的氨基的摩尔比大约在12:1到大约1:1，包括大约10:1到大约1.5:1，比如大约10:1,大约9:1，大约10:1，大约8:1，大约7:1，大约6:1，大约5:1，大约4:1，大约3:1，大约2:1，大约1.5:1。研究发现，如果所述活性成份和所述氨基化合物中氨基的摩尔比高于15:1，布洛芬或其结构类似物在经皮给药体系中经皮透过效率降低，递送能力达不到治疗效果的要求，同时也会导致载布洛芬或其结构类似物在高分子基质的载药能力下降；如果比例低于1:1，由于所形成的活性成份-氨基化合物盐熔点降低或者室温下为液体，导致高分子基质的胶体性能变差，特别是胶体的内聚力下降导致贴剂在贴敷后，在贴敷部位会存在拉丝，在皮肤残留膏体等严重问题。
进一步地，所述贴剂的高分子基质层中所述至少含有一个氨基的化合物的重量含量(指所述至少含有一个氨基的化合物的重量与高分子基质层的干重比)为大约1％到大约15％，包括大约2％到大约12％，比如大约2％，大约3％，大约4％，大约5％，大约6％，大约7％，大约8％，大约9％，大约10％，大约11％，大约12％。
所述至少含有一个氨基的化合物，优选为脂肪胺，可以是链状胺，或者是环状胺。所述至少含有一个氨基的化合物，可以是伯胺，仲胺或者叔胺。所述至少含有一个氨基的化合物，可以含有1-4个氨基，比如一个氨基，比如两个氨基，比如三个氨基，如比四个氨基。所述至少含有一个氨基的化合物包括但不限于以下化合物：乙醇胺(Am_1)，二乙醇胺(Am_2)，三乙醇胺(Am_3)，二乙胺(Am_4)，三乙胺(Am_5)，丙二胺(Am_6)，N-乙基吗啉(Am_7)，N-乙基哌啶(Am_8)，N-乙基哌嗪(Am_9)，N-羟乙基哌啶(Am_10)，N-羟乙基吡咯(Am_11)，二甲基丙二胺(Am_12)，四甲基丙二胺(Am_13)，N-十二烷基吡咯(Am_14)，三己胺(Am_15)，N-十二烷基高哌啶(Am_16)，吡啶烷-2-基-甲醇(Am_17)，乙二胺(Am_18)，四甲基乙二胺(Am_19)，亚精胺(Am_20)，精胺(Am_21)，轮环藤宁(Am_22)，3-(哌嗪-1-基)丙-1,2-二醇(Am_23)，N-羟乙基哌嗪(Am_24)，N-甲基吗啉(Am_25)，三乙烯二胺(Am_26)，三(2-氨基乙基)胺(Am_27)，2-哌嗪酮(Am_28)，3-氨基哌啶(Am_29)，1,3-环己二甲胺(Am_30)，丙二醇二(3-氨丙基)醚(Am_31)，乙二醇二(3-氨乙基)醚(Am_32)等中的一种或几种。
所述至少含有一个氨基的化合物若有其任何化学名称与化学结构不一致的地方，以下面化学分子式结构为准。
Figure PCTCN2019113909-appb-000004
本发明所述贴剂中加入高分子基质中的活性成份(即布洛芬或其结构类似物)的量，根据所需要达到的治疗效果以及贴剂的贴敷时间范围不同而不同。通过被动扩散活性成份从贴剂中进入皮肤，是经皮吸收的决定速度的步骤，因此通过这种方式所需最小给药量取决于贴剂贴敷期间治疗效果达到的最低起效浓度，本发明所述贴剂一般使用12～24小时，因此在一些实施例中本发明能够在12～24小时内连续可控地递送达到治疗效果的量。在一些实施例中，所述贴剂的高分子基质层中所述活性成份的重量含量(指活性成份的重量与高分子基质层的干重比)为大约在15％到大约45％，包括大约20％到大约40％，比如大约20％到大约35％，进一步优选范围大约25％～大约35％，在一些特殊实施例中高分子基质层中所述活性成份的重量含量为25％，在一些特殊实施例中高分子基质层中所述活性成份的重量含量为30％，在一些特殊实施例中高分子基质层中所述活性成份的重量含量为35％。
所述贴剂高分子基质层中压敏胶：
如上所述，本发明所述贴剂高分子基质层中至少包括一种药学上适合经皮给药系统的压敏胶，具体可选自基于丙烯酸的高分子化合物或者聚硅酮高分子化合物，或者它们的组合物，或者它们的复合物。
在一些实施例中，高分子基质中包括丙烯酸类高分子化合物。丙烯酸聚合物根据聚合时选择的单体不同，丙烯酸聚合物可以是任何均聚物、共聚物、三聚物以及不同丙烯酸的多聚物。根据所含官能团的不同，可为非官能化丙烯酸压敏胶和官能化丙烯酸压敏胶。
非官能化丙烯酸压敏胶包括任何不含或基本不含官能基团的丙烯酸高分子，如不含羧基、羟基、氨基、环氧基等，包括聚丙烯酸酯和聚丙烯酸酰胺或者相应的甲基丙烯酸衍生物。官能化丙烯酸压敏胶包括具有化学活性的基团，如羧基、羟基、氨基、环氧基等。
在一些实施例中，基于加入活性成份(即布洛芬或其结构类似物)的量以及需要递送的达到治疗效果的量的不同，丙烯酸高分子的种类和用量也不同。在一些例子中，丙烯酸压敏胶占高分子基质中干燥重量大约为40％到大约80％，优选大约45％到大约75％，比如大约45％到大约70％，包括约为45％，约为50％，约为55％，约为60％，约为65％，约为70％。在一些特殊实施例中，可以选择官能化丙烯酸压敏胶，在一些特殊实施例中，可以选择非官能化丙烯酸，或者两者的组合物，具体的比例根据贴剂性能要求确定，可以根据常规实验筛选。优选不含有官能团的丙烯酸压敏胶，或者在混合使用官能化丙烯酸压敏胶非官能化丙烯酸的组合物时，优选非官能化丙烯酸占有更多比例。
商业上可得的聚丙烯酸压敏胶有汉高公司(Henkel)的Duro-Tak产品,比如Duro-Tak 87-900A,Duro-Tak 87-9900，Duro-Tak 87-9301(非交联，不含醋酸乙烯酯丙 烯酸压敏胶，无官能团),Duro-Tak 87-4098(非交联醋酸乙烯酯丙烯酸压敏胶，无官能团)，Duro-Tak 87-2287(非交联醋酸乙烯酯丙烯酸压敏胶，带有羟基官能团)，Duro-Tak 87-2852(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2196(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2296(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2194(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2516(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2070(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2353(非交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak87-2154(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2510(非交联丙烯酸压敏胶，带有羟基官能团)。更多产品信息可以参考专业书籍Handbook of Pressure Sensitive Adhesive Technology，第二版，作者Donatas Satas，出版社：New York:Van Nostrand Reinhold,1989。以及Technology of Pressure-Sensitive Adhesives and Process,主编Istv á n Benedek,Mikhail M Feldstein,出版社：CRC press,2009。
在一些实施例中，高分子基质中或者包括聚硅酮类高分子压敏胶。聚硅酮压敏胶由于具有较高的药品扩散速率，但对活性成份布洛芬或其结构类似物的溶解性较小，以及和丙烯酸压敏胶不相容，因此在第一组合层中不单独使用。在一些特殊实施例中和至少一种聚丙烯酸类压敏胶联合使用。在一些特殊实施例中，聚硅酮压敏胶在高分子基质中占干燥重量比约为0％～到大约10％，优选大约1％到大约5％，包括约为1.5％，约为2％，约为2.5％，约为3％，约为3.5％，约为4％，约为4.5％，约为5％。
在一些特殊实施例中，高分子基质中包括聚硅酮类高分子压敏胶和聚丙烯酸类高分子压敏胶的复合物。硅酮聚合物具有较高的药品扩散速率，不刺激皮肤，化学稳定性好，而丙烯酸压敏胶具有较高的溶解能力，但由于两类胶体的性质差别很大，普通的物理混合只能形成混悬液的形式，导致聚硅酮胶的用量受到限制。本发明中，使用利用化学手段将聚硅酮类压敏胶和聚硅酮压敏胶交联在一起形成新的聚硅酮-聚丙烯酸复合高分子压敏胶，所述复合压敏胶平衡了丙烯酸压敏胶和聚硅酮压敏胶的性质，而且能形成混合均匀的均相。在一些例子中，聚硅酮-聚丙烯酸复合高分子在高分子基质中重量比约为40％～80％，优选大约45％～75％，包括约为45％，约为50％，55％，60％。
商业上可得的聚硅酮压敏胶有道康宁(Dow-Corning)公司的商品，如Dow
Figure PCTCN2019113909-appb-000005
SilAc Hybrid PSA；Dow
Figure PCTCN2019113909-appb-000006
SilAc Hybrid PSA；以及Bio-PSA的产品，如Bio-PSA 7-4502，Bio-PSA 7-4602，Bio-PSA 7-4302和Bio-PSA 7-4102。
进一步地，所述含有布洛芬或其结构类似物的透皮贴剂的高分子基质层中还可含有药学上可用的辅料。
所述贴剂高分子基质层中填充剂：
如上所述，布洛芬本身及所述布洛芬-氨基化合物盐都具有对高分子基质的增粘作用，导致高分子基质的内聚力减小，贴剂在皮肤贴敷处有严重的拉丝和残留，贴剂的胶体性能不能满足佩戴的要求，这在开发本发明时带来另外一个严重的挑战。本发明通过大量的实验，惊喜地发现加入药学上可接受的填充剂可以改善或解决胶体性能的问题，并且不减小活性成份布洛芬的整体经皮透过速率。
本发明发现，加入适量的填充剂增加了高分子基质的整体内聚力，从而减少了在贴敷后高分子基质在皮肤表面发生的拉丝、残留等问题；但是当内聚力提高的同时，会导致粘附力和剥离强度下降。不与任何理论的相关联，由于压敏胶的内聚力、粘附力、剥离强度和剪切强度互相依耐，改变其中一个性能，其它性能也随之发生改变，很难达到仅仅提高内聚力或者粘附力而不影响其它性质，或者不破坏压敏胶的整体胶黏系统的力学性能。内聚力的改变随着相应的粘附力的改变而变化，通过这一变化，可以通过填充剂的加入来调控含有布洛芬和氨基化合物的高分子基质的胶体性能，从而解决具有适宜的内聚力能够保持贴敷后胶体不拉丝，不残留，以及可以接受的粘附力，剥离强度和剪切强度。
在一些实施例中，高分子基质层中含有填充剂。所述填充剂的平均粒度大约在300目到大约5000目，包括大约500目到大约3000目。所述填充剂的表面积大约在1.5m 2/g到大约15m 2/g，包括大约3m 2/g到大约10m 2/g，大约4m 2/g到大约7m 2/g。所述填充剂包括但不限于滑石粉，膨润土，高岭土，胶态二氧化硅，蒙脱石等中任一种或几种。
进一步地研究发现，所述高分子基质层中的填充剂不能为金属氧化物(例如二氧化钛、氧化锌、氧化镁等)，也不能为无机盐(例如碳酸钠、碳酸镁等)。因为这些填充剂会导致布洛芬或其结构类似物的透过率严重下降。
在一些实施例中，高分子基质中含有填充剂的量占总体干燥高分子基质重量比大约0.5％到大约10％，优选范围大约在1％到大约10％，更进一步优选大约2％到大约8％，比如大约2％，大约3％，大约4％，大约5％，大约6％，大约7％，大约8％。填充剂具体加入的量需根据高分子基质中所述活性成份及含氨基化合物的量，以及所用压敏胶的种类、性质及比例来综合确定，从而可以达到在不影响活性成份扩散速度的情况下，精确调控胶体的力学性能满足佩戴要求。
所述贴剂高分子基质层中抗氧化剂：
在一些实施例中，高分子基质层中还包括抗氧化剂。所述抗氧化剂包括2,6-二叔丁基-4-甲基苯酚(BHT)，丁基羟基茴香醚(BHA)，叔丁基对苯二酚(TBHQ)，维生素C,维生素E,抗坏血酸钠，焦亚硫酸钠,聚乙二醇维生素E琥珀酸酯(TPGS)，L-抗坏血酸棕榈酸酯及这些抗氧化剂的混合物。高分子基质中抗氧化剂的含量大约在干燥基质总重量的大约0.1％～大约1％，优选大约0.1％～大约0.5％。
促透剂：
本发明意外发现经皮吸收系统中常用的促透剂在本系统中起不到预期的增加扩散速度的效果，相反的是加入不同的促透剂后，在一些特殊实施例中促透速率基本不变，或者在一些特殊实施例中反而抑制布洛芬或其结构类似物的透过速率。所述促透剂包括但不限于不同类型不同机理的促透剂，如丙二醇，PEG600，橄榄油，角鲨烯，硅油，矿物油，油酸，豆蔻酸异丙酯，棕榈酸棕榈酯，丙二醇单辛酸酯，辛癸酸甘油酯，油酸乙酯，油酸聚乙二醇甘油酯，尿素，氮酮，N-甲基吡咯烷酮，二甲基亚砜(DMSO)，甘油等。所述促透剂在一些实施例中单独使用，或者组合使用。高分子基质中促透剂的含量大约占干燥高分子基质总重量的大约0.5％～大约5％，优选大约1％～大约5％，比如大约1％，大约2％，大约2.5％，大约3％。由于促透剂基本上都是液体或是油状物，加入到本发明所述高分子基质中，会进一步增加基质的流动性，不与任何理论相关联，这样可能会导致某种原因的流动困难，因此促透剂对本发明所述的布洛芬或其结构类似物经皮给药体系的透过效率都没有帮助作用，因此本发明不需要加入任何促透剂。
本发明所述贴剂的含有活性成份(即布洛芬或其结构类似物)占有高分子基质干燥重量大约15％到45％，以及用于部分或全部成盐的氨基化合物，成功解决了布洛芬或其结构类似物扩散速率、高载药及稳定性问题。
具体地，本发明所述贴剂高分子基质层中，所述活性成份(即布洛芬或其结构类似物)的重量含量为大约15％到大约45％，所述至少含有一个氨基的化合物的重量含量为大约1％到大约15％；所述活性成份和所述至少含有一个氨基的化合物中的氨基的摩尔比大约在12:1到大约1:1；所述活性成份与所述至少含有一个氨基的化合物全部形成盐或部分形成盐。所述活性成份均匀分散或溶解在高分子基质中，并能长期稳定保存，布洛芬或其结构类似物不重新结晶，从而至少在12～24小时内能够连续稳定地递送具有治疗效果的量。
在一些实施例中，本发明贴剂可以连续在8小时内血药浓度持续升高，然后在随后的4小时内平稳下降，达到12小时稳定的临床效果。
第二组合层：
由于所述活性成份(即布洛芬或其结构类似物)及所述活性成份-氨基化合物盐对高分子基质的共同增粘作用，使高分子基质的整体内聚力减小，导致贴剂贴敷后皮肤形成严重的拉丝和残留问题，严重影响患者对于贴剂佩戴的顺应性，长时间佩戴时还有滑动或脱落的风险。本发明通过加入固体填充剂调控高分子基质的内聚力，解决了由于所述活性成份及所述活性成份-氨基化合物盐增粘作用导致的皮肤残留问题。但由于填充剂的加入，内聚力优化的同时伴随着粘附力损失。另一个方面，由于贴剂普遍存在的冷流(cold flow)现象，其中一个后果就是导致贴剂贴敷后，在贴剂的四周 留下的胶体会和环境中的灰尘混合后形成黑圈，影响使用安全性以及患者的顺应性。因此本发明要解决的另一问题就是满足良好的佩戴性能，在12～24小时使用期间，贴剂能够安全舒适地佩戴。
为解决上述问题，本发明还提供一种含有布洛芬或其结构类似物的多层经皮给药系统，包括上述含有布洛芬或其结构类似物的透皮贴剂(可简称为第一组合层)，还包括第二组合层。
所述第二组合层包括背衬层、保护层，以及位于背衬层和保护层中间的高分子基质层；所述高分子基质层包括压敏胶。
本发明意外的发现，通过增加第二组合层这样的多层结构的设计，极大程度地减弱了或者避免了上述问题，提供了一个满足佩戴要求的布洛芬经皮给药系统。本发明多层经皮给药系统性能良好，满足佩戴要求，贴敷过程中不滑落、不残留、剥离时对皮肤没有损伤，贴剂在保存和使用期间安全性好，患者佩戴顺应性好。
第二组合层的作用在于提供一个具有满足佩戴要求的布洛芬或其结构类似物经皮给药系统。所述第二组合层除了背衬层和保护层以外，位于两层中间的高分子基质层包括压敏胶，还可包括药学上可接受的辅料，和/或进一步地还可包括所述活性成份(即布洛芬或其结构类似物)或其它活性成份。第二组合层的高分子基质层中是否含有布洛芬等活性成份对于解决上述第一组合层高分子基质层的冷流问题没有实质性影响。可根据实际需要决定是否在第二组合层的高分子基质层中添加布洛芬等活性成份。进一步的研究发现，若所述第二组合层的高分子基质层中含有布洛芬或其结构类似物，其含量不能过高，若超过15％则不能解决上述冷流问题。因此，所述第二组合层的高分子基质层中布洛芬或其结构类似物的重量含量可为≤15％，例如≤10％，≤8％，或≤5％。
在一些实施例中，所述第二组合层的高分子基质层至少包括任何一种药学上可接受的聚丙烯酸压敏胶，聚硅酮压敏胶，橡胶，或者它们的两种或两种以上的混合物。在一些特殊实施例中，压敏胶可以是苯乙烯-异丁烯-苯乙烯(SIS，styrene-isobutylene-styrene)高分子嵌段。在一些实施例中，高分子基质还可以包括药学上可接受的其它辅料，如抗氧化剂，增塑剂，填充剂等。
如上所述，本发明发现第二组合层的使用，能够使布洛芬或其结构类似物的经皮给药系统能够具有满意的佩戴性能，从而能够在12～24小时的使用范围内能够达到满意的递送剂量。
在使用前将独立的所述含有布洛芬或其结构类似物的透皮贴剂和所述第二组合层组合在一起即形成本发明所述多层布洛芬经皮给药系统。
例如，所述含有布洛芬或其结构类似物的多层经皮给药系统可在使用前，揭去第二组合层的保护层，贴于所述含有布洛芬或其结构类似物的透皮贴剂的背衬层上，再 揭去所述透皮贴剂的保护层，贴于用药部位(例如患者皮肤)。也可以，先揭去所述透皮贴剂的保护层，贴于用药部位(例如患者皮肤)，再揭去第二组合层的保护层，贴于所述透皮贴剂的背衬层上。以上两种方法对于使用效果没有区别。
本发明布洛芬或其结构类似物经皮给药系统在不使用促透剂的情况下，在12～24小时使用期间内，可以连续可控地递送具有治疗效果的量，满足临床使用需求。
在一些特殊实施例中，本发明贴剂可以连续在16小时内血药浓度持续升高，然后在随后的8小时内平稳下降，达到24小稳定的临床效果。因此在不使用促透剂的情况下，本发明可以在根据治疗效果要求在12～24小时内递送具有治疗效果剂量的布洛芬或其结构类似物。
本发明可应用于退热，比如6个月～36个月儿童的高热退热。本发明也可用于止痛，比如用于局部疼痛的止痛。
在一些实施例中，所述含有布洛芬或其结构类似物的透皮贴剂和/或第二组合层中干燥高分子基质层的厚度大约在10μm到大约120μm，优选厚度大约在15μm到大约80μm。
优选地，所述第二组合层的周边宽度略宽于所述含有布洛芬或其结构类似物的透皮贴剂的周边宽度，更优选宽于大约0.5cm到大约1.0cm。
进一步地，所述透皮贴剂和/或第二组合层中高分子基质层都是单层结构。
在一些实施例中，本发明所述透皮贴剂和第二组合层都包括一个单独的背衬层和保护层。所述背衬层的一个面直接和高分子基质层连接，在使用的时候背衬层起到保护基质层和周边环境的接触，防止药物的损失。背衬层的材料一般包括聚酯、聚酯聚和醋酸乙烯复合膜、聚乙烯和醋酸乙烯酯的符合膜、聚氨酯、金属箔如金属铝衬的聚酯、无纺布等。厚度一般大约在20～250μm，优选20～100μm，比如3M公司的ScotchPak TM1109，ScotchPak TM9733，或3M公司Cotran TM9720，Cotran TM9722。所述离型膜和高分子基质层的另一面相连接，离型膜的材料一般包括聚酯、聚丙烯等，一般表面有氟化物涂层。厚度一般大约在50～100μm，优选60～80μm，比如3M公司的ScotchPak TM9744，ScotchPak TM9755。
本发明所述透皮贴剂和第二组合层可分别单独制备。对于所述含有布洛芬或其结构类似物的透皮贴剂，首先制备经皮给药系统中的高分子基质部分，将处方计算量的所述活性成份、压敏胶、氨基化合物，或者进一步还包括填充剂和氧化剂等辅料加入到合适的有机溶剂中，搅拌均匀后在室温下涂布到保护层(离型膜)上，然后在一定温度下将涂好的高分子基质干燥去除有机溶剂，最后复合背衬层。按照需求冲切或切割成需要的规格。
所述有机溶剂为能够溶解布洛芬或其结构类似物、压敏胶及氨基化合物的溶剂，包括乙酸乙酯，甲醇，乙醇，异丙醇，甲苯，乙腈，丙酮等。
需要说明的是上述制备所述含有布洛芬或其结构类似物的透皮贴剂所涉及的顺序，每个组分的加入量，搅拌的时间和速度等参数根据所要求的最终使用目的不同而不同。所述参数可根据需要调整。
本发明所涉及的制备方法可参考公开的文献方法。比如根据文献报道常规方法，将高分子基质涂布在离型膜上，然后和背衬层复合形成经皮给药系统，最后根据使用需要做出不同规格。一般涂布方式为溶液涂布。在一些实施例中，将所有组分混合后制备高分子基质，然后将制备好的高分子基质涂布在离型膜上，置于大约35～50℃下除去溶剂，然后和背衬层复合。所述活性成份和固体填充剂可以根据需要，在任何阶段都可以加入。在一些实施例中，先将高分子压敏胶，氨基化合物溶解在有机溶剂中，搅拌均匀，随后加入所述活性成份，搅拌至全部溶解，最后加入固体填充剂。在一些实施例中，先将布洛芬或其结构类似物溶解在有机溶剂中，随后先后加入高分子压敏胶，氨基化合物，上述混合物搅拌均匀后再加入固体填充剂，然后搅拌至分散均匀。所述加入的各组分的量，加入的顺序，以及搅拌时间可由本领域有专业经验的人员通过实验确定，示例性的制备方法如下：
步骤1)首先称取计算量的高分子压敏胶加入到适宜的有机溶剂，搅拌时间根据是否混合均匀决定，一般在大约15～30分钟。然后在保持搅拌情况下，加入氨基化合物和抗氧化剂，搅拌至全部溶解。随后分批加入所述活性成份，搅拌下逐渐溶解后，再加入下一批所述活性成份，直至全部加完溶解为止。最后加入固体填充剂，搅拌至全部分散均匀。
步骤2)将步骤1)所制备的混合液涂布于离型膜上，涂布厚度根据最终临床使用需要确定。
步骤3)通过具有排风功能的烘箱，在35～50℃下烘干5～15分钟，除去有机溶剂。
步骤4)将干燥后的产品和选定的适宜的背衬膜复合。
步骤5)根据使用需要冲切或切割成合适规格。
基于贴剂的一般制备方法，文献中其它报道方法也可用于本发明贴剂的制备。
本发明所述第二组合层，可参照以上所述透皮贴剂的制备方法进行制备。
在一些实施例中，本发明所述贴剂高分子基质中含有的所述活性成份(即布洛芬或其结构类似物)的含量范围大约从0.8mg/cm 2到大约4.0mg/cm 2，包括从大约1.2mg/cm 2到大约3.2mg/cm 2，从大约1.5mg/cm 2到大约2.9mg/cm 2，比如大约1.6mg/cm 2，大约1.9mg/cm 2，大约2.2mg/cm 2，大约2.3mg/cm 2，大约2.4mg/cm 2，大约2.6mg/cm 2，大约2.9mg/cm 2。根据贴敷时间范围内需要达到的血药浓度，本发明所述贴剂的给药面积大约从10cm 2到大约150cm 2，包括从大约20cm 2到大约120cm 2，比如20cm 2，30cm 2，40cm 2，50cm 2，60cm 2，70cm 2，80cm 2。在一些特殊实施例中， 本发明贴剂可以连续在8小时内血药浓度持续升高，然后在随后的4小时内平稳下降，达到12小时稳定的临床效果。在一些特殊实施例中，本发明贴剂可以连续在16小时内血药浓度持续升高，然后在随后的8小时内平稳下降，达到24小稳定的临床效果。因此本发明可以在根据治疗效果要求在12～24小时内递送具有治疗效果剂量的布洛芬或其结构类似物。
在一些实施例中，本发明应用于退热，比如6个月～36个月儿童的高热退热。在一些实施例中，本发明用于止痛，比如用于局部疼痛的止痛。
附图说明
图1表示实验例1稳定性实验结果；
图2表示实验例2体外释放实验结果；
图3表示实验例3体外透皮实验结果；
图4表示实验例4人体血药浓度实验结果；
图5表示实验例5大鼠致热-退热实验结果；
图6表示本发明含有布洛芬的透皮贴剂结构示意图(图6A)及第二组合层结构示意图(图6B)。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道商购买得到的常规产品。
在以下实施例中，道康宁Dow
Figure PCTCN2019113909-appb-000007
是丙烯酸压敏胶和聚硅酮压敏胶的复合物。Duro-tack-4098为丙烯酸和醋酸乙烯酯共聚物压敏胶，无官能团，无交联剂。Duro-tack-2074为丙烯酸压敏胶，具有羧基和羟基官能团，具有交联剂。Duro-tack-6908为聚异丁烯压敏胶，无官能团，无交联剂。Bio-PSA-7-4302为聚硅酮压敏胶。叔丁基-4-羟基苯甲醚(BHA)，为抗氧化剂。
实施例1
一种含有布洛芬的透皮贴剂，包括高分子基质层，所述高分子基质层包含活性成份布洛芬、至少含有一个氨基的化合物和压敏胶；所述高分子基质层中，全部或部分布洛芬与所述至少含有一个氨基的化合物形成盐，使形成的全部或部分布洛芬-氨基化合物盐及全部或部分游离布洛芬在高分子基质中保持均匀溶解状态，并能在使用前能够稳定保存不重新结晶。
进一步地，本实施例皮贴剂还包括背衬层和保护层；所述高分子基质层位于背衬层和保护层之间。
本实施例中，高分子基质层中布洛芬重量含量为35％；压敏胶重量含量为54％(其 中Duro-tack-4098的重量含量为50％，Bio-PSA-7-4302的重量含量为4％)；含有一个氨基的化合物(具体为Am_25)的重量含量为5％；另外还可含有药学上可接受的辅料(例如滑石粉、胶态SiO 2、蒙脱石、维生素E等)。
本实施例还提供该透皮贴剂的制备方法，包括：首先称取计算量的高分子压敏胶，加入适量乙酸乙酯中，然后在保持搅拌情况下，加入氨基化合物，或者进一步加入抗氧化剂(例如维生素E)等辅料，搅拌时间根据是否混合均匀决定，一般在大约15～30分钟。搅拌至全部溶解后，随后分批加入活性成份布洛芬，搅拌下逐渐溶解后，再加入下一批布洛芬，直至全部加完溶解为止。最后加入固体填充剂，搅拌下至全部分散均匀。将所制备的高分子基质涂布于离型膜上，涂布厚度根据最终临床使用需要确定。将涂布后的高分子基质通过具有排风功能的烘箱，在35～50℃下烘干5～15分钟，除去有机溶剂。随后干燥后的产品和适宜的背衬膜复合。最后根据使用需要裁切成合适的规格，包装成产品。
典型含有布洛芬的透皮贴剂的高分子基质层配方(实施例1-10)见表1(制备方法可参照实施例1)。
表1
Figure PCTCN2019113909-appb-000008
(表1为重量百分含量。)
比较例1 含有布洛芬的透皮贴剂，其高分子基质层配方见表1，制备方法参照实施例1。
实施例11-21
含有不同类型促透剂的布洛芬的透皮贴剂的高分子基质层配方(即实施例11-21) 及其透过效率变化见表2(制备方法可参照实施例1)。
表2
(表2为重量百分含量。)
Figure PCTCN2019113909-appb-000009
A＝透过基本无变化；B＝透过稍微降低；C＝透过明显降低
从表2的结果可以看出，添加不同类型促透剂，对透过效率变化基本没有增加，大多数情况下反而阻碍透过速率。因此本发明不需要添加任何促透剂。
实施例22
一种含有布洛芬的多层经皮给药系统，包括含有布洛芬的透皮贴剂(简称为第一组合层)，还包括第二组合层。所述第二组合层包括背衬层、保护层，以及位于背衬层和保护层中间的高分子基质层。其中，所述含有布洛芬的透皮贴剂(即第一组合层)可任选自实施例1-21含有布洛芬的透皮贴剂。
所述第二组合层的高分子基质层包括压敏胶以及药学上可接受的辅料，还可包含布洛芬等活性成份。当所述第二组合层的高分子基质层中含有布洛芬时，其重量含量≤15％，例如≤10％，≤8％，或≤5％。
所述第二组合层可参照实施例1含有布洛芬的透皮贴剂的制备方法进行制备。
典型第二组合层的高分子基质层配方(即实施例22-26)见表3。
表3
Figure PCTCN2019113909-appb-000010
(表3为重量百分含量。)
实施例27
实施例1含有布洛芬的透皮贴剂结构示意图参见图6A。实施例22第二组合层结构示意图参见图6B，二者构成含有布洛芬的多层经皮给药系统10。
含有布洛芬的透皮贴剂100与第二组合层200在使用前分别是独立的，各自包括背衬层、保护层，和位于两层中间的高分子基质层。
对于含有布洛芬的透皮贴剂100，其背衬层110内面150直接和高分子基质层120的一面贴合，背衬层110的另外一面140暴露于环境中起到保护高分子基质120的作用，保护层130的内面160和高分子基质层120的另外一面贴合，高分子基质120在使用前位于保护层110和背衬层130之间。
对于第二组合层200，背衬层210内面250直接和高分子基质层220的一面贴合，背衬层210另外一面240暴露于环境中起到保护高分子基质220的作用，保护层230的内面260和高分子基质220的另外一面贴合，高分子基质层220在使用前位于保护层210和背衬层230之间。
使用时先揭去含有布洛芬的透皮贴剂100中的保护层160，贴敷于患者的皮肤，然后再揭去第二组合层200的保护层260，完全覆盖在第一组合层100的上面，将第一组合层100完全覆盖在第二组合层200内。所述第二组合层比含有布洛芬的透皮贴剂周边宽0.5～1.0cm。
实验例1 稳定性实验
将比较例1和实施例1贴剂，置于相同的保存条件下(30±2℃，60％±10％RH)，定期通过电子显微镜观察，观察结果见图1。
连续观察结果显示，在没有加入氨基化合物情况下，比较例1在第一周内，活性成份就从高分子基质中析出，能观察到明显的晶体。实施例1在十二个月观察期内未见变化，布洛芬均匀地分散在胶黏基质中，不同倍数光学显微镜下未见晶体存在，未观察到有结晶现象，说明贴剂稳定性能好。
实验例2 体外释放实验
体外释放是贴剂的一个基本性能指标，反映的是活性成份和高分子基质中其它组 分的相互作用。高分子基质的整体性能、布洛芬和高分子以及其它组分见的相互作用如氢键、离子对、范德华力等，导致布洛芬在高分子基质中流动的行为不同。体外释放是透皮吸收的基础，只有适宜的释放能力才能满足特定的透皮吸收要求。
释放度测定法(中国药典2015年版第四部通则0931第四法-桨碟法)，以PBS为溶出介质，温度为32℃，50转/分钟，依法操作，分别于0.3h，0.5h,0.7h,1.0h,1.5h,2.0h,3.0h,6.0h,9.0h,12.0h,18.0h和24.0h取样10ml，过滤；另精密称定布洛芬对照品适量，以溶出介质溶解，配制适当浓度的溶液作为对照品溶液。
用十八烷基硅烷键合硅胶填充剂；以甲醇-磷酸盐水溶液(40mmol/L的磷酸二氢钾水溶液，磷酸调节pH＝2.50)(77:23)为流动相；检测波长为225nm；柱温50℃；理论塔板数按布洛芬计算不低于2000。照HPLC法(中国药典2015年版第四部通则0512)测定。
结果见图2。结果显示，实施例1、2、4、5均具有较快的释放行为，在前2小时基本释放完全。所述释放行为完全满足经皮吸收的要求，不会对整体经皮吸收行为照成阻碍。
实验例3 体外透皮实验
体外透皮实验通过Franz垂直扩散池测定。健康成年猪耳朵皮，所用皮肤按照标准的热分离方法，取得猪耳朵皮的角质层。接收液为pH为7.4的PBS溶液，接受池体积为7mL，设定温度32±0.1℃，搅拌速度为300转/分钟。分别于1h，2h，3h，4h，5h，6h，8h，10h，12h和24h取样，每次取样3mL，然后补加等温的空白接受液。每组样品平行6份，同时平行一份空白作为对照。根据结果计算各时间点的累积透过量。
结果见图3。结果显示，在24小时实验范围内，本发明贴剂可以调控释放速度以及释放总量，从而能够根据使用需要递送具有治疗效果剂量的布洛芬的量。
实验例4 健康志愿者人体血药浓度实验
选取健康成年男性12名，年龄24.6±2.5(22～30)岁，体重61.2±2.8(58～65)kg，受试者无药物过敏史，近两周未使用过任何药物。实验中禁服其它药物，受试期间统一饮食。选取芬必得
Figure PCTCN2019113909-appb-000011
为对照药物(400mg/布洛芬缓释胶囊，批号：17090198)，受试者口服一粒。选取实施例3和6，每人腹下部分别贴敷。12名受试者随机分为三组，每组4人。第一组口服芬必得
Figure PCTCN2019113909-appb-000012
第二组贴敷实施例3，第三组贴敷实施例6。
取血方式：上肢静脉取血；分别于0h；0.25h；0.5h；1h；2h；3h；6h；9h；12h取血，每次取血量5mL。
检测方法：HPLC法；色谱条件：
色谱柱：C18；150*4.6mm；5um；流动相：5.4g/L的磷酸二氢钾水溶液(磷酸调节pH＝2.50)：甲醇＝30:70；柱温：50℃；流速：1.0mL/min；检测波长：225nm；进样 体积：20ul；洗脱方式：等浓度洗脱；进样方式：自动进样。
样品处理方式：蛋白沉淀法(0.2ml的血清加入0.2ml的乙腈，涡旋混匀，10000r/min离心，15min，取上清液)。
具体结果见图4。结果显示，相对芬必得
Figure PCTCN2019113909-appb-000013
缓释胶囊，本发明贴剂可以连续在8小时内血药浓度持续升高，然后在随后的4小时内平稳下降，达到12小时稳定的临床效果。同时也可以连续在15小时内血药浓度持续升高，然后在随后的8小时内平稳下降，达到24小稳定的临床效果。因此本发明贴剂可以在根据治疗效果要求在12～24小时内递送具有治疗效果剂量的布洛芬。
实验例5 大鼠致热-退热实验
动物：Wistar大鼠，雄性，体重300g±20g，分成5组(每组四只大鼠)。其中一组用于贴敷实施例1的贴剂，三组用于灌胃不同剂量的美林 TM(分别为5mg、10mg和20mg)，一组用于致热后作为空白对照。
致热方法：颈后皮下注射干酵母溶液(每300g注射4ml的30％的干酵母溶液)；
温度测量方式：肛门3cm深度，电子测温计，平行测定两次取平均值(两次测量结果偏差不超过±0.1℃)
剃毛方式：麻醉后，先用电动剃毛器除取大部分毛，再均匀涂抹脱毛膏，3min后用清水冲干净。
给药方式：
贴剂组，将实施例1贴剂贴敷与大鼠腹部，用纱布固定。
Figure PCTCN2019113909-appb-000014
口服组，每组动物分别灌胃美林 TM(强生，浓度20mg/ml；生产批号：171101428)5mg、10mg、20mg。
具体结果见图5。结果显示，与口服美林 TM相对较短的退热效果相比，本发明贴剂具有长时间内稳定退热作用，退热效果平稳，持续时间长。
实验例6 贴敷实验
选取健康成年受试者者，贴敷于上臂内侧，考察皮肤残留及冷流现象。
实验分组如下：
1)分别单独使用实施例2、4、6含有布洛芬的透皮贴剂。方法：首先去掉保护层，然后贴敷与志愿者上臂内侧。
2)单独使用第二组合层(基质配方同实施例22)。方法：首先去掉保护层，然后贴敷与志愿者上臂内侧。
3)使用含有布洛芬的多层经皮给药系统：分别以实施例2、4、6含有布洛芬的 透皮贴剂作为第一组合层，联合使用第二组合层(基质配方同实施例22)。联合使用方法：揭去第二组合层的保护层，分别贴于作为第一组合层的实施例2、4、6的透皮贴剂的背衬层上，再揭去所述透皮贴剂的保护层，贴于上臂内侧。
以上各组分别于4h，8h，12h和24取下贴剂，观察贴敷部位残留情况和冷流程度，观察结果见表4。
表4
Figure PCTCN2019113909-appb-000015
从观察结果来看，本发明贴剂基本没有残留。在没有第二组合层的情况下，观察到有明显的冷流现象，如实施例4和实施例6，但组合使用后，冷流现象消除。
以上以布洛芬为活性成份进行了相关实验，由于结构、性质及功能近似，本领域技术人员可以预见布洛芬结构类似物萘普生(Naproxen)、非诺洛芬(Fenoprofen)、酮洛芬(Ketoprofen)、氟比洛芬(Flurbiprofen)、洛索洛芬(Loxoprofen)也能实现基本相同的功能、达到基本相同的技术相关。限于篇幅，未能列出相关实验。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明提供一种含有布洛芬或其结构类似物的多层经皮给药系统。所述多层经皮给药系统包括含有布洛芬或其结构类似物的透皮贴剂和第二组合层。所述透皮贴剂，包括高分子基质层，所述高分子基质层包含活性成份、至少含有一个氨基的化合物和压敏胶。所述高分子基质层中形成的全部或部分活性成份-氨基化合物盐及全部或部分游离活性成份在高分子基质中保持均匀溶解状态，并能在使用前能够稳定保存不重新结晶。本发明同时给出了经皮给药系统的制备方法和使用方法。本发明经皮给药系统在没有促透剂的情况下能够在12～24小时范围内，连续可控地递送具有治疗效果剂量的布洛芬或其结构类似物。本发明经皮给药装置具有优异佩戴能力，避免了冷流现象，具有较好的经济价值和应用前景。

Claims (10)

  1. 一种含有布洛芬或其结构类似物的透皮贴剂，其特征在于，包括高分子基质层，所述高分子基质层包含活性成份、至少含有一个氨基的化合物和压敏胶；所述活性成份为布洛芬或其结构类似物；所述布洛芬结构类似物选自萘普生、非诺洛芬、酮洛芬、氟比洛芬、洛索洛芬中一种或几种。
  2. 根据权利要求1所述的透皮贴剂，其特征在于，所述至少含有一个氨基的化合物为脂肪胺；优选选自以下化合物中的一种或几种：乙醇胺，二乙醇胺，三乙醇胺，二乙胺，三乙胺，丙二胺，N-乙基吗啉，N-乙基哌啶，N-乙基哌嗪，N-羟乙基哌啶，N-羟乙基吡咯，二甲基丙二胺，四甲基丙二胺，N-十二烷基吡咯，三己胺，N-十二烷基高哌啶，吡啶烷-2-基-甲醇，乙二胺，四甲基乙二胺，亚精胺，精胺，轮环藤宁，3-(哌嗪-1-基)丙-1,2-二醇，N-羟乙基哌嗪，N-甲基吗啉，三乙烯二胺，三(2-氨基乙基)胺，2-哌嗪酮，3-氨基哌啶，1,3-环己二甲胺，丙二醇二(3-氨丙基)醚，乙二醇二(3-氨乙基)醚。
  3. 根据权利要求1或2所述的透皮贴剂，其特征在于，所述高分子基质层中，全部或部分活性成份与所述至少含有一个氨基的化合物形成盐；
    优选地，所形成的活性成份-氨基化合物盐的熔点低于布洛芬或其相应结构类似物的熔点。
  4. 根据权利要求1-3任一项所述的透皮贴剂，其特征在于，所述高分子基质层中含有填充剂，所述填充剂选自滑石粉，膨润土，高岭土，胶态二氧化硅，蒙脱石中任一种或几种；
    优选地，所述填充剂的平均粒度在300目到5000目，包括500目到3000目；优选地，所述填充剂的表面积在1.5m 2/g到15m 2/g，包括3m 2/g到10m 2/g，4m 2/g到7m 2/g。
  5. 根据权利要求1-4任一项所述的透皮贴剂，其特征在于，所述高分子基质层中不含有促透剂。
  6. 根据权利要求1-5任一项所述的透皮贴剂，其特征在于，所述高分子基质层中所述活性成份和所述至少含有一个氨基的化合物中的氨基的摩尔比为12:1到1:1，包括10:1到1.5:1，比如10:1,9:1，10:1，8:1，7:1，6:1，5:1，4:1，3:1，2:1或1.5:1；和/或，
    所述高分子基质层中所述至少含有一个氨基的化合物的重量含量为1％到15％，包括2％到12％，比如2％，3％，4％，5％，6％，7％，8％，9％，10％，11％或12％；和/或，
    所述高分子基质层中所述活性成份的重量含量为15％到45％，包括20％到40％，比如20％到35％，进一步优选范围为25％～35％，比如25％，30％，或35％；和/或，
    所述高分子基质层中丙烯酸压敏胶的重量含量为40％到80％，优选为45％到 75％，比如45％到70％，包括45％、50％、55％、60％、65％或70％。
  7. 根据权利要求1-6任一项所述的透皮贴剂，其特征在于，所述贴剂还包括背衬层和保护层；所述高分子基质层位于背衬层和保护层之间。
  8. 一种含有布洛芬或其结构类似物的多层经皮给药系统，其特征在于，包括权利要求1-7任一项所述透皮贴剂，还包括第二组合层；所述第二组合层包括背衬层、保护层，以及位于背衬层和保护层中间的高分子基质层；所述高分子基质层包括压敏胶。
  9. 根据权利要求8所述的多层经皮给药系统，其特征在于，所述第二组合层的高分子基质层还包括药学上可接受的辅料，和/或还包括布洛芬或其结构类似物；
    优选地，所述第二组合层的高分子基质层中布洛芬或其结构类似物的重量含量为≤15％，例如≤10％，≤8％，或≤5％；优选地，所述布洛芬结构类似物选自萘普生、非诺洛芬、酮洛芬、氟比洛芬、洛索洛芬中一种或几种。
  10. 根据权利要求8或9所述的多层经皮给药系统，其特征在于，所述第二组合层的周边宽度略宽于所述透皮贴剂的周边宽度，更优选宽于0.5cm到1.0cm。
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