WO2023092644A1 - 一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用 - Google Patents

一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用 Download PDF

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WO2023092644A1
WO2023092644A1 PCT/CN2021/135663 CN2021135663W WO2023092644A1 WO 2023092644 A1 WO2023092644 A1 WO 2023092644A1 CN 2021135663 W CN2021135663 W CN 2021135663W WO 2023092644 A1 WO2023092644 A1 WO 2023092644A1
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microneedle
microneedle patch
needle body
needle
composition
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PCT/CN2021/135663
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English (en)
French (fr)
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何健文
江荣高
夏中宁
张丽杰
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海南鑫开源医药科技有限公司
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Publication of WO2023092644A1 publication Critical patent/WO2023092644A1/zh

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/37—Celastraceae (Staff-tree or Bittersweet family), e.g. tripterygium or spindletree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1767—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a composition with analgesic effect, a microneedle patch, a preparation method and application thereof.
  • Drugs for clinical treatment of rheumatoid arthritis can be generally divided into three categories: non-steroidal anti-inflammatory drugs, hormonal drugs, and disease-modifying anti-rheumatic drugs (DMARDs); among them, disease-modifying anti-rheumatic drugs are divided into traditional synthetic DMARDs , biologics DMARDs and targeted synthetic DMARDs.
  • non-steroidal anti-inflammatory drugs hormonal drugs
  • DMARDs disease-modifying anti-rheumatic drugs
  • Non-steroidal anti-inflammatory drugs clinically used to treat rheumatoid arthritis usually include aspirin, ibuprofen, etc. These drugs are mostly taken orally. Due to the "first-pass effect" drug elimination is serious and the bioavailability is low. The main adverse reaction is gastric mucosal injury, inducing and aggravating acute hemorrhagic gastritis and peptic ulcer.
  • Hormonal drugs clinically used to treat rheumatoid arthritis usually include dexamethasone and other glucocorticoids. These drugs are mainly injected into the joint cavity, which can anti-inflammation, detumescence, and relieve paralysis and pain in rheumatoid arthritis. Its medication method is technically difficult, highly traumatic and prone to infection and other complications, and patients' compliance is poor. Studies have shown that even small doses of glucocorticoids can increase the risk of hip fractures, so frequent administration is not suitable.
  • the technical problem to be solved by the present invention is to provide a composition with analgesic effect, microneedle patch and its preparation method and application, the composition provided by the present invention has lower irritation, faster With its speed of onset and strong analgesic effect, it can treat limb swelling and pain in rheumatoid arthritis.
  • composition with analgesic effect comprising the following components in parts by weight:
  • lidocaine 0.5-5 servings of lidocaine
  • the present invention also provides a biodegradable microneedle patch for treating rheumatoid arthritis paralysis and pain, wherein the active component in the microneedle patch includes the composition described in claim 1 .
  • the microneedle patch includes a base layer and a needle layer, and the needle layer includes the active component.
  • the needle body layer is prepared by processing active components, solubilizing components, and high molecular biodegradable polymer skeleton materials.
  • the solubilization component includes one or more of ethanol, Tween 80, propylene glycol, polyethylene glycol 400, glycerin and beta-cyclodextrin;
  • the polymer biodegradable polymer skeleton material is selected from one or more of polymers such as polylactic acid, polyethylene glycol diacrylate, polyglycolic acid, polycaprolactone, and polycarbonate.
  • the needle layer of the microneedle patch has a needle height of 800-1000 ⁇ m, and a needle base width of 200-400 ⁇ m.
  • the base liner is selected from one or more of povidone K90 and sodium polyglutamate.
  • the present invention also provides a method for preparing the above-mentioned microneedle patch, comprising the following steps:
  • the base liner material is dissolved with deionized water to obtain the base liner stock solution, and then the base liner stock solution is poured above the above-mentioned microneedle master template to cover the needle body layer, and dried after high-speed centrifugation to make the base liner and the base liner
  • the needle body layer is firmly combined and formed, and then the microneedle master template is peeled off to obtain a microneedle patch.
  • the preparation method of said microneedle master template comprises the following steps:
  • the master template material polysiloxane and curing agent amylose were placed in deionized water to stir and disperse, then heated to gelatinization, cooled and swollen, and then vacuum-dried, and the degassed dry mixture was placed on the surface of the stainless steel metal microneedle template. After curing and drying in a constant temperature desiccator, take it out, and peel it off from the metal microneedle to obtain the polysiloxane microneedle master template of the needle body.
  • the present invention also provides an application of the above-mentioned composition in the preparation of a medicament suitable for treating paralysis and pain in rheumatoid arthritis.
  • the present invention provides a composition with analgesic effect, comprising the following components in parts by weight: 1 part of capsaicin, 0.5 to 5 parts of melittin, 0.5 to 5 parts of lidocaine, 0.8-20 parts of tripterygium glycosides, 0.8-20 parts of total glucosides of paeony, and 0.5-5 parts of iguratimod.
  • the present invention uses capsaicin, melittin, lidocaine, tripterygium glycosides, total glucosides of paeony, and iguratimod as active components, and the combined compatibility of the six active components has a synergistic effect, and has obvious Anti-rheumatoid arthritis and pain relief of joint paralysis.
  • capsaicin is the main analgesic ingredient
  • melittin has strong anti-inflammatory activity, and at the same time has a protective effect on articular chondrocytes. effect, reducing the dose of capsaicin.
  • Lidocaine can eliminate the pungent and irritating adverse reactions of capsaicin on skin tissue, and has local anesthetic and analgesic effects at the same time.
  • Iguratimod can inhibit the production of inflammatory cytokines, tumor necrosis factor, lymphocytes and immunoglobulin, and has an autoimmune regulatory effect.
  • Tripterygium glycosides and total glucosides of paeony have immunosuppressive effects, and have synergistic anti-rheumatic effects with iguratimod.
  • the present invention prepares biodegradable microneedles with good puncture performance by using active components, solubilizing components and biodegradable framework materials in specific usage amounts, through a specific preparation method.
  • the microneedles can pierce the stratum corneum and produce
  • the drug release microchannel can increase the permeability, availability and onset speed of the drug, and deliver the drug to the synovial membrane of the patient's joint in a minimally invasive way, which can quickly relieve pain and take effect with the release of the drug Play the role of anti-rheumatoid arthritis.
  • the invention provides a composition with analgesic effect, comprising the following components in parts by weight: 1 part of capsaicin, 0.5 to 5 parts of melittin, 0.5 to 5 parts of lidocaine, and 0.8 to 20 parts of tripterygium glycosides 0.8-20 parts of total glucosides of paeony, 0.5-5 parts of iguratimod.
  • the composition with analgesic effect is based on 1 part by weight of capsaicin, including 0.5 to 5 parts of melittin, preferably 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or any value between 0.5 and 5 parts.
  • composition with analgesic effect also includes 0.5 to 5 parts of lidocaine, preferably 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or 0.5 to 5 parts any value.
  • composition with analgesic effect also includes 0.8 to 20 parts of tripterygium glycosides, preferably 0.8, 1, 2, 3, 4, 5, 7, 10, 12, 15, 18, 20, or 0.8 to 20 parts Any value between copies.
  • composition with analgesic effect also includes 0.8 to 20 parts of total glucosides of paeony, preferably 0.8, 1, 2, 3, 4, 5, 7, 10, 12, 15, 18, 20, or 0.8 to 20 parts Any value between copies.
  • composition with analgesic effect also includes 0.5-5 parts of iguratimod, preferably 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or 0.5-5 parts any value of .
  • the present invention also provides a biodegradable microneedle patch for treating paralysis and pain of rheumatoid arthritis, and the active component in the microneedle patch includes the above composition. Specifically, it can be used for the treatment of joint synovitis.
  • the active component with strong analgesic effect is prepared into a microneedle patch with low irritation, rapid onset of action and biodegradable, and the microneedle patch has the effect of alleviating the pain of erosive bursitis.
  • the present invention uses the composition in a microneedle patch.
  • the diameter of the microneedle is usually on the order of hundreds of microns, which can only penetrate the epidermis and epithelial parts of the skin without hurting the capillaries and nerves in the dermis.
  • Combining drug therapy can realize systemic or local drug delivery of chemical drugs or biological products, which belongs to minimally invasive and semi-invasive transdermal drug delivery system.
  • the method of microneedle transdermal drug delivery can realize local or systemic delivery of drugs from the epidermis to the body, avoiding the degradation of the gastrointestinal tract and avoiding the "first-pass effect" of the liver. It is minimally invasive and has good patient compliance. Achieve self-administration.
  • Biodegradable microneedles release drugs through the degradation of the matrix, and the matrix material can be degraded into non-toxic components and eliminated in vivo through the body's metabolic pathways.
  • the invention is a microneedle patch suitable for rheumatoid arthritis paralysis and pain, and is a brand-new treatment method for rheumatoid arthritis paralysis pain.
  • the tapered three-dimensional structure of the microneedle can pierce the skin with a thickness of about 10-20 ⁇ m.
  • the stratum corneum and produce drug release microchannels, because microneedles break through the skin barrier of transdermal drug delivery, can increase the permeability, availability and onset speed of drugs, and deliver drugs to the synovium of patients' joints in a minimally invasive way, Play a role in rapid pain relief and inhibition of rheumatoid arthritis.
  • the microneedle patch provided by the invention includes a base layer and a needle layer, and the needle layer includes the active component.
  • the needle body layer is processed and prepared from active components, solubilizing components, and high molecular biodegradable polymer skeleton materials.
  • the solubilization component includes one or more of ethanol, Tween 80, propylene glycol, polyethylene glycol 400, glycerin, and beta-cyclodextrin; the beta-cyclodextrin is selected from hydroxypropyl One or more of beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, and sodium sulfobutyl-beta-cyclodextrin.
  • the polymer biodegradable polymer skeleton material is selected from one or more of polymers such as polylactic acid, polyethylene glycol diacrylate, polyglycolic acid, polycaprolactone, and polycarbonate.
  • the mass ratio of the active component, solubilizing component, and polymer biodegradable polymer skeleton material is 1:(1.5 ⁇ 22.5):(0.3 ⁇ 4.5), preferably 1:(2 ⁇ 20): (0.5-4), more preferably 1: (5-15): (1-2).
  • the needle body layer of the microneedle patch has a needle height of 800-1000 ⁇ m, preferably 800, 900, 1000, or any value between 800-1000 ⁇ m, and a needle body base width of 200-400 ⁇ m, preferably 200, 300, 400, or any value between 200 and 400 ⁇ m.
  • the needles on the microneedle patch are arranged in an array, and the distance between adjacent needles is 100-300 ⁇ m, preferably 100, 200, 300, or any value between 100-300 ⁇ m.
  • the needles are arranged in a 10*10 arrangement, that is, there are 10 rows of needles in total, and each row has 10 needles.
  • the base liner is selected from one or more of povidone K90 and sodium polyglutamate.
  • the thickness of the underlayer is 50-500 ⁇ m, preferably 100-400 ⁇ m, more preferably 200-300 ⁇ m.
  • the present invention also provides a method for preparing the above-mentioned microneedle patch, comprising the following steps:
  • the base liner material is dissolved with deionized water to obtain the base liner stock solution, and then the base liner stock solution is poured above the above-mentioned microneedle master template to cover the needle body layer, and dried after high-speed centrifugation to make the base liner and the base liner
  • the needle body layer is firmly combined and formed, and then the microneedle master template is peeled off to obtain a microneedle patch.
  • the present invention first prepares a microneedle master template, and the preparation method of the microneedle master template includes the following steps:
  • the master template material polysiloxane and curing agent amylose were placed in deionized water to stir and disperse, then heated to gelatinization, cooled and swollen, and then vacuum-dried, and the degassed dry mixture was placed on the surface of the stainless steel metal microneedle template. After curing and drying in a constant temperature desiccator, take it out, and peel it off from the metal microneedle to obtain the polysiloxane microneedle master template of the needle body.
  • the polysiloxane is selected from polydimethylsiloxane, cyclomethicone, aminosiloxane, polymethylphenylsiloxane, polyether polysiloxane copolymer, etc. or more.
  • the gelatinization temperature is 65-85°C, preferably 70-80°C.
  • the present invention also provides an application of the above-mentioned composition in preparing a medicine suitable for treating paralysis and pain of rheumatoid arthritis.
  • the present invention also provides an application of the above-mentioned composition in preparing a medicine suitable for treating autoimmune and erosive joint synovitis paralysis pain.
  • the preparation form of the medicine can be microneedle patch, patch, plaster, gel, cream, ointment.
  • the present invention uses capsaicin, melittin, lidocaine, tripterygium glycosides, total glucosides of paeony, and iguratimod as active components, and the combined compatibility of the six active components has a synergistic effect, and has obvious Anti-rheumatoid arthritis and pain relief of joint paralysis.
  • capsaicin is the main analgesic ingredient
  • melittin has strong anti-inflammatory activity, and at the same time has a protective effect on articular chondrocytes. effect, reducing the dose of capsaicin.
  • Lidocaine can eliminate the pungent and irritating adverse reactions of capsaicin on skin tissue, and has local anesthetic and analgesic effects at the same time.
  • Iguratimod can inhibit the production of inflammatory cytokines, tumor necrosis factor, lymphocytes and immunoglobulin, and has an autoimmune regulatory effect.
  • Tripterygium glycosides and total glucosides of paeony have immunosuppressive effects, and have synergistic anti-rheumatic effects with iguratimod.
  • the present invention prepares biodegradable microneedles with good puncture performance by using active components, solubilizing components and biodegradable framework materials in specific usage amounts, through a specific preparation method.
  • the microneedles can pierce the stratum corneum and produce
  • the drug release microchannel can increase the permeability, availability and onset speed of the drug, and deliver the drug to the synovial membrane of the patient's joint in a minimally invasive way, which can quickly relieve pain and take effect with the release of the drug Play the role of anti-rheumatoid arthritis.
  • composition with analgesic effect the microneedle patch and its preparation method and application provided by the present invention will be described below in conjunction with the examples, and the protection scope of the present invention is not limited by the following examples.
  • Example 1 The difference between this example and Example 1 is that the active components only include 1 part of capsaicin, 3 parts of melittin, and 3 parts of lidocaine, and the rest are the same as in Example 1.
  • Example 1 The only difference between this example and Example 1 is that the active components only include 8 parts of tripterygium glycosides, 8 parts of total glycosides of paeony, and 3 parts of iguratimod
  • biodegradable polymer skeleton material contains 13 parts of polyglycolic acid, supplemented with 5 parts of thickener lactose, and the rest are the same as in Example 1.
  • the biodegradable microneedle patch suitable for paralysis and pain provided by this embodiment is composed of a base lining layer and a needle body layer, wherein the needle body layer is composed of active components, solubilizing components, polymer biodegradable Composed of degradable polymer skeleton materials; wherein, the base liner is composed of povidone K90 and sodium polyglutamate.
  • the active components in this example include: 1 part of capsaicin, 3 parts of melittin, 3 parts of lidocaine, 8 parts of tripterygium glycosides, 8 parts of total glycosides of paeony, and 3 parts of iguratimod.
  • the solubilization components of the active ingredient are 35 parts of ethanol, 3 parts of Tween 80, 3 parts of propylene glycol, 3 parts of polyethylene glycol 400, 3 parts of glycerin, 10 parts of sulfobutylbeta cyclodextrin sodium, water 35 servings.
  • the active component and the solubilizing component are stirred and mixed and uniformly dispersed to obtain an aqueous solution of the active component.
  • the polymer biodegradable polymer skeleton material in this embodiment comprises: 13 parts of polyethylene glycol diacrylate, supplemented with 5 parts of thickener lactose.
  • the base liner comprises: 2 parts of povidone K90, 3 parts of sodium polyglutamate
  • the preparation method of the biodegradable microneedle patch suitable for paralysis and pain provided by this example is as follows:
  • polysiloxane microneedle master template put the master template material polysiloxane (polydimethylsiloxane in this case) and curing agent amylose into deionized water and stir to disperse, then heat to 70°C to paste After cooling and swelling, vacuum drying is carried out, and the degassed dry mixture is placed on the surface of a commercially available stainless steel metal microneedle template.
  • the metal microneedle template has needles arranged in 10*10, with a needle height of 900 ⁇ m and a needle base width of 300 ⁇ m. After curing and drying in a constant temperature desiccator, take it out, and gently peel it off from the metal microneedle to obtain a 10*10 needle body polysiloxane microneedle master template.
  • Preparation of the needle body layer mix the active components, clathrates, and polymer biodegradable polymer skeleton materials evenly to obtain the needle body layer stock solution, take the needle body layer stock solution and pour it into the microneedle master template, and centrifuge at a high speed Finally, the stock solution is evenly filled in the needle cavity of the microneedle master template, and a needle body layer is formed in the needle cavity after drying.
  • the base lining layer Dissolve the base lining layer material with deionized water to obtain the base lining layer stock solution, then pour the base lining layer stock solution above the above-mentioned microneedle master template, cover the needle body layer, dry it after high-speed centrifugation, and make the base lining layer stock solution.
  • the lining layer and the needle body layer are firmly combined and formed, and then the microneedle master template is peeled off to obtain a self-made microneedle patch.
  • Animal experiment 1 rat skin puncture test to confirm the mechanical strength of the needle body layer
  • Puncture results the mouse skin punctured by the microneedles of Example 1, Comparative Example 1 and Comparative Example 2 formed dense, uniformly distributed blue holes, and the puncture results were good; the mouse skin punctured by the microneedle of Comparative Example 3 formed sparse, slightly distributed shallow holes. Blue hole, poor puncture result; indicating that polyethylene glycol diacrylate and lactose are used as the skeleton material for the needle body layer, which has better mechanical hardness and excellent puncture performance. Therefore, the skeleton material of the needle body layer is preferably polyethylene glycol diacrylate and lactose.
  • mice Animal experiment 2: The analgesic effect of the microneedle patch was confirmed by the paw withdrawal reaction experiment of mice
  • Quantitative indicators use the microneedle patch prepared in Example 1 and Comparative Examples 1-3 for inflammatory pain model mice, and measure the latency of paw withdrawal reaction of the hind paw of the inflammatory mouse with a smart hot plate instrument, as the microneedle patch has little effect on inflammation. A measure of analgesic effect in mice.
  • mice in the first four groups measured their basic response indicators to pain, that is, the paw withdrawal time to a fixed pain threshold, and then injected carrageenan into the feet of the mice with inflammation in the first four groups to prepare the inflammatory pain model.
  • the feet of mice with inflammation in the group were respectively applied with the microneedle patch of Example 1, the microneedle patch of Comparative Example 1, the microneedle patch of Comparative Example 2, and diclofenac sodium cream, and then measured the microneedle patches of the first four groups at 30min, 60min, and 90min Rat Pain Response Index.
  • the fifth group of mice was used as a blank without any treatment (the pain threshold was measured synchronously).
  • the data were analyzed by SPSS (version 23.0) statistical software, and the measurement data were expressed by "mean ⁇ standard deviation (X ⁇ S)".
  • the sample t test was used to compare the means before and after within the group using the paired sample t test, and P ⁇ 0.05 indicated that the difference was statistically significant.
  • the single factor ANOVA analysis results show that, from the experimental results, compared with the diclofenac sodium cream group in the comparative example 1 group, the two groups of mice have no significant difference in the paw withdrawal time of the fixed pain threshold (P>0.05), indicating that the active ingredient Only containing capsaicin, melittin, lidocaine has obvious analgesic effect;
  • the microneedle patch of embodiment 1, comparative example 1 and comparative example 2 all has different intensity of analgesic effect (P ⁇ 0.05), the intensity decreases in turn.
  • the combination of active components including capsaicin, melittin, lidocaine, tripterygium glycosides, total glucosides of paeony, and iguratimod has the strongest analgesic strength.
  • Type II collagen-induced arthritis (CIA) solution configuration Dissolve type II collagen with 0.1M acetic acid solution to prepare 2 g/L type II collagen acetic acid solution; then use 2 g/L bovine type II collagen acetic acid The solution was thoroughly mixed and emulsified with an equal volume of incomplete Freund's adjuvant (IFA) to obtain a CIA solution.
  • IFA incomplete Freund's adjuvant
  • CIA collagen-induced arthritis
  • the rats were divided into an experimental group and a blank group, with 10 rats in each group.
  • the rats in the blank experimental group were not given any treatment.
  • the swelling index of the normal feet of the two groups of rats were measured before the experiment.
  • inject the CIA solution to the tail of the rats in the experimental group to prepare the arthritis model, measure the swelling degree of the arthritic feet of the rats on the 7th day after modeling, and after judging that the modeling is successful use the microneedles of Example 1 to the rats in the experimental group Patch, respectively, on the 7th day, the 14th day, and the 21st day to measure the swelling degree of the rat's foot.
  • Rats in the blank group were simultaneously measured for foot swelling.
  • the effect of microneedle patch on rat foot swelling is shown in Table 2
  • Example 1 The difference between this example and Example 1 is that the parts by weight of the active components are: 1 part of capsaicin, 0.5 part of melittin, 0.5 part of lidocaine, 0.8 part of tripterygium glycosides, 0.8 part of total glucosides of paeony, Alamod 0.5 parts.
  • the solubilizing component is the same as in Example 1.
  • Quantitative index is the same as embodiment 1.
  • mice in the first two groups measured their basic response indicators to pain, that is, the paw withdrawal time to a fixed pain threshold, and then injected carrageen into the feet of the mice with inflammation in the first two groups to prepare the inflammation. Pain model, then apply the microneedle patch and diclofenac sodium cream of this embodiment (i.e. Example 2) to the feet of the first two groups of inflammatory mice, and then measure the pain of the first two groups of mice at 30min, 60min, and 90min respectively Response indicators. The third group of mice was used as blank without any treatment (the pain threshold was measured synchronously).
  • Example 2 The results of single factor ANOVA analysis showed that there was a significant difference (P ⁇ 0.05) between Example 2 and the blank group in the paw withdrawal reaction time after medication, indicating that the active components of Example 2 had definite analgesic effect. At the same time, compared with Example 1, there is a statistically significant difference in the paw withdrawal reaction time after medication (P ⁇ 0.05), indicating that the analgesic effect of the active ingredient in Example 2 is significantly smaller than that in Example 1.
  • CIA type II collagen-induced arthritis
  • CIA collagen-induced arthritis
  • the rats were divided into an experimental group and a blank group, with 10 rats in each group.
  • the rats in the blank experimental group were not given any treatment.
  • the swelling index of the normal feet of the two groups of rats were measured before the experiment.
  • inject the CIA solution to the tail of the rats in the experimental group to prepare the arthritis model, measure the swelling degree of the arthritic feet of the rats on the 7th day after modeling, and after judging that the modeling is successful use the microneedles of Example 2 to the rats in the experimental group Patch, respectively, on the 7th day, the 14th day, and the 21st day to measure the swelling degree of the rat's foot.
  • Rats in the blank group were simultaneously measured for foot swelling.
  • the effect of microneedle patch on rat foot swelling is shown in Table 4
  • the result of statistical analysis shows that the swelling degree of mouse foot after the administration of Example 2 is obviously higher than that of Example 1 (P ⁇ 0.05), and the preliminary analysis result is that the weight portion of the active component of Example 2 is less than that of Example 1, and the anti-rheumatoid activity Intensity is lower than Example 1.
  • Example 1 The difference between this example and Example 1 is that the parts by weight of the active components are: 1 part of capsaicin, 5 parts of melittin, 5 parts of lidocaine, 20 parts of tripterygium glycosides, 20 parts of total glycosides of paeony, Alamode 5 servings.
  • the solubilizing component is the same as in Example 1.
  • Example 1 The preparation method of the biodegradable microneedle patch suitable for paralysis and pain provided in this example is "Example 1".
  • mice Animal experiment 6: The analgesic effect of the microneedle patch was confirmed by the paw withdrawal reaction experiment of mice
  • Quantitative index is the same as embodiment 1.
  • mice in the first two groups measured their basic response indicators to pain, that is, the paw withdrawal time to a fixed pain threshold, and then injected carrageen into the feet of the mice with inflammation in the first two groups to prepare the inflammation. Pain model, then the microneedle patch of this embodiment (i.e. Example 3) and diclofenac sodium cream were applied to the feet of the first two groups of inflammatory mice, and then the pain of the first two groups of mice was measured at 30min, 60min, and 90min respectively Response indicators. The third group of mice was used as blank without any treatment (the pain threshold was measured synchronously).
  • Example 3 The results of single factor ANOVA analysis showed that there was a significant difference (P ⁇ 0.05) between Example 3 and the blank group in the paw withdrawal reaction time after the medication, which indicated that the active components of Example 3 had the effect of prolonging the pain threshold reaction time, and had the effect on inflammatory pain. Has inhibitory activity. Simultaneously, the paw withdrawal reaction time after the administration of Example 3 was significantly shorter than that of Example 1 (P ⁇ 0.05), indicating that the prolongation effect of the active components of Example 3 on the pain threshold was significantly lower than that of Example 1.
  • Example 3 The weight part of the active component is greater than that of Example 1, but the inhibitory effect on pain is lower than that of Example 1.
  • the reason for the analysis is that there is a peak of transdermal absorption in the transdermal delivery route of microneedles, and the skin absorbs the active component. There is a maximum amount, and when the maximum absorption value is exceeded, the absorption of the active ingredient by the skin reaches a bottleneck, and even if the concentration of the active ingredient is increased, the absorption of the active ingredient by the skin tends to be flat.
  • CIA type II collagen-induced arthritis
  • CIA collagen-induced arthritis
  • the rats were divided into an experimental group and a blank group, with 10 rats in each group.
  • the rats in the blank experimental group were not given any treatment.
  • the swelling index of the normal feet of the two groups of rats were measured before the experiment.
  • Example 3 the degree of swelling of mouse paws in Example 3 was significantly higher than that in Example 1 ((P ⁇ 0.05)), that is, the anti-rheumatoid activity of Example 3 was lower than that of Example 1.
  • Embodiment 3 active component weight portion is greater than embodiment 1, and anti-rheumatoid activity is lower than embodiment 1, except that skin has maximum absorption effect (increase active component concentration but skin absorption does not increase) to pharmaceutical active component through analysis
  • the drug loading of the needle layer of the microneedle patch also has a maximum value. Even if the drug loading of the needle layer is increased, the drug release efficiency of the needle layer does not necessarily increase.
  • preferred embodiment 1 active ingredient is a maximum value.

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Abstract

一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用，所述的组合物具有较低的刺激性、较快的起效速度和较强的镇痛作用，可治疗类风湿性关节炎肢体肿大和疼痛。

Description

一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用
本申请要求于2021年11月26日提交中国专利局、申请号为202111422821.0、发明名称为“一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，具体涉及一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用。
背景技术
临床上治疗类风湿性关节炎的药物总体上可分为三类：非甾体抗炎药、激素类药物、改善病情抗风湿药(DMARDs)；其中改善病情抗风湿药又分为传统合成DMARDs、生物制剂DMARDs和靶向合成DMARDs。
临床上用于治疗类风湿关节炎的非甾体抗炎药通常包括阿司匹林、布洛芬、等，该类药物多以口服为主，因“首过效应”药物消除严重，生物利用度低，其主要的不良反应为胃粘膜损伤，诱发和加重急性出血性胃炎和消化性溃疡。
临床上治疗类风湿关节炎的激素类药物通常包括地塞米松等糖皮质激素，该类药物以关节腔注射为主，起到对类风湿性关节炎的抗炎、消肿、缓解麻痹疼痛，其用药方式技术难度高，创伤性高易引起感染等并发症，患者依从性差，有研究表明即使是小剂量的糖皮质激素也能增加髋关节骨折的风险，不适合频繁给药。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种具有镇痛作用的组合物、微针贴片及其制备方法以及应用，本发明提供的组合物具有较低的刺激性、较快的起效速度和较强的镇痛作用，可治疗类风湿性关节炎肢体肿大和疼痛。
本发明提供了一种具有镇痛作用的组合物，包括以下重量份的组分：
1份的辣椒碱；
0.5～5份的蜂毒肽；
0.5～5份的利多卡因；
0.8～20份的雷公藤多苷；
0.8～20份的白芍总苷；
0.5～5份的艾拉莫德。
本发明还提供了一种用于治疗类风湿关节炎麻痹疼痛生物可降解的微针贴片，所述微针贴片中活性组分包括权利要求1所述的组合物。
优选的，所述微针贴片包括基衬层和针体层，所述针体层包括所述活性组分。
优选的，所述针体层由活性组分、增溶组分、高分子生物可降解聚合物骨架材料加工制备而成。
优选的，所述增溶组份包括乙醇、吐温80、丙二醇、聚乙二醇400、甘油和倍他环糊精中的一种或多种；
所述高分子生物可降解聚合物骨架材料选自聚乳酸、聚乙二醇二丙烯酸酯、聚乙醇酸、聚已内酯、聚碳酸酯等聚合物中的一种或多种。
优选的，所述微针贴片的针体层的针高800～1000μm，针体基底宽度200～400μm。
优选的，所述基衬层选自由聚维酮K90和聚谷氨酸钠中的一种或多种构成。
本发明还提供了一种上述微针贴片的制备方法，包括以下步骤：
A)将活性组分、增溶组分、高分子生物可降解聚合物骨架材料混合均匀，得针体层原液，取针体层原液浇注到微针母模板中，经高速离心后使原液均匀填充于微针母模板的针腔中，干燥后针腔中形成针体层；
B)将基衬层材料用去离子水溶散得基衬层原液，再将基衬层原液浇注到上述微针母模板的上方，覆盖针体层，经高速离心后干燥，使基衬层和针体层牢固结合并成型，随后剥离微针母模板，得到微针贴片。
优选的，所述微针母模板的制备方法包括以下步骤：
将母模板材料聚硅氧烷和固化剂直链淀粉置于去离子水中搅拌分散，随后加热至糊化，冷却溶胀后进行真空干燥，将脱气的干燥混合物置于不锈钢金属微针模板表面，置于恒温干燥器中固化干燥后取出，从金属微针上剥离即可获得针体的聚硅氧烷微针母模板。
本发明还提供了一种上述组合物在制备适用于治疗治疗类风湿关节炎麻痹疼痛的药物中的应用。
与现有技术相比，本发明提供了一种具有镇痛作用的组合物，包括以下重量份的组分：辣椒碱1份、蜂毒肽0.5～5份、利多卡因0.5～5份、雷公藤多苷0.8～20份、白芍总苷0.8～20份、艾拉莫德0.5～5份。本发明以辣椒碱、蜂毒肽、利多卡因、雷公藤多苷、白芍总苷、艾拉莫德为活性组分，6种活性组分的组合配伍有协同增效的作用，具有明显的抗类风湿性关节炎和缓解关节麻痹疼痛的作用。其中，辣椒碱为主要的镇痛成分，蜂毒肽具有强烈的抗炎活性，同时对关节软骨细胞具有保护作用，两者相须为用，蜂毒肽消炎的同时可以提高辣椒碱的镇痛效果，降低辣椒碱的剂量。利多卡因可以消除辣椒碱对皮肤组织辛辣、刺激的不良反应，同时有局部麻醉镇痛作用。艾拉莫德能抑制炎性细胞因子、肿瘤坏死因子、淋巴细胞以及免疫球蛋白的产生，具有自身免疫调节作用。雷公藤多苷和白芍总苷有免疫抑制作用，与艾拉莫德有协同抗风湿作用。
另外，本发明将活性组分与特定用法用量的增溶组分、生物可降解骨架材料，通过特定制备方法制成穿刺性能良好的生物可降解微针，该微针能刺破角质层并产生释药微通道，可增加药物的渗透性、利用度和起效速度，将药物以微创方式输送到患者关节滑膜中，能给迅速起到镇痛作用，并随着药物的释放起效起到抗类风湿关节炎的作用。
具体实施方式
本发明提供了一种具有镇痛作用的组合物，包括以下重量份的组分：辣椒碱1份、蜂毒肽0.5～5份、利多卡因0.5～5份、雷公藤多苷0.8～20份、白芍总苷0.8～20份、艾拉莫德0.5～5份。
在本发明中，所述具有镇痛作用的组合物以1重量份的辣椒碱为基准，包括0.5～5份的蜂毒肽，优选为0.5、1、1.5、2、2.5、3、3.5、4、4.5、5，或0.5～5份之间的任意值。
所述具有镇痛作用的组合物还包括0.5～5份的利多卡因，优选为0.5、1、1.5、2、2.5、3、3.5、4、4.5、5，或0.5～5份之间的任意值。
所述具有镇痛作用的组合物还包括0.8～20份雷公藤多苷，优选为0.8、1、2、3、4、5、7、10、12、15、18、20，或0.8～20份之间的任意值。
所述具有镇痛作用的组合物还包括0.8～20份白芍总苷，优选为0.8、1、2、3、4、5、7、10、12、15、18、20，或0.8～20份之间的任意值。
所述具有镇痛作用的组合物还包括0.5～5份的艾拉莫德，优选为0.5、1、1.5、2、2.5、3、3.5、4、4.5、5，或0.5～5份之间的任意值。
本发明还提供了一种用于治疗类风湿关节炎麻痹疼痛生物可降解的微针贴片，所述微针贴片中活性组分包括上述组合物。具体可以用于关节滑膜炎的治疗。
本发明将所述具有强效镇痛作用的活性组分制备成刺激性低、起效快、生物可降解的微针贴片，该微针贴片具有缓解侵蚀性滑囊炎疼痛的作用。
本发明将组合物用于微针贴片中，微针的直径通常为几百微米的级别，其仅可穿透皮肤的表皮和上皮部位，不伤及真皮中的毛细血管和神经，微针结合药物治疗可实现化药或生物制品的全身或局部的药物递送，属于微创的、半侵入式的经皮给药系统。微针经皮给药的方式可实现药物由表皮向体内局部或全身递送，避免胃肠道的降解的同时避开了肝脏的“首过效应”，具有微创性，患者依从性好，可实现自行给药。生物可降解微针通过基质的降解实现药物的释放，基质材料可降解为无毒成分并通过身体代谢途径实现体内清除。
本发明适用于类风湿性关节炎麻痹疼痛的微针贴片，是一种全新的治疗类风湿性关节炎麻痹疼痛的治疗方式，微针的锥形三维结构可以刺穿皮肤厚约10-20μm的角质层并产生释药微通道，因微针突破经皮给药的皮肤屏障，可增加药物的渗透性、利用度和起效速度，将药物以微创方式输送到患者关节滑膜中，起到快速镇痛和抑制类风湿性关节炎的作用。
本发明提供的微针贴片包括基衬层和针体层，所述针体层包括所述活性组分。
在本发明中，所述针体层由活性组分、增溶组分、高分子生物可降解聚合物骨架材料加工制备而成。
其中，所述增溶组份包括乙醇、吐温80、丙二醇、聚乙二醇400、甘油和倍他环糊精中的一种或多种；所述倍他环糊精选自羟丙基倍他环糊精、羟乙基倍他环糊精、甲基倍他环糊精、磺丁基倍他环糊精钠其中的一种或多种。
所述高分子生物可降解聚合物骨架材料选自聚乳酸、聚乙二醇二丙烯酸 酯、聚乙醇酸、聚已内酯、聚碳酸酯等聚合物中的一种或多种。
在本发明中，所述活性组分、增溶组分、高分子生物可降解聚合物骨架材料的质量比为1：(1.5～22.5)：(0.3～4.5)，优选为1：(2～20)：(0.5～4)，进一步优选为1：(5～15)：(1～2)。
在本发明中，所述微针贴片的针体层的针高800～1000μm，优选为800、900、1000，或800～1000μm之间的任意值，针体基底宽度200～400μm，优选为200、300、400，或200～400μm之间的任意值。
所述微针贴片上的针体呈阵列排布，相邻针体的距离为100～300μm，优选为100、200、300，或100～300μm之间的任意值。在本发明的一些具体实施方式中，所述针体为10*10排布的针体，即针体共10排，每排10个。
在本发明中，所述基衬层选自由聚维酮K90和聚谷氨酸钠中的一种或多种构成。所述基衬层的厚度为50～500μm，优选为100～400μm，进一步优选为200～300μm。
本发明还提供了一种上述微针贴片的制备方法，包括以下步骤：
A)将活性组分、增溶组分、高分子生物可降解聚合物骨架材料混合均匀，得针体层原液，取针体层原液浇注到微针母模板中，经高速离心后使原液均匀填充于微针母模板的针腔中，干燥后针腔中形成针体层；
B)将基衬层材料用去离子水溶散得基衬层原液，再将基衬层原液浇注到上述微针母模板的上方，覆盖针体层，经高速离心后干燥，使基衬层和针体层牢固结合并成型，随后剥离微针母模板，得到微针贴片。
具体的，本发明首先制备微针母模板，所述微针母模板的制备方法包括以下步骤：
将母模板材料聚硅氧烷和固化剂直链淀粉置于去离子水中搅拌分散，随后加热至糊化，冷却溶胀后进行真空干燥，将脱气的干燥混合物置于不锈钢金属微针模板表面，置于恒温干燥器中固化干燥后取出，从金属微针上剥离即可获得针体的聚硅氧烷微针母模板。
其中，所述聚硅氧烷选自聚二甲基硅氧烷、环甲基硅氧烷、氨基硅氧烷、聚甲基苯基硅氧烷、聚醚聚硅氧烷共聚物等一种或多种。
所述糊化的温度为65～85℃，优选为70～80℃。
本发明还提供了一种上述组合物在制备适用于治疗类风湿关节炎麻痹疼痛的药物中的应用。
本发明还提供了一种上述组合物在制备适用于治疗自身免疫性、侵蚀性关节滑膜炎麻痹疼痛的药物中的应用。
所述药物的制剂形式可以为微针贴片、贴剂、贴膏剂、凝胶剂、乳膏剂、软膏剂。
本发明以辣椒碱、蜂毒肽、利多卡因、雷公藤多苷、白芍总苷、艾拉莫德为活性组分，6种活性组分的组合配伍有协同增效的作用，具有明显的抗类风湿性关节炎和缓解关节麻痹疼痛的作用。其中，辣椒碱为主要的镇痛成分，蜂毒肽具有强烈的抗炎活性，同时对关节软骨细胞具有保护作用，两者相须为用，蜂毒肽消炎的同时可以提高辣椒碱的镇痛效果，降低辣椒碱的剂量。利多卡因可以消除辣椒碱对皮肤组织辛辣、刺激的不良反应，同时有局部麻醉镇痛作用。艾拉莫德能抑制炎性细胞因子、肿瘤坏死因子、淋巴细胞以及免疫球蛋白的产生，具有自身免疫调节作用。雷公藤多苷和白芍总苷有免疫抑制作用，与艾拉莫德有协同抗风湿作用。
另外，本发明将活性组分与特定用法用量的增溶组分、生物可降解骨架材料，通过特定制备方法制成穿刺性能良好的生物可降解微针，该微针能刺破角质层并产生释药微通道，可增加药物的渗透性、利用度和起效速度，将药物以微创方式输送到患者关节滑膜中，能给迅速起到镇痛作用，并随着药物的释放起效起到抗类风湿关节炎的作用。
为了进一步理解本发明，下面结合实施例对本发明提供的具有镇痛作用的组合物、微针贴片及其制备方法以及应用进行说明，本发明的保护范围不受以下实施例的限制。
对比例1
本实施例与实施例1的区别仅在于，活性组分仅包含辣椒碱1份、蜂毒肽3份、利多卡因3份，其余同实施例1。
对比例2
本实施例与实施例1的区别仅在于，活性组分仅包含雷公藤多苷8份、白芍总苷8份、艾拉莫德3份
对比例3
本实施例与实施例1的区别仅在于，高分子可生物降解的聚合物骨架材料包含聚乙醇酸13份，辅以增粘剂乳糖5份，其余同实施例1。
实施例1
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片，由基衬层和针体层构成，其中，所述针体层由活性组分、增溶组分、高分子生物可降解聚合物骨架材料构成；其中，基衬层由聚维酮K90、聚谷氨酸钠构成。
本实施例中活性组分包含：辣椒碱1份、蜂毒肽3份、利多卡因3份、雷公藤多苷8份、白芍总苷8份、艾拉莫德3份。其中，活性组分的增溶组分为乙醇35份、吐温80 3份、丙二醇3份、聚乙二醇400 3份、甘油3份、磺丁基倍他环糊精钠10份、水35份。将活性组分与增溶组分搅拌混合并分散均匀，得活性组分水溶液。
本实施例中高分子生物可降解的聚合物骨架材料包含：聚乙二醇二丙烯酸酯13份，辅以增粘剂乳糖5份。
本实施例中基衬层包含：聚维酮K90 2份、聚谷氨酸钠3份
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片的加工制备方法如下：
制备聚硅氧烷微针母模板：将母模板材料聚硅氧烷(本案例选择聚二甲基硅氧烷)和固化剂直链淀粉置于去离子水中搅拌分散，随后加热至70℃糊化，冷却溶胀后进行真空干燥，将脱气的干燥混合物置于市售的不锈钢金属微针模板表面，金属微针模板有10*10排列的针体，针高900μm，针体基底宽度300μm，置于恒温干燥器中固化干燥后取出，从金属微针上轻轻剥离即可获得10*10针体的聚硅氧烷微针母模板。
制备针体层：将所述活性组分、包合物、高分子生物可降解聚合物骨架材料混合均匀，得针体层原液，取针体层原液浇注到微针母模板中，经高速离心后使原液均匀填充于微针母模板的针腔中，干燥后针腔中形成针体层。
制备基衬层：将基衬层材料用去离子水溶散得基衬层原液，再将基衬层原液浇注到上述微针母模板的上方，覆盖针体层，经高速离心后干燥，使基衬层和针体层牢固结合并成型，随后剥离微针母模板，即得自制微针贴片。
动物实验1：鼠皮穿刺实验确认针体层的机械强度
取剃净毛发的鼠皮，剔除鼠皮内侧的肌肉和脂肪组织，使用生理盐水清洗，并用吸水纸吸干鼠皮表面水分。将鼠皮外侧面朝上放置，使用实施例1和对比例1～3制备的微针贴片按压鼠皮5min，用4％台盼蓝溶液染色1min，并用棉签擦拭鼠皮表面残留的台盼蓝溶液至干净，通过观察鼠皮上微针形成的孔洞，判断微针的穿刺效果。
穿刺结果：实施例1、对比例1和对比例2微针穿刺的鼠皮形成致密、均匀分布的蓝色孔洞，穿刺结果良好；对比例3微针穿刺的鼠皮形成稀疏、少量分布的浅蓝色孔洞，穿刺结果不良；说明针体层选用聚乙二醇二丙烯酸酯和乳糖为骨架材料的机械硬度较好，穿刺性能优良。故针体层骨架材料优选为聚乙二醇二丙烯酸酯和乳糖。
动物实验2：小鼠压板缩爪反应实验确认微针贴片的镇痛作用
小鼠压板缩爪反应模型的制备：小鼠后足注入鹿角菜制备炎症痛模型。
量化指标：对炎症痛模型小鼠使用实施例1和对比例1-3制备的微针贴片，通过智能热板仪测量炎症小鼠后爪缩爪反应潜伏期，作为微针贴片对炎症小鼠镇痛作用的衡量指标。
量化实验分为五组，每组10只小鼠。前四组小鼠在实验前分别测定其对疼痛的基础反应指标，即对固定痛阈的缩足时间，随后给前四组炎症小鼠足部注射鹿角菜制备炎症痛模型，再对前四组炎症小鼠足部分别施用实施例1微针贴片、对比例1微针贴片、对比例2微针贴片、双氯芬酸钠乳膏，随后在30min、60min、90min分别测量前四组小鼠的疼痛反应指标。第五组小鼠作为空白不作任何处理(同步测量其痛阈)。
数据均采用SPSS(23.0版)统计软件进行分析，计量资料采用“均数±标准差(X±S)表示”，多组间均数比较采用单因素方差分析，两组间均数比较采用独立样本t检验，组内前后均数比较采用配对样本t检验，以P＜0.05表示差异具有统计学意义。
微针贴片对小鼠压板实验镇痛作用的影响见表1所示
表1小鼠压板实验结果
Figure PCTCN2021135663-appb-000001
单因素ANOVA分析结果表明，从实验结果可知，对比例1组与双氯芬酸钠乳膏组比较，两组小鼠对固定痛阈的缩足时间没有明显的区别(P＞0.05)，说明活性组分仅包含辣椒碱、蜂毒肽、利多卡因有明显的镇痛作用；与空白组比较，实施例1、对比例1和对比例2微针贴片均有不同强度的镇痛作用(P＜0.05)，强度依次递减。活性组分包含辣椒碱、蜂毒肽、利多卡因、雷公藤多苷、白芍总苷、艾拉莫德的组合镇痛强度最强。
动物实验3：Ⅱ型胶原诱导关节炎(CIA)大鼠模型实验确认微针贴片抗类风湿性关节炎作用
Ⅱ型胶原诱导型关节炎(CIA)溶液的配置：用0.1M的醋酸溶液溶解Ⅱ型胶原蛋白，配制成浓度为2g/L的Ⅱ型胶原乙酸溶液；再使用2g/L牛Ⅱ型胶原乙酸溶液与与等体积的不完全弗氏佐剂(IFA)充分混合乳化，得CIA溶液。
Ⅱ型胶原诱导关节炎(CIA)大鼠模型的建立：每只大鼠尾根部皮内注射0.2ml的CIA溶液，第7天用同样方法进行第2次免疫，每只大鼠尾根部皮内注射0.1ml的CIA溶液。注射两周后观察大鼠足部小趾关节轻微肿胀，即可判断大鼠关节炎建模成功。
实验将大鼠分为实验组和空白组，每组10只大鼠，空白实验组大鼠不作任何处理，两组大鼠在实验前分别测量其正常足部的肿胀度指标。随后给实验组大鼠尾部注射CIA溶液制备关节炎模型，建模后的第7天测量大鼠关节炎足部的肿胀度，判断建模成功后，给实验组大鼠使用实施例1微针贴片，分别在第7天、第14天、第21天分别测量大鼠足部的肿胀度。空白组大鼠同步测量足部肿胀度。使用微针贴片对大鼠足部肿胀度的影响见表2
表2大鼠足部肿胀度实验结果
Figure PCTCN2021135663-appb-000002
经配对样本t检验，实施例1大鼠在建模后第七天的足部肿胀度与实验前有明显的差异(P＜0.05)，说明该组大鼠建模成功；实施例1大鼠用药后的第7天、第14天、第21天的足部肿胀度与实验前的差异不明显(P＞0.05)，说明实施例1含活性组分的微针贴片具有抗类风湿关节炎的作用。
实施例2
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片，其结构和组成同“实施例1”。
本实施例与实施例1的区别在于，活性组分的重量份为：辣椒碱1份、蜂毒肽0.5份、利多卡因0.5份、雷公藤多苷0.8份、白芍总苷0.8份、艾拉莫德0.5份。增溶组分同实施例1。
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片的加工制备方法同“实施例1”。
动物实验4：小鼠压板缩爪反应实验确认微针贴片的镇痛作用
小鼠压板缩爪反应模型的制备同实施例1。
量化指标同实施例1。
量化实验分为三组，前二组小鼠在实验前分别测定其对疼痛的基础反应指标，即对固定痛阈的缩足时间，随后给前二组炎症小鼠足部注射鹿角菜制备炎症痛模型，再对前二组炎症小鼠足部分别施用本实施例(即实施例2)微针贴片和双氯芬酸钠乳膏，随后在30min、60min、90min分别测量前二组小鼠的疼痛反应指标。第三组小鼠作为空白不作任何处理(同步测量其痛阈)。
本例微针贴片对小鼠压板实验镇痛作用的影响见表3所示
表3小鼠压板实验结果
Figure PCTCN2021135663-appb-000003
Figure PCTCN2021135663-appb-000004
单因素ANOVA分析结果表明，用药后的缩足反应时间，实施例2与空白组存在明显的差异(P＜0.05)，说明实施例2的活性组分具有确切的镇痛作用。同时，实施例2与实施例1比较，用药后缩足反应时间的差异具有统计学意义(P＜0.05)，说明实施例2活性组分的镇痛作用明显小于实施例1。
动物实验5：Ⅱ型胶原诱导关节炎(CIA)大鼠模型实验确认微针贴片抗类风湿性关节炎作用
Ⅱ型胶原诱导型关节炎(CIA)溶液的配制同实施例1。
Ⅱ型胶原诱导关节炎(CIA)大鼠模型的建立同实施例1。
实验将大鼠分为实验组和空白组，每组10只大鼠，空白实验组大鼠不作任何处理，两组大鼠在实验前分别测量其正常足部的肿胀度指标。随后给实验组大鼠尾部注射CIA溶液制备关节炎模型，建模后的第7天测量大鼠关节炎足部的肿胀度，判断建模成功后，给实验组大鼠使用实施例2微针贴片，分别在第7天、第14天、第21天分别测量大鼠足部的肿胀度。空白组大鼠同步测量足部肿胀度。使用微针贴片对大鼠足部肿胀度的影响见表4
表4大鼠足部肿胀度实验结果
Figure PCTCN2021135663-appb-000005
经配对样本t检验，实施例2大鼠在建模后第七天的足部肿胀度与实验前有明显的差异(P＜0.05)，说明该组大鼠建模成功；实施例2大鼠用药后的第7天、第14天、第21天的足部肿胀度与建模后的差异明显(P＜0.05)，说明大鼠在关节炎诱导足部肿胀后，使用实施例2微针贴片后第七天开始对鼠足炎症肿胀具有改善和抑制作用。同时，统计分析结果表明实施例2用药后鼠足的肿胀度明显高于实施例1(P＜0.05)，初步分析结果为实施例2活性组分的重量份小于实施例1，抗类风湿活性强度低于实施例1。
实施例3
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片，其结构和组成同“实施例1”。
本实施例与实施例1的区别在于，活性组分的重量份为：辣椒碱1份、蜂毒肽5份、利多卡因5份、雷公藤多苷20份、白芍总苷20份、艾拉莫德5份。增溶组分同实施例1。
本实施例提供的适用于麻痹疼痛的生物可降解的微针贴片的加工制备方法“实施例1”。
动物实验6：小鼠压板缩爪反应实验确认微针贴片的镇痛作用
小鼠压板缩爪反应模型的制备同实施例1。
量化指标同实施例1。
量化实验分为三组，前二组小鼠在实验前分别测定其对疼痛的基础反应指标，即对固定痛阈的缩足时间，随后给前二组炎症小鼠足部注射鹿角菜制备炎症痛模型，再对前二组炎症小鼠足部分别施用本实施例(即实施例3)微针贴片和双氯芬酸钠乳膏，随后在30min、60min、90min分别测量前二组小鼠的疼痛反应指标。第三组小鼠作为空白不作任何处理(同步测量其痛阈)。
本例微针贴片对小鼠压板实验镇痛作用的影响见表5所示
表5小鼠压板实验结果
Figure PCTCN2021135663-appb-000006
单因素ANOVA分析结果表明，用药后的缩足反应时间，实施例3与空白组存在明显的差异(P＜0.05)，说明实施例3活性组分具有延长痛阈反应时间的作用，对炎症疼痛具有抑制活性。同时，实施例3用药后缩足反应时间明显小于实施例1(P＜0.05)，说明实施例3活性组分对痛阈的延长作用明显低于实施例1。实施例3活性组分重量份大于实施例1，而对疼痛的抑制作用低于实施例1，分析原因为微针的透皮给药途径存在透皮吸收的峰值，皮肤对活性 组分的吸收存在最大量，超过吸收最大值时皮肤对活性组分的吸收达到瓶颈，即使增加活性组分的浓度，皮肤对其吸收趋于平缓。
动物实验7：Ⅱ型胶原诱导关节炎(CIA)大鼠模型实验确认微针贴片抗类风湿性关节炎作用
Ⅱ型胶原诱导型关节炎(CIA)溶液的配制同实施例1。
Ⅱ型胶原诱导关节炎(CIA)大鼠模型的建立同实施例1。
实验将大鼠分为实验组和空白组，每组10只大鼠，空白实验组大鼠不作任何处理，两组大鼠在实验前分别测量其正常足部的肿胀度指标。
随后给实验组大鼠尾部注射CIA溶液制备关节炎模型，建模后的第7天测量大鼠关节炎足部的肿胀度，判断建模成功后，给实验组大鼠使用实施例3微针贴片，分别在第7天、第14天、第21天分别测量大鼠足部的肿胀度。空白组大鼠同步测量足部肿胀度。使用微针贴片对大鼠足部肿胀度的影响见表6
表6大鼠足部肿胀度实验结果
Figure PCTCN2021135663-appb-000007
经配对样本t检验，实施例3大鼠在建模后第七天的足部肿胀度与实验前有明显的差异(P＜0.05)，说明该组大鼠建模成功；实施例3大鼠用药后的第7天、第14天、第21天的足部肿胀度与建模后的差异明显(P＜0.05)，说明大鼠在关节炎诱导足部肿胀后，使用实施例3微针贴片后第七天开始对鼠足炎症肿胀具有改善和抑制作用。同时，统计分析结果表明实施例3用药后鼠足的肿胀度明显高于实施例1((P＜0.05))，即实施例3抗类风湿活性强度低于实施例1。实施例3活性组分重量份大于实施例1，而抗类风湿活性低于实施例1，经分析除皮肤对药物活性组分存在最大吸收效应(增加活性组分浓度而皮肤吸收不增加)的因素外，还应考虑到微针贴片针体层的载药量也存在最大值，即使增加针体层的载药量，针体层的释药效率不一定增加。综合比较，优选实施例1活性组分。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通 技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种具有镇痛作用的组合物，其特征在于，包括以下重量份的组分：
    1份的辣椒碱；
    0.5～5份的蜂毒肽；
    0.5～5份的利多卡因；
    0.8～20份的雷公藤多苷；
    0.8～20份的白芍总苷；
    0.5～5份的艾拉莫德。
  2. 一种用于治疗类风湿关节炎麻痹疼痛生物可降解的微针贴片，其特征在于，所述微针贴片中活性组分包括权利要求1所述的组合物。
  3. 根据权利要求2所述的微针贴片，其特征在于，包括基衬层和针体层，所述针体层包括所述活性组分。
  4. 根据权利要求3所述的微针贴片，其特征在于，所述针体层由活性组分、增溶组分、高分子生物可降解聚合物骨架材料加工制备而成。
  5. 根据权利要求4所述的微针贴片，其特征在于，所述增溶组份包括乙醇、吐温80、丙二醇、聚乙二醇400、甘油和倍他环糊精中的一种或多种；
    所述高分子生物可降解聚合物骨架材料选自聚乳酸、聚乙二醇二丙烯酸酯、聚乙醇酸、聚已内酯、聚碳酸酯等聚合物中的一种或多种。
  6. 根据权利要求3所述的微针贴片，其特征在于，所述微针贴片的针体层的针高800～1000μm，针体基底宽度200～400μm。
  7. 根据权利要求3所述的微针贴片，其特征在于，所述基衬层选自由聚维酮K90和聚谷氨酸钠中的一种或多种构成。
  8. 一种如权利要求1～7任意一项所述的微针贴片的制备方法，其特征在于，包括以下步骤：
    A)将活性组分、增溶组分、高分子生物可降解聚合物骨架材料混合均匀，得针体层原液，取针体层原液浇注到微针母模板中，经高速离心后使原液均匀填充于微针母模板的针腔中，干燥后针腔中形成针体层；
    B)将基衬层材料用去离子水溶散得基衬层原液，再将基衬层原液浇注到 上述微针母模板的上方，覆盖针体层，经高速离心后干燥，使基衬层和针体层牢固结合并成型，随后剥离微针母模板，得到微针贴片。
  9. 根据权利要求8所述的制备方法，其特征在于，所述微针母模板的制备方法包括以下步骤：
    将母模板材料聚硅氧烷和固化剂直链淀粉置于去离子水中搅拌分散，随后加热至糊化，冷却溶胀后进行真空干燥，将脱气的干燥混合物置于不锈钢金属微针模板表面，置于恒温干燥器中固化干燥后取出，从金属微针上剥离即可获得针体的聚硅氧烷微针母模板。
  10. 一种如权利要求1所述的组合物在制备适用于治疗治疗类风湿关节炎麻痹疼痛的药物中的应用。
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