WO2022183679A1 - 一种经皮肤给药层 - Google Patents

一种经皮肤给药层 Download PDF

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WO2022183679A1
WO2022183679A1 PCT/CN2021/111213 CN2021111213W WO2022183679A1 WO 2022183679 A1 WO2022183679 A1 WO 2022183679A1 CN 2021111213 W CN2021111213 W CN 2021111213W WO 2022183679 A1 WO2022183679 A1 WO 2022183679A1
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parts
heat transfer
sustained
drug delivery
release
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PCT/CN2021/111213
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English (en)
French (fr)
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张铿
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张铿
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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
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic 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
    • A61K47/30—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A61M2205/368—General characteristics of the apparatus related to heating or cooling by electromagnetic radiation, e.g. IR waves

Definitions

  • the present invention relates to the technical field of drug delivery devices, in particular to a transdermal drug delivery layer.
  • the bruise When the body is accidentally bruised during exercise, the bruise is manifested as bloodstains, epidermal peeling, oozing or bleeding spots, followed by an inflammatory reaction, local redness, swelling and pain. Self-healing, the wound will be healed in 3 days; however, for severe abrasions, gauze is currently used, but this treatment method does not promote inflammation, and it is still treated through the body's healing function.
  • the purpose of the present invention is to provide a transdermal drug delivery layer, which combines graphene, nano-silica and polyolefin with heat transfer components with graphene, nano-silica and polyolefin to form a sustained-release drug , by receiving infrared radiation on the sustained-release layer, so that the sustained-release drug of the sustained-release layer can slowly release the effective components on the skin surface.
  • a transdermal drug delivery layer comprising in turn: a heating layer and a sustained release layer;
  • the heating layer has a heating function, and is used for urging the sustained-release layer to release the sustained-release drug in a heated state, and the heating temperature is 40-60° C.; the sustained-release layer is attached to the affected part of the skin;
  • the sustained-release drug includes: a heat transfer component and an effective component, and in terms of mass percentage, the ratio between the heat transfer component and the effective component is (0.1-10): 1;
  • the heat transfer components include: graphene, nano-silica and polyolefin;
  • the effective components include: liposomes, and cholesterol, electrolytes and drugs in the liposomes respectively; the phase transition temperature of the liposomes is 40-60 DEG C, and the membrane is removed at the phase transition temperature, The drug is released outside the membrane; the liposome includes: distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline.
  • the effective components in parts by mass, include: 20-30 parts of liposomes, 1-5 parts of cholesterol, 20-25 parts of electrolytes and 20-25 parts of drugs.
  • the distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline are mixed in a mass ratio of (1-3):1.
  • the heat transfer component further includes: polyvinyl alcohol and polyvinylpyrrolidone.
  • the heat transfer components in parts by mass, include: 15-25 parts of polyolefin, 30-45 parts of nano-silicon dioxide, 30-45 parts of graphene, 8-10 parts of polyolefin. Vinyl alcohol and 15-19 parts of polyvinylpyrrolidone.
  • the heat transfer components in parts by mass, include: 30-45 parts of graphene, 30-45 parts of nano-silicon dioxide and 15-25 parts of polyolefin.
  • the heating layer is equipped with an intensity-adjustable infrared device.
  • the heating layer is provided with a transparent medicine tank; the irradiation end of the infrared device illuminates the medicine tank.
  • the irradiating ends of the infrared device there are multiple irradiating ends of the infrared device and are arranged in sequence, and the irradiating ends irradiate the sustained-release layer intermittently.
  • the transdermal drug delivery layer can be used for anti-inflammatory on the affected part of the skin, and the effective components of the slow-release layer are heated through the heating layer, so that the electrolytes and drugs in the effective components are slowly released to the skin surface, and the drug can be released on the skin.
  • the drug is released over a long period of time, and the affected area of the skin is healed by the drug.
  • a transdermal drug delivery layer comprising in turn: a heating layer and a sustained release layer;
  • the heating layer has a heating function, and is used for urging the sustained-release layer to release the sustained-release drug in a heated state, and the heating temperature is 40-60° C.; the sustained-release layer is attached to the affected part of the skin;
  • the sustained-release drug includes: a heat transfer component and an effective component, and in terms of mass percentage, the ratio between the heat transfer component and the effective component is (0.1-10): 1;
  • the heat transfer components include: graphene, nano-silica and polyolefin;
  • the effective components include: liposomes, and cholesterol, electrolytes and drugs in the liposomes respectively; the phase transition temperature of the liposomes is 40-60 DEG C, and the membrane is removed at the phase transition temperature, The drug is released outside the membrane; the liposome includes: distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline.
  • the transdermal drug delivery layer can be used for anti-inflammatory on the affected part of the skin, and the effective components of the slow-release layer are heated through the heating layer, so that the electrolytes and drugs in the effective components are slowly released to the skin surface, and the drug can be released on the skin.
  • the drug is released over a long period of time, and the affected area of the skin is healed by the drug.
  • the heating layer is a non-medicating layer, which can be the carrier of the slow-release layer or be provided separately from the slow-release layer; when the slow-release layer is applied to the affected part of the skin, it is only necessary to activate the heating function of the heating layer, and the infrared light from the heating layer will be emitted from the heating layer. It will be irradiated on the slow-release layer; while the slow-release layer is made of graphene, nano-silica and polyolefin, because the thermal conductivity of graphene, nano-silica and polyolefin decreases in a gradient shape, because the effective components will interact with the heat transfer layer.
  • the components are mixed, so the temperature of the effective components can be controlled only by controlling the ratio of graphene, nano-silica and polyolefin; at the same time, graphene, nano-silica and polyolefin in the heat transfer component
  • the overall particle size of the olefin is larger than that of the effective component, so it can increase the overall volume of the buffering drug, and its heat transfer component has a large heat transfer area, which is conducive to promoting distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline
  • the two alkalis interact with the lipid layer of the skin stratum corneum and disintegrate, which can change the keratin lipid structure and further reduce the keratin barrier, so that electrolytes and drugs can act on the affected part of the skin; The affected area is more likely to absorb the drug.
  • Distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline are liposomes, which can release drugs at a temperature of 40-60 °C; wherein, the phase transition temperature of distearoyl phosphatidyl choline is 50 -60 °C, the phase transition temperature of dimyristoyl phosphatidylcholine is 20-30 °C, and the phase transition temperature can be controlled within 40-60 °C by reasonably mixing the two liposomes with a certain comparison. And at the phase transition temperature, the membrane fluidity of the thermosensitive liposome is enhanced, so that the drug can be released to the affected area.
  • This scheme increases cholesterol in the liposome, which can improve the rigidity of the liposome, prevent the drug from breaking when it contacts the heat transfer component, and improve the stability of the drug in the lipid.
  • the in parts by mass it includes: 20-30 parts of liposomes, 1-5 parts of cholesterol, 20-25 parts of electrolytes and 20-25 parts of drugs.
  • the distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline are mixed in a mass ratio of (1-3):1.
  • the heat transfer component further includes: polyvinyl alcohol and polyvinylpyrrolidone.
  • Polyvinyl alcohol is made of pharmaceutical grade polyvinyl alcohol, which has good biocompatibility. When it is released to the skin, it can promote the formation of a layer of film attached to the surface of the skin and enhance the bonding effect of the drug on the skin.
  • Polyvinylpyrrolidone is physiologically inert, does not stimulate the skin and mucous membranes, etc. It can increase the hydrophilicity and lubricity of drugs in polyvinyl alcohol, making it easier for drugs to move in polyvinyl alcohol; when polyvinyl alcohol and polyvinylpyrrolidone are used at the same time It can increase the sustained release amount of the drug by a small amount.
  • the heat transfer components in parts by mass, include: 15-25 parts of polyolefin, 30-45 parts of nano-silicon dioxide, 30-45 parts of graphene, 8-10 parts of polyolefin. Vinyl alcohol and 15-19 parts of polyvinylpyrrolidone.
  • the heat transfer component in parts by mass, comprises: 30-45 parts of graphene, 30-45 parts of nano-silicon dioxide and 15-25 parts of polyolefin.
  • the heating layer is equipped with an intensity-adjustable infrared device.
  • the infrared device can emit infrared light, and its light intensity can be adjusted to realize the function of automatically adjusting the radiation temperature, so that the temperature in the slow-release layer is controllable, and the rate of the drug in the slow-release process is controllable. At the same time, the infrared device can partially act on the subcutaneous tissue, thereby promoting blood circulation and accelerating the absorption of drugs in the affected area.
  • the heating layer is provided with a transparent medicine tank; the irradiation end of the infrared device illuminates the medicine tank.
  • the medicine tank is used to place the medicine.
  • the irradiation end of the infrared device illuminates the medicine tank, since the medicine tank is transparent, it can transmit infrared light, and then the temperature of the slow-release layer is raised to 40-60°C; and when the temperature is too high or too low reduce the infrared radiation temperature.
  • the sustained-release layer is equivalent to a ring-shaped wearing object, which can be worn on the body; because the infrared device has a neatly arranged irradiation end, the irradiation end can be irradiated for the middle affected area in different positions; the irradiation end of this scheme is preferably intermittently irradiated On the slow-release layer, irradiate from left to right, the number of lights on is 3, and the lights will be temporarily turned off after lighting up. This cycle of irradiation can prevent local overheating of the slow-release layer; at the same time, the number of irradiation ends is not limited to the horizontal plane when they are arranged in sequence. , it can also be a ring structure or an arc structure.
  • the ratio between heat transfer components and effective components is 5:1;
  • the heat transfer components in parts by mass, include: 20 parts of polyolefin, 40 parts of nano-silica, and 40 parts of graphene; the polyolefin is polypropylene;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is aspirin.
  • the ratio between heat transfer components and effective components is 5:1;
  • Heat transfer components in parts by mass, including: 100 parts of polypropylene;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is aspirin.
  • the ratio between heat transfer components and effective components is 5:1;
  • Heat transfer components in parts by mass, including: 40 parts of nano-silica;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is aspirin.
  • the ratio between heat transfer components and effective components is 5:1;
  • Heat transfer components in parts by mass, including: 40 parts of graphene;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is aspirin.
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is aspirin.
  • the heat transfer component of 5g and the effective component of 1g in Example A and Comparative Examples A1-A3 were mixed in proportion; wherein the heat transfer component of blank group A4 was 1g;
  • the treatment effect was counted after 7 days; and the patient's diet, work and rest and activities were strictly controlled during the treatment process; no traditional Chinese medicine and western medicine, no physical therapy, and no excessively strenuous activities were allowed.
  • Grade 3 The clinical symptoms disappeared, the pain in the affected area dissipated, the activity function recovered, and the patient could move freely without any obstacle.
  • Grade 2 The pain in the affected area is relieved, although the patient cannot move freely, the movement disorder is reduced to mild, and the movement function is slightly recovered, and moderate activities can be performed.
  • Grade 1 There is no improvement in symptoms, or there is a possibility of accompanying exacerbation.
  • grades 3 to 2 are effective therapeutic effects, and the therapeutic effects of patients are shown in Table 1;
  • Example A As can be seen from Table 1, the heat transfer components of Example A used polyolefin, nano-silica and graphene as heat transfer components, and the effective components had uniform heat transfer during infrared irradiation, which ensured the effective components.
  • the sustained release rate is stable, not too high or too low, further ensuring that the effective components are still retained in the next infrared irradiation, so Example A has the best effective rate of 92%.
  • Comparative example A2 only uses nano-silica, and the thermal conductivity is moderate, which is located between polyolefin and graphene, and the efficiency is better than that of the embodiment using only nano-silica and graphene;
  • comparative example A3 only uses graphene, Graphene has good thermal conductivity. Due to its good thermal conductivity, heat is not easy to preserve, so that the effective component cannot reach 40-60 °C without infrared irradiation, so the treatment effect is not good, and only 60% effective.
  • Heat transfer components in parts by mass, including: 20 parts of polyolefin, 40 parts of nano-silica, 40 parts of graphene, 9 parts of polyvinyl alcohol and 16 parts of polyvinylpyrrolidone;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; the electrolyte is NaCl; the drug is Ginkgo biloba extract.
  • Heat transfer components in parts by mass, including: 15 parts of polyolefin, 45 parts of nano-silica, and 30 parts of graphene;
  • the active ingredients include: 20 parts of liposomes, 5 parts of cholesterol, 20 parts of electrolytes and 25 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; electrolyte is KCl; ginkgo biloba extract is used as medicine.
  • Heat transfer components in parts by mass, including: 20 parts of polyolefin, 40 parts of nano-silica, and 40 parts of graphene;
  • the active ingredients include: 25 parts of liposomes, 3 parts of cholesterol, 22 parts of electrolytes and 21 parts of drugs; liposomes are distearoyl phosphatidyl choline and dimyristoyl Phosphatidyl choline; distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline in a mass ratio of 1:1; electrolyte is KCl; ginkgo biloba extract is used as medicine.
  • Example B-Example D The active components of Example B-Example D are respectively mixed in proportion; before mixing, the active components are shaken by ultrasonic wave until they are evenly mixed; the sustained-release medicine prepared above is applied to the affected part of epidermal peeling caused by severe abrasion, Repeatedly and intermittently irradiate the affected area with infrared light for 15 minutes, and irradiate every 2 hours from 8:00 am to 8:00 pm;
  • the treatment effect was counted after 7 days; and the patient's diet, work and rest and activities were strictly controlled during the treatment process; no traditional Chinese medicine and western medicine, no physical therapy, and no excessively strenuous activities were allowed.
  • Grade 3 The clinical symptoms disappeared, the pain in the affected area dissipated, the activity function recovered, and the patient could move freely without any obstacle.
  • Grade 2 The pain in the affected area is relieved, although the patient cannot move freely, the movement disorder is reduced to mild, and the movement function is slightly recovered, and moderate activities can be performed.
  • Grade 1 There is no improvement in symptoms, or there is a possibility of accompanying exacerbation.
  • grades 3 to 2 are effective therapeutic effects, and the therapeutic effects of patients are shown in Table 2;

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Abstract

一种经皮肤给药层，依次包括，加热层和缓释层。加热层用于在加热状态下促使缓释层释放药物，加热温度为40-60℃。缓释层贴合于皮肤患处，缓释层包括，热传组分和有效组分。按质量百分比，热传组分与有效组分之间的比例为(0.1-10)：1。热传组分包括，石墨烯、纳米二氧化硅和聚烯烃。有效组分包括，脂质体、胆固醇、电解质和药物。脂质体的相变温度为40-60℃，脂质体包括：二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱。所述给药层用于对皮肤患处进行消炎，通过加热层对缓释层的加热，使有效组分内的电解质和药物缓释至皮肤表面。

Description

一种经皮肤给药层 技术领域
本发明涉及给药装置的技术领域，尤其涉及一种经皮肤给药层。
背景技术
身体在运动过程中出现意外擦伤时，擦伤表现为血痕、表皮剥脱、渗血或出血斑点，继而可出现炎症反应，局部会有红肿和疼痛；现有对于轻度擦伤主要是由身体自主修复，伤口会在3天完成治愈；但对于严重的擦伤情况时，现有主要是采用纱布包扎，但这种处理方式对炎证没有促进作用，仍是通过身体的治愈功能进行治疗。
发明内容
本发明的目的在于提出一种经皮肤给药层，其通过带有石墨烯、纳米二氧化硅和聚烯烃的热传组分，结合石墨烯、纳米二氧化硅和聚烯烃形成的缓释药物，通过缓释层上接收红外辐射，以使缓释层的缓释药物在皮肤表面的缓释出有效组分。
为达此目的，本发明采用以下技术方案：
一种经皮肤给药层，依次包括：加热层和缓释层；
所述加热层具有加热功能，用于在加热状态下促使所述缓释层缓释出缓释药物，加热温度为40-60℃；所述缓释层贴合于皮肤的患处；
所述缓释药物包括：热传组分和有效组分，按质量百分比，所述热传组分与所述有效组分之间的比例为(0.1-10)：1；
所述热传组分包括：石墨烯、纳米二氧化硅和聚烯烃；
所述有效组分包括：脂质体，以及分别在脂质体内的胆固醇、电解质和药 物；所述脂质体的相变温度为40-60℃，并于所述相变温度下脱膜，将所述药物释放至膜外；所述脂质体包括：二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱。
优选地，所述有效组分，按质量份数，包括：20-30份的脂质体、1-5份的胆固醇、20-25份的电解质和20-25份的药物。
优选地，所述二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为(1-3)：1混合。
优选地，所述热传组分还包括：聚乙烯醇和聚乙烯吡咯烷酮。
更优地，所述热传组分，按质量份数，包括：15-25份的聚烯烃、30-45份的纳米二氧化硅、30-45份的石墨烯、8-10份的聚乙烯醇和15-19份的聚乙烯吡咯烷酮。
优选地，所述热传组分，按质量份数，包括：30-45份的石墨烯、30-45份的纳米二氧化硅和15-25份的聚烯烃。
优选地，所述加热层安装有强度可调节的红外装置。
优选地，所述加热层设有透明的药物槽；所述红外装置的照射端照向所述药物槽。
优选地，所述红外装置的照射端为多个并依次排列，所述照射端间歇式地照射于所述缓释层。
本发明的有益效果：
本经皮肤给药层，能用于对皮肤患处进行消炎，通过加热层对缓释层的有效组分进行加热，使有效组分内的电解质和药物缓释至皮肤表面，实现了药物在皮肤在长时间药物缓释，并通过药物治愈皮肤的患处。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。
一种经皮肤给药层，依次包括：加热层和缓释层；
所述加热层具有加热功能，用于在加热状态下促使所述缓释层缓释出缓释药物，加热温度为40-60℃；所述缓释层贴合于皮肤的患处；
所述缓释药物包括：热传组分和有效组分，按质量百分比，所述热传组分与所述有效组分之间的比例为(0.1-10)：1；
所述热传组分包括：石墨烯、纳米二氧化硅和聚烯烃；
所述有效组分包括：脂质体，以及分别在脂质体内的胆固醇、电解质和药物；所述脂质体的相变温度为40-60℃，并于所述相变温度下脱膜，将所述药物释放至膜外；所述脂质体包括：二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱。
本经皮肤给药层，能用于对皮肤患处进行消炎，通过加热层对缓释层的有效组分进行加热，使有效组分内的电解质和药物缓释至皮肤表面，实现了药物在皮肤在长时间药物缓释，并通过药物治愈皮肤的患处。
加热层为非施药层，其可为缓释层的载体或与缓释层隔开设置；当缓释层涂于皮肤患处后，只需启动加热层的加热功能，从加热层的红外光线会照射于缓释层；而缓释层选用石墨烯、纳米二氧化硅和聚烯烃，由于石墨烯、纳米二氧化硅和聚烯烃的导热性能呈梯度状依次下降，由于有效组分会与热传组分混合，因此只需通过控制石墨烯、纳米二氧化硅和聚烯烃三者的比例，即可控制有效组分的温度；同时，热传组分中的石墨烯、纳米二氧化硅和聚烯烃的整体粒度大于有效组分，因此能增大缓冲药物的整体体积，且其热传组分的传热面积大，有利于促使二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱两者与皮肤角质层的脂质层发生相互作用而解体，进而能改变角质脂质结构，进一步地降 低角质的屏障，以使电解质和药物作用于皮肤的患处；且由于屏障度下降，皮肤的患处更容易吸收药物。
二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱为脂质体，在40-60℃的温度下能释放药物；其中，二硬脂酰基磷脂酰胆碱的相变温度为50-60℃，二肉豆蔻酰磷脂酰胆碱的相变温度为20-30℃，合理地将两种脂质体以一定的比较混合即可实现将相变温度控制于40-60℃内，并在相变温度下使热敏脂质体的膜流动性增强，以使药物释放至患处。
本方案在脂质体内增加胆固醇，能提高脂质体的刚性，防止药物接触于热传组分时破裂，提高了药物在脂质内的稳定性。
优选地，按质量份数，包括：20-30份的脂质体、1-5份的胆固醇、20-25份的电解质和20-25份的药物。
优选地，所述二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为(1-3)：1混合。
更优地，所述热传组分还包括：聚乙烯醇和聚乙烯吡咯烷酮。
聚乙烯醇采用医药级聚乙烯醇，具有良好的生物相容性，当其被释放至皮肤后，能促使形成一层膜贴于皮肤的表面，增强药物在皮肤的粘结效果。
聚乙烯吡咯烷酮具有生理惰性，不对皮肤、粘膜等有刺激，能增加药物在聚乙烯醇的亲水性和润滑性，使药物更容易在聚乙烯醇运动；当聚乙烯醇和聚乙烯吡咯烷酮同时使用时能小量提高药物的缓释量。
进一步优化地，所述热传组分，按质量份数，包括：15-25份的聚烯烃、30-45份的纳米二氧化硅、30-45份的石墨烯、8-10份的聚乙烯醇和15-19份的聚乙烯吡咯烷酮。
优选地，所述热传组分，按质量份数，包括：30-45份的石墨烯、30-45份 的纳米二氧化硅和15-25份的聚烯烃。
优选地，所述加热层安装有强度可调节的红外装置。
红外装置能发出红外光线，其光线强调可调节，实现自动调节辐射温度的功能，以使缓释层内的温度可控，药物在缓释过程的速率可控。同时，红外装置能部分作用于皮下组织，进而促进血液循环，加快患处药物的吸收。
更优地，所述加热层设有透明的药物槽；所述红外装置的照射端照向所述药物槽。
药物槽用于放置药物，当红外装置的照射端照射药物槽时，由于药物槽为透明，能透到红外光，进而使缓释层升温至40-60℃；并在温度过高或过低时降低红外辐射温度。
同时，所述红外装置的照射端为多个并依次排列，所述照射端间歇式地照射于所述缓释层。
缓释层相当于环状穿戴物，可被穿戴于身体上；由于红外装置上带有整齐排列的照射端，照射端能针对不同位置的中患处进行照射；本方案的照射端优选间歇式照射于缓释层，如左至右地照射，灯亮数为3，灯亮完后暂时熄灭，如此循环照射，能防止缓释层的局部过热；同时，照射端为多个并依次排列时不限于水平面，亦可为环状结构或弧形结构。
实施例A：
热传组分与有效组分之间的比例为5：1；
热传组分，按质量份数，包括：20份的聚烯烃、40份的纳米二氧化硅、40份的石墨烯；聚烯烃为聚丙烯；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆 碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用阿斯匹林。
对比例A1：
热传组分与有效组分之间的比例为5：1；
热传组分，按质量份数，包括：100份的聚丙烯；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用阿斯匹林。
对比例A2：
热传组分与有效组分之间的比例为5：1；
热传组分，按质量份数，包括：40份的纳米二氧化硅；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用阿斯匹林。
对比例A3：
热传组分与有效组分之间的比例为5：1；
热传组分，按质量份数，包括：40份的石墨烯；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用阿斯匹林。
空白组A4：
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用阿斯匹林。
分别将实施例A、对比例A1-A3中5g的热传组分与1g的有效组分按比例混合；其中空白组A4的热传组分为1g；混合前，将有效组分通过超声波震动至混合均匀；将上述制备得的缓释药物布施于严重擦伤引发的表皮剥脱患处，通过红外光对患处进行反复地间歇性照射，照射时长为15min，早上8点至晚上8点中每隔2小时照射一次；
在7天后统计治疗效果；且在治疗过程中严格控制患者的饮食、作息及活动；不能吃任何中药和西药，不能接受任何物理治疗；不能做过于剧烈的活动。
本设计针对患者7天后作出了治疗效果的评判标准等级：
3级：临床症状消失，患处的疼痛消散、活动功能恢复，能自由活动，没有任何障碍。
2级：患处的疼痛减轻，虽不能自由活动，活动障碍减至轻度，活动功能稍有恢复，可进行适度的活动。
1级：症状毫无任何改善，或者伴随加重的可能性。
经7天后，3级～2级为有效的治疗效果，患者的治疗效果如表1所示；
表1-经皮肤给药层对擦伤的治疗效果
Figure PCTCN2021111213-appb-000001
说明：
1、由表1可知，实施例A的热传组分使用了聚烯烃、纳米二氧化硅和石墨烯作为热传组分，有效组分在红外照射时传热均匀，保证了有效组分的缓释速度稳定，不会过高或过低，进一步确保在下一次红外照射时亦仍保留有效组分，因此实施例A有最佳的有效率，为92％。
2、由表1可知，对比例A1只使用了聚丙烯，聚丙烯相对于纳米二氧化硅和石墨烯的传热效果低，有利于热量储存，但体系中缺乏导热较好的材料，因此热量仅在于局部，不能很好地使有效组分的温度整体控制在40-60℃，因此治疗效果不理想，有效率仅为56％，且3级的治疗效果不明显，只有1人。对比例A2只使用了纳米二氧化硅的导热效果适中，位于聚烯烃与石墨烯之间，有效率优于只使用纳米二氧化硅和石墨烯的实施例；对比例A3只使用了石墨烯，石墨烯导热性好，由于其导热性好，热量不容易保存，使有效组分在没有红外照射时达不到40-60℃，因而治疗效果不佳，只有60％的有效率。
实施例B：
取热传组分5g，有效组分1g混合成缓释药物；
热传组分，按质量份数，包括：20份的聚烯烃、40份的纳米二氧化硅、40份的石墨烯、9份的聚乙烯醇和16份的聚乙烯吡咯烷酮；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电 解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为NaCl；药物选用银杏提取物。
实施例C：
取热传组分0.5g，有效组分5g混合成缓释药物；
热传组分，按质量份数，包括：15份的聚烯烃、45份的纳米二氧化硅、30份的石墨烯；
有效组分，按质量份数，包括：20份的脂质体、5份的胆固醇、20份的电解质和25份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为KCl；药物选用银杏提取物。
实施例D：
取热传组分10g，有效组分1g混合成缓释药物；
热传组分，按质量份数，包括：20份的聚烯烃、40份的纳米二氧化硅、40份的石墨烯；
有效组分，按质量份数，包括：25份的脂质体、3份的胆固醇、22份的电解质和21份的药物；脂质体为二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱；二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为1：1；电解质为KCl；药物选用银杏提取物。
分别将实施例B-实施例D的有效组分按比例混合；混合前，将有效组分通过超声波震动至混合均匀；将上述制备得的缓释药物布施于严重擦伤引发的表皮剥脱患处，通过红外光对患处进行反复地间歇性照射，照射时长为15min，早上8点至晚上8点中每隔2小时照射一次；
在7天后统计治疗效果；且在治疗过程中严格控制患者的饮食、作息及活动；不能吃任何中药和西药，不能接受任何物理治疗；不能做过于剧烈的活动。
本设计针对患者7天后作出了治疗效果的评判标准等级：
3级：临床症状消失，患处的疼痛消散、活动功能恢复，能自由活动，没有任何障碍。
2级：患处的疼痛减轻，虽不能自由活动，活动障碍减至轻度，活动功能稍有恢复，可进行适度的活动。
1级：症状毫无任何改善，或者伴随加重的可能性。
经7天后，3级～2级为有效的治疗效果，患者的治疗效果如表2所示；
表2-经皮肤给药层对擦伤的治疗效果
Figure PCTCN2021111213-appb-000002
以上结合具体实施例描述了本发明的技术原理。这些描述只是为了解释本发明的原理，而不能以任何方式解释为对本发明保护范围的限制。基于此处的解释，本领域的技术人员不需要付出创造性的劳动即可联想到本发明的其它具体实施方式，这些方式都将落入本发明的保护范围之内。

Claims (9)

  1. 一种经皮肤给药层，其特征在于，依次包括：加热层和缓释层；
    所述加热层具有加热功能，用于在加热状态下促使所述缓释层缓释出缓释药物，加热温度为40-60℃；所述缓释层贴合于皮肤的患处；
    所述缓释药物包括：热传组分和有效组分，按质量百分比，所述热传组分与所述有效组分之间的比例为(0.1-10)：1；
    所述热传组分包括：石墨烯、纳米二氧化硅和聚烯烃；
    所述有效组分包括：脂质体，以及分别在脂质体内的胆固醇、电解质和药物；所述脂质体的相变温度为40-60℃，并于所述相变温度下脱膜，将所述药物释放至膜外；所述脂质体包括：二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱。
  2. 根据权利要求1所述的经皮肤给药层，其特征在于，所述有效组分，按质量份数，包括：20-30份的脂质体、1-5份的胆固醇、20-25份的电解质和20-25份的药物。
  3. 根据权利要求2所述的经皮肤给药层，其特征在于，所述二硬脂酰基磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱以质量比为(1-3)：1混合。
  4. 根据权利要求2所述的经皮肤给药层，其特征在于，所述热传组分还包括：聚乙烯醇和聚乙烯吡咯烷酮。
  5. 根据权利要求4所述的经皮肤给药层，其特征在于，所述热传组分，按质量份数，包括：15-25份的聚烯烃、30-45份的纳米二氧化硅、30-45份的石墨烯、8-10份的聚乙烯醇和15-19份的聚乙烯吡咯烷酮。
  6. 根据权利要求2所述的经皮肤给药层，其特征在于，所述热传组分，按质量份数，包括：30-45份的石墨烯、30-45份的纳米二氧化硅和15-25份的聚烯烃。
  7. 根据权利要求1-6任意一项所述的经皮肤给药层，其特征在于，所述加热层安装有强度可调节的红外装置。
  8. 根据权利要求7所述的经皮肤给药层，其特征在于，所述加热层设有透明的药物槽；所述红外装置的照射端照向所述药物槽。
  9. 根据权利要求7所述的经皮肤给药层，其特征在于，所述红外装置的照射端为多个并依次排列，所述照射端间歇式地照射于所述缓释层。
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