WO2017186046A1 - 一种皮肤促渗方法及其促渗剂 - Google Patents

一种皮肤促渗方法及其促渗剂 Download PDF

Info

Publication number
WO2017186046A1
WO2017186046A1 PCT/CN2017/081167 CN2017081167W WO2017186046A1 WO 2017186046 A1 WO2017186046 A1 WO 2017186046A1 CN 2017081167 W CN2017081167 W CN 2017081167W WO 2017186046 A1 WO2017186046 A1 WO 2017186046A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
sponge
needle
skin penetration
promoting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/081167
Other languages
English (en)
French (fr)
Inventor
陈铭
王德祥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiamen University
Original Assignee
Xiamen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xiamen University filed Critical Xiamen University
Publication of WO2017186046A1 publication Critical patent/WO2017186046A1/zh
Priority to US16/028,036 priority Critical patent/US10555896B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • 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
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A61K8/987—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of species other than mammals or birds
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—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 or 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • 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
    • 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
    • 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

Definitions

  • the invention relates to a skin penetration promoting method and a substance, in particular to a sponge bone needle as a physical penetration enhancer for skin, and increases percutaneous absorption of a drug and an active ingredient.
  • the skin is the largest organ in the human body and the most direct route of administration.
  • dermal administration has many unique advantages over other routes of administration, including avoiding first-pass effects, direct action on local lesions, sustained release administration, and controlled drug release rate, patient compliance. Wait a minute.
  • Skin administration is the most challenging of the non-invasive routes of administration, and it is also most promising to replace the injection to deliver the drug component to the lesion.
  • skin has always been the object of human protection and beautification. As you age, your skin will gradually become dry, dull, aging, stains, etc. The most common way to combat these problems is by applying skin care products on the skin surface, in which the active active ingredients with special effects are absorbed through the skin. After that, it can make the skin moist and lustrous, wrinkles are reduced, and the spots are faded. Therefore, the research and application of transdermal absorption of drugs and active ingredients has become increasingly widespread.
  • the essence of the skin is a biofilm barrier against the invasion of external pathogens such as bacteria, viruses or exogenous allergens.
  • external pathogens such as bacteria, viruses or exogenous allergens.
  • non-polar small molecules molecular weight ⁇ 500 Da
  • various drugs or active substances with different physical and chemical properties especially biomacromolecules (polysaccharides, peptides, proteins, enzymes, nucleic acids with a molecular weight of at least ⁇ 10 4 Da, ⁇ 10 5 Da or even ⁇ 10 6 Da) Etc.)
  • biomacromolecules polysaccharides, peptides, proteins, enzymes, nucleic acids with a molecular weight of at least ⁇ 10 4 Da, ⁇ 10 5 Da or even ⁇ 10 6 Da
  • the delivery of lesions deep into the skin is extremely challenging and a difficult and important research area in the field of skin administration.
  • Chemical methods include the use of transdermal penetration enhancers, nanocarrier techniques (such as liposomes, microemulsions, multipolymer nanoparticles, micelles, quantum dots, gold nanoparticles) and the like. Because the chemical penetration-infiltration method is not significant enough to promote the penetration of biomacromolecules, and many chemical penetration enhancers and nanoparticle systems suffer from the problems of metabolism and cytotoxicity in the body, the application and industrialization of chemical penetration-enhancing methods are greatly affected. limit.
  • physical penetration techniques include iontophoresis, ultrasonic introduction, electroporation, and microneedle.
  • Microneedle administration is a new type of physical osmosis and treatment that has emerged in recent years. Its principle is to form a large number of micron-sized pores on the skin, the depth up to the epidermis, and even to the dermis layer, providing the most direct and effective way for the absorption of active ingredients of drugs or cosmetics, thereby improving the therapeutic and cosmetic beauty. Effect. In theory, properties such as molecular weight and polarity do not affect the pores formed by the microneedles. When the microneedle is applied to the skin, the nerve tissue and the microvessel are generally not injured, and the human body does not produce pain, and the formed small hole can heal itself in a short time without causing skin damage.
  • microneedles The manufacturing method of microneedles is becoming more and more mature, but the selection of microneedle materials has always been a problem.
  • the polymer microneedle has insufficient mechanical strength and is difficult to penetrate the dense stratum corneum; the single crystal silicon microneedle has high brittleness, high cost and safety to be studied; although the metal material is safer, the microneedle is not only complicated but also has complicated processes. The problem of high cost.
  • Sponge bone needle is a siliceous or calcareous fibrous material that acts as a skeleton in the sponge body, and has a single-axis, three-axis, multi-axis type.
  • the research on sponge needles mostly focuses on the nanostructure, optical properties, growth mechanism and regulation, bionics, etc. of sponge needles.
  • the role of the needle that is, as a physical penetration enhancer for the skin, thereby increasing the transdermal absorption of the drug and the active ingredient has not been fully developed.
  • Another object of the present invention is to provide the use of a sponge bone needle skin physical penetration enhancer composition.
  • the present invention provides a skin penetration enhancer comprising a composition of a sponge or a sponge needle or a biologically effective amount of a sponge needle.
  • the skin penetration enhancer further comprises a pharmaceutical ingredient.
  • the skin penetration enhancer further comprises a skin care active ingredient.
  • the skin penetration enhancer comprises 0.1%-100% (W/W) of a sponge bone needle.
  • the sponge bone needle composition is a phosphate solution, and the mass concentration of the sponge bone needle reaches 10 ⁇ 100 mg/mL.
  • the phosphate buffer has a molar concentration of 0.05 M - 0.5 M and a pH 7.4 phosphate buffer.
  • the skin physical penetration enhancer includes a skin drug penetration enhancer, a skin care cosmetic penetration enhancer, and the like.
  • a sponge bone needle or a composition containing a sponge bone needle is applied to the cleaned skin.
  • sponge bone needle as a physical penetration enhancer for skin is as follows:
  • Phosphate buffer solution was added to the sponge bone needle to make the mass concentration of the sponge bone needle reach 10 to 100 mg/mL, and a sponge bone needle suspension was obtained.
  • the phosphate buffer may be a phosphate buffer having a molar concentration of 0.05 M - 0.5 M and a pH of 7.4.
  • the sponge bone needle skin physical penetration enhancer composition includes a sponge bone needle pharmaceutical preparation composition, a sponge bone needle cosmetic preparation composition, and the like.
  • the sponge bone needle skin physical penetration enhancer composition can be directly applied to the cleaned skin, and the direct application can massage the skin with fingers or with other tools (such as a electric massage device), and instantly open the skin stratum corneum channel, increasing Transdermal absorption of its active ingredients.
  • the skin penetration cosmetic physical penetration enhancer is used as follows:
  • the massage site can then be washed with normal saline or water to wash away the residual sponge needle.
  • the drug or active ingredient to be transdermally applied is then applied evenly over the massaged skin.
  • the skin to which the sponge needle has been applied is relatively fragile due to the formation of a large number of channels on the surface, and it is necessary to protect the skin from moisturizing and sun protection.
  • the skin cells stimulate the proliferation and growth under the stimulation of the sponge bone needle, the cells are replaced, the surface cuticle is removed, the collagen synthesis and secretion are increased, and the skin is obviously improved.
  • the invention uses the sponge bone needle as a physical penetration enhancer to overcome the stratum corneum barrier of the skin. Promote the percutaneous absorption of active ingredients of drugs, vaccines and cosmetics, so that they can enter the skin layers or be absorbed into the blood circulation through the skin capillaries/lymphatic vessels. They can be used for local or systemic administration of skin, and can also be used for skin care cosmetics. In addition, increase the transdermal absorption of drugs and active ingredients.
  • Fig. 1 is a morphological diagram and particle size distribution of a sponge bone needle under a microscope; wherein a is a schematic diagram of the length of a single sponge needle, b is a morphology diagram of a plurality of sponge bone needles, and c is a particle size distribution map.
  • Figure 2 is a histogram of the distribution of ANTS-fucoidan in the skin in Example 1;
  • Example 3 is a graph showing experimental results of the control group and the experimental group of Example 1; A is a blank control group, and B is an experimental group.
  • Figure 4 is a histogram of the distribution of FITC-dextran in the skin in Example 2;
  • Example 5 is a graph showing experimental results of the control group and the experimental group of Example 2; A is a blank control group, and B is an experimental group.
  • the invention provides a skin physical penetration enhancer and a use method for promoting transdermal absorption of a drug and an active ingredient, and can be applied to the beauty field and the medical field in the future to develop a more effective transdermal method and a transdermal system to promote the development of the industry.
  • the above summary of the invention and the specific embodiments described below are intended to illustrate the present invention more effectively, but it should be understood that the invention is not limited to the contents listed herein. It is not intended to limit the invention.
  • Example 1 Fresh pork skin was taken to take a 40 mm diameter disc to remove subcutaneous fat tissue, and the pig hair was shaved to no more than 2 mm. The pig skin is rinsed with water and mounted on a transdermal device to remove air bubbles between the pig skin and the buffer in the receiving cell. Add 1mL buffer to the drug pool (15mm diameter), test the conductivity of the pig skin with a waveform generator and a multimeter, apply 100mV, 100Hz AC. If the current through the pig skin is less than 5 ⁇ A, the skin's stratum corneum barrier function is intact. Used for experiments.
  • the buffer was aspirated, and 100 ⁇ L of phosphate buffer containing 10 mg of sponge bone needle was added to the drug-sending tank, and the control group was a phosphate buffer solution to which no sponge needle was added.
  • the massage site is massaged for 2 minutes, so that the sponge needle can pierce the pig skin and produce small holes.
  • the skin of the part is washed with buffer or water, the residual sponge needle is removed, and the conductivity of the pig skin is tested by the above method, and the current passed is increased to about 100 ⁇ A.
  • the buffer was removed and 150 ⁇ L of a solution containing 1.5 mg of ANTS-fucoidan (1-30 kDa) was added to spread the liquid evenly over the skin of the sponge needle.
  • the entire apparatus was then placed in a transdermal cell carrying 37 ° C of flowing water while a micro magnetic stir bar was placed in the receiving cell and rotated at 600 r/min. After transdermally for 16 hours, it was washed five times with buffer and the pig skin was removed. Two methods were used to detect the effect of sponge needle penetration. (1) A tissue block having a diameter of 5 mm was cut with a punch at the administration site of the skin, and rapidly frozen in a frozen embedding agent.
  • the tissue-embedded block was cut into a sheet having a thickness of 20 ⁇ m on a cryostat, and the sheet was sealed with a neutral gum.
  • the sponge of the experimental group with the sponge-needle massage had many sponge needles left in the skin of the stratum corneum of the tissue, and some even had The depth of the dermis layer is reached, and obvious fluorescence is observed in the stratum corneum, epidermis layer and dermis layer, which means that the sponge bone massage is added to the skin, and the sponge bone needle penetrates into the skin to form no skin.
  • Liquid-methanol (volume ratio of 1:1), the first layer of the stratum corneum, the second to fifth layer of the stratum corneum, the sixth to ten layers of the stratum corneum, the epidermal layer and the dermis layer of ANTS-, respectively, at a room temperature of 200 r / min Fucoidan.
  • the fluorescence value of ANTS in the soaking solution was read on a full-wavelength microplate reader, and the content of ANTS-Fucoidan in each layer of skin tissue was obtained by comparing the standard curve. The results showed that compared with the control group, the accumulation and distribution of ANTS-fucoidan in the skin layers increased under the action of the bone needle, especially in the deep layer of the skin.
  • the total percutaneous absorption of ANTS ⁇ Fucoidan (1–30kDa) increased from 6.58% to 13.40%.
  • Example 2 Pig skin was treated in the same manner as in Example 1. After the conductivity was measured, the buffer was removed, and 150 ⁇ L of a solution containing 1.5 mg of FITC-Dextran (average molecular weight of 10 kDa) and 10 mg of sponge needle was added, and the control group was not added with a sponge. The bone needle is massaged for 2 minutes with a mini massage device or a manual massage. Place in a transdermal pool for 16h. The same two methods were used to qualitatively and quantitatively measure the permeation of FITC-Dextran. The results of confocal microscopy were similar to those in Example 1.
  • Sponge bone needles formed numerous micropores on the skin, and the fluorescence intensity of the stratum corneum, epidermal layer and dermis layer of the experimental group was significantly higher than that of the control group. Quantitative results show that the experimental group The FITC-Dextran entering the epidermis was 17.3 times that of the control group, and the FITC-Dextran entering the dermis was 4.25% of the total amount, while the content of the dermis in the control group was almost zero, indicating that the sponge bone massage was administered at the same time. The absorption of the active ingredient can also be promoted, and the effect is remarkable.
  • FIG. 2 is a view showing the experimental results of the control group and the experimental group of FIG. 1 (fluorescence pattern of the tissue section).
  • Example 2 Pig skin was treated in the same manner as in Example 1. After the conductivity was measured, the buffer was removed, and 150 ⁇ L of a solution containing 1.5 mg of FITC-dextran (average molecular weight of 10,000 Da) and 10 mg of sponge needle was added, and the control group did not. Add a sponge needle and massage for 2 minutes with a mini massage device or manual massage. Place in a transdermal pool for 16h. The permeation amount of FITC-dextran was qualitatively and quantitatively determined by the same two methods. The results of confocal microscopy were similar to those in Example 1.
  • Sponge bone needles formed numerous micropores on the skin, and the fluorescence intensity of the stratum corneum, epidermal layer and dermis layer of the experimental group was significantly higher than that of the control group. Quantitative results showed that the FITC-dextran entering the epidermal layer in the experimental group was 17.3 times that of the control group, and the FITC-dextran entering the dermis was 4.25% of the total amount, while the content in the dermis of the control group was almost zero. It is indicated that the simultaneous administration of the sponge needle massage can also promote the absorption of the active ingredient, and the effect is remarkable.
  • Fig. 4 The histogram of the distribution of FITC-Dextran in the skin in Example 2 is shown in Fig. 4; the experimental results of the control group and the experimental group of Example 2 (fluorescence pattern of the tissue section) are shown in Fig. 5.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Birds (AREA)
  • Botany (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Anesthesiology (AREA)
  • Medical Informatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种皮肤促渗方法及其促渗剂，含有海绵骨针或海绵骨针的组合物或海绵骨针的生物学有效量。所述的促渗剂可抹于皮肤上，克服皮肤角质层屏障，促进药物、疫苗及化妆品活性成分的经皮吸收，使之进入皮肤各层或者经皮肤毛细血管/淋巴管吸收而进入全身血液循环，可用于皮肤局部给药或全身给药，也可用于护肤化妆品中，增加药物及活性成分经皮吸收。

Description

一种皮肤促渗方法及其促渗剂 技术领域
本发明涉及皮肤促渗方法及物质，尤其是涉及海绵骨针作为皮肤物理促渗剂，增加药物及活性成分经皮吸收。
背景技术
皮肤是人体最大的器官，也是最直接的给药途径。在医药领域，皮肤给药相对于其他给药途径而言有很多独特的优势，包括避免首过效应、直接作用于局部病变部位、缓释给药并且药物释放速度可控、病人治疗的顺应性好等。皮肤给药在非入侵性给药途径中又最具挑战性，也最有希望来替代注射给药把药物成分送达病变部分。另一方面，在医学美容领域，皮肤一直是人类保护与美化的对象。随着年龄的增长，皮肤会逐渐出现干燥、暗沉、衰老、色斑等问题，对抗这些问题最常见的方法就是通过在皮肤表面涂敷护肤品，其中具有特殊作用的活性有效成分经皮肤吸收后能够使皮肤水润亮泽，皱纹减少，色斑淡化等。因此，药物及活性成分经皮吸收的研究与应用也日趋广泛。
然而，皮肤的本质就是一种生物膜屏障，用以抵挡外界病原体，比如细菌、病毒或者外源性致敏原的入侵。一般只有极少数的非极性小分子(分子量<500Da)可以被动地通过皮肤屏障。因此，把各种理化性质不同的药物或者活性物质，尤其是生物大分子药物(分子量至少有～104Da,～105Da甚至～106Da的多糖、多肤、蛋白质、生物酶、核酸等)输送到皮肤深层的病变部位是极具挑战性的，也是皮肤给药领域的研究难点和重点。目前，促进药物经皮吸收的方法大致分为化 学方法和物理方法。化学方法包括使用透皮促渗剂、纳米载体技术(如脂质体、微乳、多聚物纳米颗粒、胶束、量子点、金纳米粒)等。由于化学促渗方法对生物大分子的促渗效果不够显著，而且很多化学促渗剂和纳米颗粒系统因自身体内代谢和细胞毒性的问题，使得化学促渗方法的应用和产业化受到很大的限制。另一方面，物理促渗技术包括离子导入法、超声波导入法、电穿孔法及微针法等。其中很多物理促渗技术效果显著，但是对仪器设备的要求高，不易携带，设计和生产成本高，而且只能用于小面积的皮肤给药，因此也大大限制了其应用。微针给药，是近年来兴起的一种新式物理促渗和治疗手段。它的原理是在皮肤上形成大量微米级的孔道，深度可达表皮层，甚至到真皮层，为药物或化妆品活性成分的吸收提供了最直接有效的途径，从而提高了药物治疗和美容美颜的效果。理论上，分子量大小、极性等性状不会影响透皮成分通过微针形成的孔道。在皮肤上施用微针时，一般不会伤及神经组织和微血管，人体不会产生痛觉，而形成的小孔在短时间内便能自愈，不会产生皮肤损伤。
微针的制造方法日渐成熟，但微针材料的选择始终是一个问题。聚合物微针机械强度不够，难以穿透致密角质层；单晶硅微针脆性高，成本也高且安全性有待考究；金属材质虽然较为安全，但用于制作微针除了工艺复杂，同样也有成本高的问题。
海绵骨针是海绵体内起骨架作用的硅质或钙质纤维状物，具有单轴、三轴、多轴等类型。目前对海绵骨针的研究多集中在海绵骨针纳米结构、光学特性、生长机制与调控、仿生学等方面，而海绵骨针的类微 针的作用，即作为皮肤物理促渗剂，从而增加药物及活性成分经皮吸收的应用尚未得到充分开发。
发明内容
本发明的目的在于提供海绵骨针作为皮肤物理促渗剂的应用。
本发明的另一目的在于提供海绵骨针皮肤物理促渗剂组合物的应用。
本发明提供的一种皮肤促渗剂，含有海绵骨针或海绵骨针的组合物或海绵骨针的生物学有效量。
所述的一种皮肤促渗剂，还包括药物成份。
所述的一种皮肤促渗剂，还包括护肤活性成份。
所述一种皮肤促渗剂，含海绵骨针0.1％‐100％(W/W)。
所述海绵骨针组合物为磷酸盐溶液，海绵骨针的质量浓度达到10‐100mg/mL。所述磷酸盐缓冲液摩尔浓度为0.05M‐0.5M,pH为7.4的磷酸盐缓冲液。
所述皮肤物理促渗剂包括皮肤药物促渗剂和护肤化妆品促渗剂等。
采用海绵骨针作为皮肤物理促渗剂的使用方法之一如下:
海绵骨针或含有海绵骨针生物学有效量的组合物涂抹于清洁后的皮肤。
采用海绵骨针作为皮肤物理促渗剂的使用方法之二如下:
在海绵骨针中加入磷酸盐缓冲液，使海绵骨针的质量浓度达到10～100mg/mL，得海绵骨针混悬液。按摩皮肤，清洗按摩部位，洗去残留海绵骨针，再将含有药物或化妆品活性成分的制剂涂抹于海绵 骨针处理后的皮肤上。
所述磷酸盐缓冲液可采用摩尔浓度为0.05M‐0.5M,pH为7.4的磷酸盐缓冲液。
所述海绵骨针皮肤物理促渗剂组合物包括海绵骨针药物制剂组合物和海绵骨针化妆品制剂组合物等。
所述海绵骨针皮肤物理促渗剂组合物可直接涂抹于清洁后的皮肤上，所述直接涂抹可采用手指或借助其他工具(如电动按摩仪)按摩皮肤，瞬间打开皮肤角质层通道，增加其活性成分的经皮吸收。
所述护肤化妆品物理促渗剂的使用方法如下:
将海绵骨针直接涂抹在清洁后的皮肤上，用手指或借助其他工具(如电动按摩仪)按摩皮肤，瞬间打开皮肤角质层通道，而后可用生理盐水或清水清洗按摩部位，洗去残留海绵骨针，再将化妆品精华液或其他制剂涂抹于海绵骨针处理后的皮肤上，增加其活性成分的经皮吸收。
根据需要调整按摩时间和按摩强度，如待吸收成分分子量较大，较难吸收，可适当延长按摩时间或增加按摩强度。而后可用生理盐水或清水清洗按摩部位，洗去残留海绵骨针。而后施加待透皮的药物或活性成分，使之均匀分布在按摩过的皮肤上。施用过海绵骨针的皮肤由于表面形成大量通道，较为脆弱，需要做好保湿、防晒等保护工作。皮肤细胞在海绵骨针刺激下会加快增殖生长，细胞更替，表面角质层蜕去，胶原蛋白合成分泌增加，皮肤明显得到改善。
本发明将海绵骨针作为作为皮肤物理促渗剂，克服皮肤角质层屏障， 促进药物、疫苗及化妆品活性成分的经皮吸收，使之进入皮肤各层或者经皮肤毛细血管/淋巴管吸收而进入全身血液循环，可用于皮肤局部给药或全身给药，也可用于护肤化妆品中，增加药物及活性成分经皮吸收。
附图说明
图1为海绵骨针在显微镜下形态图及粒径分布；其中a为单根海绵骨针长度示意图，b为多根海绵骨针形态图，c为粒径分布图。
图2为实施例1中ANTS-岩藻多糖在皮肤中的分布柱状图；
图3为实施例1对照组与实验组的实验结果图；A为空白对照组，B为实验组。
图4为实施例2中FITC-葡聚糖在皮肤中的分布柱状图；
图5为实施例2对照组与实验组的实验结果图；A为空白对照组，B为实验组。
具体实施方式
本发明提供一种促进药物及活性成分透皮吸收的皮肤物理促渗剂和使用方法，未来可供美容领域和医学领域应用，开发更加有效的透皮方法和透皮系统，促进行业发展。在本发明中，以上所述发明内容和以下所述具体实施例操作均是为了更有效地阐述本发明，但应该理解本发明并不仅限于此处所列的内容，所用的术语与实施例并不是对本发明的限定。
下面通过两个实施例来具体描述本发明及其应用。
实施例1:取新鲜猪皮截取直径为40mm的圆片，除去皮下脂肪组织，将猪毛剃至不长于2mm。将猪皮用清水冲洗干净，安装在透皮装置上，除去猪皮与接收池中缓冲液间的气泡。在给药池(直径15mm)加入1mL缓冲液，用波形发生器和万用表测试猪皮电导性能，施加100mV,100Hz交流电，若通过猪皮的电流小于5μA，则说明皮肤角质层屏障功能完好，可以用于实验。吸去缓冲液，在给药池中加入100μL含10mg海绵骨针的磷酸盐缓冲液，对照组为不添加海绵骨针的磷酸盐缓冲液。借助迷你按摩装置或者手动按摩，按摩给药部位2min，使海绵骨针能够刺透猪皮，产生小孔。按摩完成后，缓冲液或清水清洗该部位皮肤，去掉残留海绵骨针，再用上述方法测试猪皮此时电导率，发现通过的电流增至100μA左右。除去缓冲液，加入150μL含1.5mg ANTS‐岩藻多糖(1‐30kDa)的溶液，使液体均匀铺在海绵骨针按摩过的皮肤。接着将整个装置放入载有37℃流动水的透皮池中，同时在接收池中放入微型磁力搅拌子，以600r/min的速度转动。透皮16h后，用缓冲液清洗五次，取下猪皮。采用两种方法检测海绵骨针促透效果。(1)在皮肤的给药部位用冲子切下直径为5mm的组织块，迅速冻在冷冻包埋剂中。在冷冻切片机上将包有组织的包埋块切成厚度为20μm的薄片，用中性树胶封片。使用共聚焦显微镜观察，与不加海绵骨针，按摩后给药的对照组相比，加海绵骨针按摩的实验组的组织薄片角质层一侧皮肤中残留许多海绵骨针，有的甚至已达到真皮层深度，同时角质层、表皮层和真皮层均可观察到明显的荧光，说明在皮肤上加上海绵骨针按摩，海绵骨针刺入皮肤，能在皮肤上形成无 数小通道，促进了ANTS‐岩藻多糖通过角质层，进入表皮和真皮组织。(2)取下猪皮后，用冲子把给药部位的皮肤切下，使用胶带剥离方法依次剥下10层角质层，刮下表皮层，切碎真皮层，分组浸泡于4mL磷酸盐缓冲液一甲醇(体积比为1:1)，室温200r/min的方式分别提取第一层角质层，第二到五层角质层，第六到十层角质层，表皮层和真皮层中ANTS‐Fucoidan。在全波长酶标仪上读取浸泡液中ANTS荧光值，对照标准曲线得出各层皮肤组织中ANTS‐Fucoidan的含量。结果表明，与对照组相比，骨针作用下，ANTS‐岩藻多糖在皮肤各层的累积和分布的变化均有增加，尤其是皮肤深层。ANTS‐Fucoidan(1‐30kDa)经皮总吸收从6.58％增加至13.40％。
海绵骨针在显微镜下形态图参见图1；实施例1ANTS-岩藻多糖在皮肤中的分布柱状图参见图2；实施例1对照组与实验组的实验结果图(组织切片荧光图)参见图3。
实施例2:与实施例1一样处理猪皮，检测过电导率后，除去缓冲液，加入150μL含1.5mg FITC‐Dextran(平均分子量为10kDa)和10mg海绵骨针的溶液，对照组不加海绵骨针，借助迷你按摩装置或者手动按摩，按摩2min。放入透皮池透皮16h。用同样的两种方法分别定性和定量检测FITC‐Dextran的透过量。共聚焦显微观察结果与实施例1相似，海绵骨针可在皮肤上形成无数微孔，且实验组皮肤的角质层、表皮层和真皮层的荧光强度明显高于对照组。定量结果显示，实验组 中进入表皮层的FITC‐Dextran是对照组的17.3倍，进入真皮层的FITC‐Dextran是总给量的4.25％，而对照组真皮层中含量几乎为零，说明了给药同时海绵骨针按摩同样能够促进有效成分的吸收，且效果显著。
图参见图2；实施例1对照组与实验组的实验结果图(组织切片荧光图)参见图3。
实施例2:与实施例1一样处理猪皮，检测过电导率后，除去缓冲液，加入150μL含1.5mg FITC-葡聚糖(平均分子量为10000Da)和10mg海绵骨针的溶液，对照组不加海绵骨针，借助迷你按摩装置或者手动按摩，按摩2min。放入透皮池透皮16h。用同样的两种方法分别定性和定量检测FITC-葡聚糖的透过量。共聚焦显微观察结果与实施例1相似，海绵骨针可在皮肤上形成无数微孔，且实验组皮肤的角质层、表皮层和真皮层的荧光强度明显高于对照组。定量结果显示，实验组中进入表皮层的FITC-葡聚糖是对照组的17.3倍，进入真皮层的FITC-葡聚糖是总给量的4.25％，而对照组真皮层中含量几乎为零，说明了给药同时海绵骨针按摩同样能够促进有效成分的吸收，且效果显著。
实施例2中FITC-Dextran在皮肤中的分布柱状图参见图4；实施例2对照组与实验组的实验结果图(组织切片荧光图)参见图5。

Claims (11)

  1. 一种皮肤促渗剂，含有海绵骨针或海绵骨针的组合物或海绵骨针的生物学有效量。
  2. 如权利要求1所述的一种皮肤促渗剂，其特征在于还包括药物成份。
  3. 如权利要求1的一种皮肤促渗剂，其特征在于还包括护肤成份。
  4. 如权利要求1的一种皮肤促渗剂，其特征在于含海绵骨针0.1％-100％(W/W)。
  5. 如权利要求1所述的一种皮肤促进剂，其特征在于所述海绵骨针组合物为磷酸盐混悬液，海绵骨针的质量浓度达到10‐100mg/mL。
  6. 如权利要求5所述的一种皮肤促进剂，其特征在于所述磷酸盐缓冲液摩尔浓度为0.05M‐0.5M,pH为7.4的磷酸盐缓冲液。
  7. 一种促进皮肤的渗透方法，其特征在于将海绵骨针或含有海绵骨针的组合物或含海绵骨针的生物学有效量涂抹在皮肤上。
  8. 根据权利要求7所述的一种促进皮肤渗透的方法，其特征在于所述的含海绵骨针组合物为海绵骨针的磷酸盐缓冲液，海绵骨针的质量浓度达到10‐100mg/mL。
  9. 如权利要求8所述一种促进皮肤渗透的方法，其特征在于所述磷酸盐缓冲液采用摩尔浓度为0.05M‐0.5M,pH为7.4的磷酸盐缓冲液。
  10. 如权利要求7所述一种促进皮肤渗透的方法，其特征在于所述护肤促渗的方法如下:
    将所述海绵骨针涂抹在皮肤上，按摩皮肤，清洗按摩部位，洗去残留海绵骨针，再将含有药物或化妆品活性成分的制剂涂抹于海绵骨针处理后的皮肤上。
  11. 如权利要求8所述一种促进皮肤渗透的方法，其特征在于所述护肤促渗的方法如下:
    将所述海绵骨针组合物直接涂抹在皮肤上，按摩皮肤。
PCT/CN2017/081167 2016-04-27 2017-04-20 一种皮肤促渗方法及其促渗剂 Ceased WO2017186046A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/028,036 US10555896B2 (en) 2016-04-27 2018-07-05 Skin penetration enhancing method and its penetration enhancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610267935.5A CN105999535A (zh) 2016-04-27 2016-04-27 海绵骨针作为皮肤物理促渗剂的应用
CN201610267935.5 2016-04-27

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/028,036 Continuation US10555896B2 (en) 2016-04-27 2018-07-05 Skin penetration enhancing method and its penetration enhancer

Publications (1)

Publication Number Publication Date
WO2017186046A1 true WO2017186046A1 (zh) 2017-11-02

Family

ID=57081384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/081167 Ceased WO2017186046A1 (zh) 2016-04-27 2017-04-20 一种皮肤促渗方法及其促渗剂

Country Status (3)

Country Link
US (1) US10555896B2 (zh)
CN (2) CN105999535A (zh)
WO (1) WO2017186046A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3824875A4 (en) * 2018-06-29 2022-05-18 SR Biotek Inc. MEDICATED MICRONEEDLE AND METHOD OF MANUFACTURE THEREOF

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105999535A (zh) 2016-04-27 2016-10-12 厦门大学 海绵骨针作为皮肤物理促渗剂的应用
CN106166326A (zh) * 2016-08-19 2016-11-30 王子元 一种非介入导入方法
CN109381422B (zh) * 2017-08-07 2020-11-06 厦门大学 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN108697639B (zh) * 2017-08-07 2021-08-03 厦门大学 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN111012916B (zh) * 2018-10-09 2021-10-01 厦门大学 一种表面修饰的海绵骨针及其制备方法和用途
US20220062352A1 (en) * 2018-12-03 2022-03-03 Demata Therapeutics, LLC Compositions for the treatment of conditions
CN111407721B (zh) * 2019-01-08 2024-04-30 复旦大学 一种促进活性成分渗透皮肤的体系
CN111744052B (zh) * 2019-03-27 2021-07-09 厦门大学 一种海绵质止血材料的制备方法
CN110613892A (zh) * 2019-07-10 2019-12-27 厦门大学 一种经皮给药系统
KR20220040464A (ko) * 2019-07-23 2022-03-30 더마타 테라퓨틱스, 엘엘씨 피부 충전제로 병태의 치료를 위한 조성물
CN110859794A (zh) * 2019-10-10 2020-03-06 深圳市人民医院 一种外泌体经皮递送制剂及其用途
CN111643436B (zh) * 2020-07-16 2022-03-15 陕西中鸿科瑞再生医学研究院有限公司 一种含海绵骨针的生发剂
CN113908108A (zh) * 2021-10-10 2022-01-11 广州吉腾生物科技有限公司 快速修复皮肤的海绵骨针及其制备方法及其应用
CN116173390B (zh) * 2022-12-30 2026-03-24 苏州纳通生物纳米技术有限公司 便于定量给药的处理皮肤至稳态的方法
CN117100681A (zh) * 2023-05-11 2023-11-24 厦门大学 离子液体与海绵骨针的促渗组合物及其活性组合物和应用
CN116553563B (zh) * 2023-05-17 2024-02-02 济生(上海)实业有限公司 硅质海绵骨针的纯化方法及其透皮修护痤疮皮肤的应用
CN117487782B (zh) * 2023-09-19 2024-11-29 广州旭朗生物科技有限公司 一种水解海绵及其提取和应用
CN117379680A (zh) * 2023-10-12 2024-01-12 深圳市宗匠科技有限公司 美容物质输出控制方法、美容仪及存储介质
CN118319803A (zh) * 2024-03-15 2024-07-12 广州市百集生物科技有限公司 一种深层修复组合物及其应用
CN121015548A (zh) * 2025-09-16 2025-11-28 深圳市百悦生物科技有限公司 海绵骨针辅助外泌体透皮递送促进皮肤修复的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040055957A1 (en) * 1997-01-10 2004-03-25 Palm Scott K. Filterable composite adsorbents
WO2008043071A2 (en) * 2006-10-05 2008-04-10 Maria Villani Use of spongilla spicules as a dermabrasion device or resurfacing modality
WO2015156455A1 (ko) * 2014-04-08 2015-10-15 주식회사 파이온텍 해면에서 얻은 천연 바이오 스폰지로부터 미세침의 정제 및 추출 방법
CN105858669A (zh) * 2016-04-27 2016-08-17 厦门大学 高纯度海绵骨针的制备方法
CN105999535A (zh) * 2016-04-27 2016-10-12 厦门大学 海绵骨针作为皮肤物理促渗剂的应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0318498B1 (pt) * 2002-07-01 2016-07-05 Maria Villani composições terapêuticas à base de porifera para o tratamento e a prevenção de doenças da pele
JP5479498B2 (ja) * 2009-02-10 2014-04-23 ピオン−テック・カンパニー・リミテッド Ｄｄｓメカニズムを有する薬草ピーリング粉末を含む化粧料組成物
KR101323613B1 (ko) * 2011-12-02 2013-11-01 주식회사 에스알바이오텍 코팅된 마이크로 골편을 포함하는 피부 필링용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040055957A1 (en) * 1997-01-10 2004-03-25 Palm Scott K. Filterable composite adsorbents
WO2008043071A2 (en) * 2006-10-05 2008-04-10 Maria Villani Use of spongilla spicules as a dermabrasion device or resurfacing modality
WO2015156455A1 (ko) * 2014-04-08 2015-10-15 주식회사 파이온텍 해면에서 얻은 천연 바이오 스폰지로부터 미세침의 정제 및 추출 방법
CN105858669A (zh) * 2016-04-27 2016-08-17 厦门大学 高纯度海绵骨针的制备方法
CN105999535A (zh) * 2016-04-27 2016-10-12 厦门大学 海绵骨针作为皮肤物理促渗剂的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG, XIAOHONG ET AL.: "An Introduction to the study on Natural Characteristics of Sponge Spicules and Bionic Applications", ADVANCES IN EARTH SCIENCE, vol. 21, no. 10, 31 October 2006 (2006-10-31), pages 1008 - 1013 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3824875A4 (en) * 2018-06-29 2022-05-18 SR Biotek Inc. MEDICATED MICRONEEDLE AND METHOD OF MANUFACTURE THEREOF

Also Published As

Publication number Publication date
US20180311143A1 (en) 2018-11-01
US10555896B2 (en) 2020-02-11
CN112957606A (zh) 2021-06-15
CN105999535A (zh) 2016-10-12

Similar Documents

Publication Publication Date Title
WO2017186046A1 (zh) 一种皮肤促渗方法及其促渗剂
Lee et al. Advancements in skin‐mediated drug delivery: Mechanisms, techniques, and applications
Benson et al. Topical and transdermal drug delivery: principles and practice
Brown et al. Transdermal drug delivery systems: skin perturbation devices
Donnelly et al. Novel delivery systems for transdermal and intradermal drug delivery
Nanda et al. Current developments using emerging transdermal technologies in physical enhancement methods.
DK2510980T3 (en) Method of dermocosmetic treatment of skin by application of NGF-containing compositions
Zhang et al. Skin delivery of hydrophilic biomacromolecules using marine sponge spicules
Kalghatgi et al. Transdermal drug delivery using cold plasmas
WO2019029154A1 (zh) 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN100408126C (zh) 表皮针及其制作方法
Barry Penetration enhancer classification
KR100976418B1 (ko) 수분 투과에 대하여 방향성을 지닌 시트를 이용한 마스크팩
CN108697639B (zh) 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN110613892A (zh) 一种经皮给药系统
CN117100682A (zh) 中空海绵骨针及其制备方法和应用
CN215135863U (zh) 微电流纳米微针晶片装置
KR20190042001A (ko) 비침습적 수송 방법
US20210085945A1 (en) Non-invasive Transportation Method
Grice et al. Electrical and physical methods of skin penetration enhancement
CN112587791A (zh) 微电流纳米微针晶片装置及导入外泌体的方法
Bambale et al. Exploring Novel Treatments for Alopecia: Nanoparticles, Iontophoresis, and Cell Therapy
Prasad et al. Polymeric gels: vehicles for enhanced drug delivery across skin
Júnior et al. Drug Delivery-Associated Dermatological Technologies and Techniques
Dhurat et al. Classification of Microneedles

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17788698

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17788698

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 26.04.2019)