WO2019029154A1 - 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途 - Google Patents

一种经皮吸收组合物及其在制备经皮吸收制剂中的用途 Download PDF

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WO2019029154A1
WO2019029154A1 PCT/CN2018/077288 CN2018077288W WO2019029154A1 WO 2019029154 A1 WO2019029154 A1 WO 2019029154A1 CN 2018077288 W CN2018077288 W CN 2018077288W WO 2019029154 A1 WO2019029154 A1 WO 2019029154A1
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Prior art keywords
needle
sponge
skin
percutaneous absorption
group
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English (en)
French (fr)
Inventor
陈铭
王德祥
刘春云
张赛曼
张弛
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Xiamen University
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Xiamen University
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Priority to US17/052,999 priority Critical patent/US11413237B2/en
Priority to CN201880000113.8A priority patent/CN108697639B/zh
Publication of WO2019029154A1 publication Critical patent/WO2019029154A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • 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
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H37/00—Accessories for massage
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
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    • 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
    • A61K47/46—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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K8/0225—Granulated powders
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K8/0245—Specific shapes or structures not provided for by any of the groups of A61K8/0241
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    • A61K8/0279—Porous; Hollow
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    • A61K8/0291—Micelles
    • A—HUMAN NECESSITIES
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    • A61K8/04—Dispersions; Emulsions
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    • 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
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
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    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/884—Sequential application

Definitions

  • the invention relates to the field of transdermal administration preparations, in particular to a percutaneous absorption composition and the use thereof in preparing a percutaneous absorption preparation, the sponge bone needle as a physical penetration enhancer for skin, synergistic with different types of nanomedicines The effect, which in turn greatly increases the use of drugs and active ingredients in skin delivery systems.
  • the skin is the largest organ in the human body and the most direct route of administration. Compared to other routes of administration (eg, oral administration, injectable administration, etc.), skin administration has many unique advantages, including avoiding first-pass effects of the liver, destruction of the gastrointestinal tract, and infections caused by injection administration. It can also directly affect the local lesions of the skin, and can be administered slowly or controlled release. The adverse drug reactions are few and can be terminated at any time, which greatly improves the convenience and compliance of patients. .
  • the essence of the skin is a biofilm barrier, especially the outermost stratum corneum, to protect the body from various harmful substances and foreign pathogens (such as bacteria, fungi, parasites, viruses, heavy metals). And invasion of various chemical toxins, etc.).
  • a small number of small molecular substances molecular weight ⁇ 500Da
  • the drug molecules or biologically active components especially the increasingly popular biomacromolecules and active substances, including polysaccharides.
  • Polypeptides, proteins, nucleic acids, siRNAs, etc. are difficult to penetrate through the skin. Therefore, how to overcome the skin barrier, safely and effectively transport various biological macromolecular drugs or active substances with different physical and chemical properties to the lesion site, is a very challenging task, and also a research difficulty in the field of skin administration. And hot spots.
  • Chemical penetration-enhancing methods mainly include chemical penetration enhancers (such as DMSO, azone and pyrrolidone), peptide penetration enhancers (such as SPACE, etc.), and nanocarrier systems (such as liposomes, microemulsions, and transdermal glues). And transfer bodies, etc.).
  • chemical penetration enhancers such as DMSO, azone and pyrrolidone
  • peptide penetration enhancers such as SPACE, etc.
  • nanocarrier systems such as liposomes, microemulsions, and transdermal glues.
  • transfer bodies etc.
  • the physical osmosis method mainly includes ultrasonic introduction method, iontophoresis method, electroporation method, thermal cauterization method, laser micro-drilling method and micro-needle method, etc.
  • Some of the physical osmosis methods have significant effects, but due to their requirements for instruments and equipment. High cost, high design and production cost, not easy to carry, and due to its invasive method of administration, it often causes a series of problems such as stinging, skin irritation and burning sensation, and is only suitable for small area skin administration. The earth limits its application.
  • Microneedle technology is a new type of physical penetration promotion method that has been developed in recent years. It can form a large number of micron-sized pores on the surface of the skin in a minimally invasive manner.
  • the microneedle has a diameter of 50-200 ⁇ m and a length of several hundred micrometers to several millimeters. Etc., can pass through the stratum corneum of the skin, reach the epidermis, and even the dermis, but it is not easy to touch the pain nerves located in the dermis.
  • the skin stratum corneum after microneedle action can form a large number of micro-water pore channels, promoting a series of drugs, cosmetic active ingredients and nano-carriers including polysaccharides, peptides, proteins, hormones, vaccines and other biologically active ingredients.
  • the system and the like enter the body and are used for the treatment and prevention of skin problems and various diseases, and the application prospect is very broad, and there are few reports of side effects.
  • microneedle technology is mainly administered in the form of microneedle patch.
  • Long-term use may cause skin irritation, and the area of microneedle patch is fixed and relatively limited, although the enlargement of the administration area can increase the degree of drug penetration.
  • it also increases the irritation to the skin and reduces the compliance of the patient's medication. Therefore, it is generally only suitable for drug delivery with small doses and high activity, such as insulin or vaccine products.
  • the sharpness of the end of the microneedle and the density of the microneedle arrangement depend on the production and etching process, and the preparation materials, preparation processes and industrialization requirements are high, and the microneedles are usually arranged in an array, for the nose. Non-flat areas are difficult to function.
  • Sponge spicules are siliceous or calcareous fibrous materials that serve as skeleton support in the sponge. They have a variety of structural forms, including uniaxial, biaxial, triaxial and multiaxial. Studies have found that sponge needles have good optical properties and mechanical properties. At present, the research on sponge needles focuses on the optical properties, nanostructures and bionics of sponge needles. However, for those sponge needles that have high mechanical strength and sharp ends, there may be less research and development similar to microneedle action.
  • the sponge needle can be used as a kind of micro-needle skin physical penetration enhancer, and it has more advantages than the micro-needle, such as: the dosage, the use mode and the use area are flexible; It can stay in the stratum corneum of the skin for a long time and form a large number of persistent microchannels to better promote the percutaneous absorption of biomacromolecules or active ingredients; and so on.
  • this method also has certain limitations, and is more suitable for some pharmaceutical or cosmetic active ingredients with relatively small molecular weight and good stability, and for the penetration of biological macromolecules (>50KDa) with large molecular weight or poor stability. Still relatively limited. Therefore, it would be an object of the present invention to develop a more effective route of penetration.
  • transdermal absorption composition and its use in the preparation of a transdermal absorption composition comprising a sponge needle and a nanoparticle.
  • the synergistic action of the sponge bone needle and the nanoparticle loaded with the drug and/or the cosmetic further greatly promotes the percutaneous absorption of a series of biological macromolecules such as a pharmaceutical or cosmetic active ingredient.
  • a transdermal absorption composition comprising a sponge needle and a nanoparticle, the nanoparticle comprising a drug and/or a cosmetic.
  • the nanoparticles comprise nanosized particles of a nanocarrier, drug and/or cosmetic loaded with a drug and/or a cosmetic.
  • the nanocarrier loaded with the drug and/or the cosmetic means that the drug and/or the cosmetic is wrapped inside the nanoparticle or the drug and/or the cosmetic is adsorbed on the nanoparticle;
  • the nanoparticle of the drug and/or the cosmetic means that Drugs and cosmetics are directly pulverized into nano-sized granules, especially for Chinese medicines and cosmetics.
  • the nanoparticles of the present invention can be prepared according to conventional preparation methods in the art unless otherwise specified.
  • the nanocarrier comprises a nanoliposome, a solid lipid nanoparticle, a nanocapsule, a nanosphere, a polymer micelle, a nanosuspension.
  • the nanoliposome is a microparticle composed of a bilayer composed of a lipid such as phospholipid or cholesterol, and has a particle diameter of 1 nm to 1 ⁇ m, and has a single-chamber liposome and a multi-chamber liposome.
  • solid lipid nanoparticles are solid particles made of various lipid materials such as fatty acids, fatty alcohols and phospholipids which are solid at room temperature;
  • nanocapsules and nanospheres are made of polylactic acid, Polylactide glycolide, chitosan, gelatin and other biodegradable polymer materials are prepared, and can also be prepared by using non-degradable ethyl cellulose, acrylic resin, etc.;
  • polymer micelles are, for example, polylactic acid-polyethylene Polymer micelles formed by water-soluble block copolymer or graft copolymer such as alcohol block copolymer, chitosan or polylactic acid-glycolic acid (PLGA) block copolymer spontaneously dissolved in water; nanosuspension It is produced by pulverizing a drug in the presence of an additive such as a surfactant and water.
  • the nanoliposomes comprise common nanoliposomes (CL), flexible nanoliposomes (FL), and plastids.
  • CL common nanoliposomes
  • FL flexible nanoliposomes
  • plastids plastids
  • the sponge needle is derived from a bee sponge (Haliclona sp.).
  • the sponge needle should have a purity level that can be used for skin administration, and the purity is not less than 90%, for example, 95% or more, 98% or more, 99% or more, etc., and preferably, It should be uniform in shape and complete in structure.
  • the sponge needle is combined with a nanoparticle in the form of a sponge needle solution prepared by buffering, deionized water, double distilled water or physiological saline, wherein the sponge needle is prepared.
  • the mass concentration is from 0.01 to 100%, such as 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 20%, 40%, 60%, 80%, 100%.
  • the buffer solution is, for example, a PBS phosphate buffer solution having a molar concentration of 0.01 to 0.2 M and a pH of 4 to 9.
  • the percutaneous absorption preparation is directly prepared from a sponge bone needle and a nano particle, for example, the sponge bone needle and the nano particle are respectively prepared according to the method provided by the invention, or according to other medicine production and cosmetic production.
  • the preparation process is obtained, or the sponge bone needle and the nano particle are mixed and prepared according to the related processes of drug production and cosmetic production; or the percutaneous absorption preparation is added to the sponge bone needle and the nano particle, and then according to the drug production and the cosmetics production.
  • the related processes are prepared, or the sponge bone needles, the nanoparticles, and the auxiliary materials are mixed, and are prepared according to the related processes of drug production and cosmetics production.
  • the method of use comprises: directly applying a sponge needle in a percutaneous absorption preparation to the cleaned skin, and then applying the nanoparticles. Further, after the sponge bone needle in the percutaneous absorption preparation is directly applied to the cleaned skin, the strength and action time of the massage can be controlled by manual or electric massage, and then buffer, deionized water and double distilled water are used. Or wash the sponge needle remaining on the surface of the skin with saline, and then apply the nanoparticles.
  • the method of use comprises: applying the percutaneous absorption preparation directly to the cleaned skin. It can also be combined with manual or electric massage to control the intensity and duration of the massage to promote absorption.
  • the medicament of the present invention may be a pharmaceutically acceptable salt of a drug monomer or a drug monomer, or a combination of at least two drug monomers having the same or different pharmacological effects, or the same or different drugs.
  • the "pharmaceutically acceptable salt” as used in the present invention refers to a salt capable of retaining the pharmaceutically active and the properties of the parent compound, and includes, for example, a pharmaceutically acceptable metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, and the like.
  • the pharmaceutically acceptable metal salt includes, for example, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an aluminum salt, a zinc salt, etc.; a pharmaceutically acceptable ammonium salt such as an ammonium salt, etc.; a pharmaceutically acceptable organic amine addition salt For example, it includes an alcohol amine salt, an addition salt of morpholine, piperidine, etc.; a pharmaceutically acceptable amino acid addition salt includes, for example, a lysine salt, an arginine salt, a glycinate, a phenylalanine salt, and aspartame. Acid salts, glutamate, etc.; not limited to this.
  • the cosmetic of the present invention may be a single component or a combination of components having the same or different effects, such as moisturizing, whitening, anti-oxidation, anti-wrinkle, anti-aging and the like.
  • excipients of the present invention should be excipients which are pharmaceutically or cosmetically prepared and which comply with relevant regulations, and include, for example, diluents, solvents, excipients, absorbents, wetting agents, binders, disintegrating agents, Lubricants, solubilizers, emulsifiers, suspending agents, surfactants, film formers, propellants, antioxidants, flavoring agents, fragrances, bactericides, preservatives, and the like.
  • the percutaneous absorption composition of the invention combines the sponge bone needle with the nanoparticle loaded with the drug and the cosmetic, and can overcome the barrier of the stratum corneum of the skin, and can prolong the release of the active ingredient of the drug or the cosmetic by utilizing the sustained release property of the nanoparticle. Improve its stability, reduce its toxic side effects and skin irritation, and thus greatly promote a more efficient, stable and safe transdermal absorption of a series of biomacromolecules such as pharmaceutical or cosmetic active ingredients.
  • Figure 1 is a diagram showing the shape and structure of a sponge needle under a microscope.
  • Figure 2 is a comparison of the results of the control group of ANTS-Fucoidan and the sponge-needle needle group in Example 1 (including the distribution histogram of each layer of A skin, the fluorescence diagram of the tissue section of the B control group, and the tissue section of the C-needle group). Fluorescence map, wherein the scales of B and C are 100 ⁇ m, the same below), wherein the concentration of ANTS-Fucoidan is 10 mg/mL, the concentration of the bone needle solution is 100 mg/mL (corresponding to a mass concentration of 10%), and the solvent is 0.2 M PBS ( pH 7.4), the amount of massage is 100 ⁇ L, the same below.
  • Example 3 is a comparison result of the control group of the ANTS-Fucoidan and the sponge-needle group synergistic flexible nanoliposome group in Example 1 (including the distribution histogram of each layer of A skin, the fluorescence diagram of the tissue section of the B control group, and C).
  • Fig. 4 is a graph showing the results of comparison of the total absorption of skin in the control group, the sponge bone needle group and the sponge bone needle synergistic flexible nanoliposome group of the ANTS-Fucoidan in Example 1.
  • Figure 5 is a comparison of the results of the FITC-Hyaluronic acid control group and the single sponge bone needle group in Example 2 (including the distribution histogram of the layers of the A skin, the fluorescence of the B control group, and the C-needle tissue section). Fluorescence diagram), wherein the concentration of FITC-Hyaluronic acid is 1 mg/mL, the concentration of bone needle solution is 100 mg/mL (corresponding to a mass concentration of 10%), the solvent is 0.2 M PBS (pH 7.4), and the amount of massage is 100 ⁇ L. .
  • Figure 6 is a comparison of the results of the FITC-Hyaluronic acid control group and the sponge bone needle group in combination with ordinary nanoliposomes in Example 2 (including the distribution histogram of each layer of A skin, the fluorescence map of the B control group) and C The bone needle cooperates with the fluorescence map of the tissue section of the ordinary nano-liposome group), wherein the ordinary nano-liposome has a 90G content of 4%, the same below.
  • Figure 7 is a comparison of the results of the FITC-Hyaluronic acid control group and the sponge-needle group synergistic flexible nano-liposomes in Example 2 (including the distribution histogram of the layers of the A skin, the fluorescence map of the B control group) and C The fluorescence diagram of the bone needle synergistic flexible nano-liposome tissue section), wherein the flexible liposome 90G content is 4%, and the surfactant polyoxyethylene (20) oil ether content is 1.2%, the same below.
  • Figure 8 is a comparison of the total absorption of skin in the control group, the sponge bone needle group, the sponge bone needle synergy with the ordinary nano liposome group and the sponge bone needle synergistic flexible nanoliposome group in the second embodiment of the FITC-Hyaluronic acid group. .
  • Figure 9 is a comparison of the results of the conventional nanoliposome group and the sponge bone needle group of FITC-Hyaluronic acid in combination with common nanoliposomes in Example 2 (including the distribution histogram of the layers of A skin, B ordinary nanoliposomes). Fluorescence maps of tissue sections and fluorescence maps of C-needle needles in combination with tissue sections of common nanoliposomes).
  • Figure 10 is a comparison of the results of the flexible nanoliposome group of FITC-Hyaluronic acid and the sponge-needle group synergistic flexible nanoliposomes in Example 2 (including the distribution histogram of the layers of A skin, B flexible nano-liposomes). Fluorescence maps of tissue sections and fluorescence maps of C-needle-needle synergistic flexible nanoliposome tissue sections).
  • Figure 11 is a comparison of the results of the microneedle group and the sponge bone needle group of FITC-Hyaluronic acid in Example 2 (including the histogram of the distribution of the layers of the A skin, the fluorescence diagram of the tissue section of the B microneedle group, and the tissue of the C-needle group). Sliced fluorescence map).
  • Example 12 is a comparison result of the microneedle synergistic flexible nanoliposome group and the sponge bone acupuncture synergistic flexible nanoliposome of FITC-Hyaluronic acid in Example 2 (including the distribution histogram of each layer of A skin, B microneedle) Fluorescence of tissue sections of synergistic flexible nanoliposomes and fluorescence of C-needle-assisted flexible nanoliposome tissue sections).
  • Figure 13 is a comparison of the results of the two methods of massage between the sponge and the needle in the 360h and the control group and the microneedle group.
  • Figure 14 is a comparison of the morphology of a sponge needle derived from a bee sponge and a sponge needle derived from a calcium sponge, a litchi sponge, and a mountain sponge (including a high-purity bee sponge needle, B low purity) Bee sponge bone needle, C calcareous sponge bone needle, D litchi sponge bone needle, E mountain sponge bone needle, the scale in the figure are 100 ⁇ m).
  • Fig. 15 is a view showing the results of infiltration-promoting effect of sponge needles of different species and different forms.
  • Figure 16 is a comparison of the absorption of FITC-Hyaluronic acid in various layers of skin after the action of litchi sponge needle and high-purity bee sponge needle in Example 10 (including the distribution histogram of the layers of A skin, B litchi Fluorescence map of tissue sections of sponge bone needle group and fluorescence diagram of tissue section of C bee sponge bone group).
  • Figure 17 is a comparison of the absorption of FITC-Hyaluronic acid in various layers of the skin after the Litchi sponge needle and the high-purity bee sponge needle in Example 10, respectively, in combination with the flexible nano-liposomes (including the distribution of the layers of A skin) Histogram, fluorescence diagram of tissue fragment of B-split sponge-needle-needle synergistic flexible nano-liposome group and fluorescence diagram of tissue slice of C-bee sponge-needle-needle synergistic flexible nano-liposome group).
  • Figure 18 is a schematic diagram of skin irritation test results of high purity and low purity bee sponge needles (including A high purity bee sponge needle stimulating skin 0h, B low purity bee sponge needle stimulating skin 0h, C high purity bee sponge needle Stimulate the skin for 24h, D low-purity bee sponge needle stimulates the skin for 24h, E high-purity bee sponge needle stimulates the skin for 48h, F low-purity bee sponge needle stimulates the skin for 48h, G is high-purity bee sponge needle to stimulate the skin for 96h, H Low-purity bee sponge needle stimulates skin for 96h, I high-purity bee sponge needle stimulates skin for 168h, J low-purity bee sponge needle stimulates skin for 168h, K high-purity bee sponge needle stimulates skin for 240h, L low-purity bee sponge needle Irritating skin 240h).
  • a high purity bee sponge needle stimulating skin 0h B low purity bee sponge needle stimulating skin 0h
  • Fig. 19 is a graph showing changes in skin barrier function recovery with time after high-purity bee sponge needle and low-purity bee sponge needle stimulating the skin.
  • Pre-treatment of pig skin Take fresh pig skin, remove the subcutaneous fat layer, shave the pig hair to a length no longer than 2mm, use it immediately or freeze it at -20 °C ⁇ -80 °C for use.
  • ANTS-Fucoidan average molecular weight of 60 KDa
  • ANTS-Fucoidan flexible nanoliposome solution containing 1 to 100 mg/ml
  • the pigskin was taken out at 37 ° C, 600 r / min, and after 16 hours of transdermal. Both the quantitative and qualitative methods were used to simultaneously detect the penetration-promoting effect of the sponge bone on the ANTS-Fucoidan drug.
  • the absorption of ANTS-Fucoidan in the stratum corneum, active epidermal layer, dermis layer and receiving cell was read by a full-wavelength microplate reader according to the detection wavelength of ANTS (excitation wavelength: 350 nm and emission wavelength: 520 nm).
  • FIG. 1 The shape and structure of the sponge needle under the microscope are shown in Fig. 1; the comparison results of the control group of ANTS-Fucoidan and the sponge bone needle group in Example 1 (including the distribution histogram of the skin layers and the fluorescence diagram of the tissue section) 2, the comparison results of the control group and the sponge-needle group synergistic flexible nano-liposome group of the ANTS-Fucoidan in Example 1 are shown in FIG. 3; the control group of the ANTS-Fucoidan in Example 1, the sponge needle group and See Figure 4 for a comparison of the total absorption of the sponge-needle-needle synergistic flexible nanoliposome group.
  • FIG. 5 The comparison results of the FITC-Hyaluronic acid control group and the single sponge bone needle group in Example 2 are shown in Fig. 5; the comparison results of the FITC-Hyaluronic acid control group and the sponge bone needle group in combination with ordinary nanoliposomes in Example 2
  • Figure 6 is a comparison of the results of the FITC-Hyaluronic acid control group and the sponge bone needle group synergistic flexible nanoliposomes in Example 2. See Figure 7; the FITC-Hyaluronic acid control group and the sponge needle in Example 2.
  • the results of the comparison of the total absorption of skin in the group, the sponge bone and the common nano-liposome group and the sponge-needle-needle synergistic flexible nano-liposome group are shown in Fig.
  • Example 2 the sponge-needle group synergy of FITC-Hyaluronic acid in Example 2
  • FIG. 9 The results of comparison between the ordinary nano-liposome group and the ordinary nano-liposome group are shown in FIG. 9; the FITC-Hyaluronic acid sponge-needle group of Example 2 is synergistically flexible nano-liposome group and flexible nano-liposome alone. See Figure 10 for a comparison of the results of the group.
  • the sponge needle of the present invention was compared with a conventional microneedle (Dermaroller) method.
  • the comparison results of the microneedle group of FITC-Hyaluronic acid and the sponge bone needle group of Example 2 are shown in Fig. 11; the synergistic flexible nano-liposome microneedle group of FITC-Hyaluronic acid and the sponge-needle synergistic flexible nanometer of Example 2.
  • See Figure 12 for a comparison of the results of the liposome group. The results show that the effect of the sponge needle is significantly better than the traditional microneedle.
  • the sponge bone needle of the second embodiment is combined with the manual massage and the electric massage method, and the result of the transepidermal water loss within 360 hours of the microneedle group is shown in FIG. 13 , which shows that the sponge bone needle can stay in the skin for a long time compared with the micro needle.
  • the stratum corneum also forms a large number of persistent microchannels that promote transdermal absorption of biomacromolecules or active ingredients.
  • Fig. 14 is a view showing the high purity and low purity of a sponge bone needle derived from a bee sponge (Haliclona sp.) used in the present invention, and a morphology comparison with a sponge needle derived from a calcium sponge, a litchi sponge, and a mountain sponge.
  • the high-purity bee sponge needle (Fig. 14A) and the low-purity bee sponge needle (Fig. 14B) are double-pointed, and the high-purity bee sponge needle is more uniform and structurally intact. Less impurities.
  • the calcareous sponge needle (Fig. 14C) has a three-pointed shape; the litchi sponge needle (Fig. 14D) is spherical; the mountain sponge needle (Fig. 14E) has a single pointed shape.
  • the above-mentioned sponge bone needles derived from different species and having different morphology were examined for the effect of promoting penetration.
  • the results are shown in Fig. 15.
  • the high-purity (purity 99.5%) bee sponge needle has a much higher rate of skin conductance before and after the action than the calcareous sponge needle (purity 95.1%), litchi sponge Bone needle (purity 93.2%), mountain sponge needle (purity 96.7%) and low-purity bee sponge needle (purity 69.9%), indicating high-purity bee sponge needle compared to calcareous sponge needle, litchi sponge bone Needle, mountain sponge bone needle and low-purity bee sponge bone needle have a more obvious effect of promoting penetration.
  • Example 2 the absorption of FITC-Hyaluronic acid in various layers of the skin was observed after the action of the litchi sponge needle and the high-purity bee sponge needle. As shown in Fig. 16, the bee sponge needle group has a better penetration promoting effect.
  • the absorption of FITC-Hyaluronic acid in various layers of the skin was compared with that of the high-purity bee sponge needle and the high-purity bee sponge needle.
  • the percutaneous total absorption of FITC-Hyaluronic acid in the skin layer of the bee sponge needle and the flexible nanoliposome group was 37.89%, while the litchi sponge bone needle synergized with the FITC in the flexible nanoliposome group.
  • the total percutaneous absorption of Hyaluronic acid in the skin layers was 4.76%, indicating that the bee sponge needle and the flexible nanoliposome group have better penetration-enhancing effect.
  • the flexible liposome was extruded through a 200 nm membrane with a particle size of 168.13 ⁇ 2.99 nm; the flexible liposome was extruded through a 100 nm membrane with a particle size of 130.57 ⁇ 0.65 nm.
  • Test method Take 1mL syringe, add 1mL pure water, ordinary liposome, flexible liposome, add 500g pressure (measured by platform scale), calculate the time of completely penetrating through 100nm membrane, calculate the sample with pure water as control The ratio of pure water passage time is used to examine the deformability of the liposome.
  • the total skin absorption of the sponge-needle-needle synergistic flexible nanoliposome group is greater than that of the sponge nanoneedle in combination with the general nano-liposome group.
  • the total skin absorption of the liposome group was increased compared with the total skin absorption of the ordinary nanoliposome group, which also indicated that the sponge needle and the flexible nanoliposome produced a synergistic effect.

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Abstract

一种经皮吸收组合物及其在制备经皮吸收制剂中的用途，所述经皮吸收组合物包括海绵骨针和纳米颗粒。所述经皮吸收组合物在克服皮肤角质层屏障的同时，利用各种纳米颗粒的缓控释特性延长药物或化妆品活性成分的释放、提高其稳定性，降低其毒副作用和皮肤刺激性等。

Description

一种经皮吸收组合物及其在制备经皮吸收制剂中的用途 技术领域
本发明涉及经皮给药制剂领域，具体涉及一种经皮吸收组合物及其在制备经皮吸收制剂中的用途，海绵骨针作为一种皮肤物理促渗剂，与不同类型的纳米药物协同作用，进而大幅增加药物及活性成分在皮肤给药系统中的应用。
背景技术
皮肤是人体最大的器官，同时也是最直接的给药途径。相比于其他给药途径(如：口服给药、注射给药等)，皮肤给药具有很多独特的优势，包括避免肝脏的首过效应、胃肠道的破坏及注射给药引起的感染和痛楚等；同时其还可以直接作用于皮肤局部病变部位，可缓释或控释给药，药物不良反应少且可随时终止给药，极大地改善了患者治疗的便利性和依从性，等等。
然而，皮肤的本质是一种生物膜屏障，尤其是其最外层的角质层，用以保护机体免受外界各种有害物质和外源性病原体(如细菌、真菌、寄生虫、病毒、重金属和各种化学毒素等)的入侵。一般只有极少数的小分子物质(分子量<500Da)可以有效地通过皮肤角质层屏障，而绝大部分药物分子或生物活性成分，尤其是越来越热门的生物大分子药物和活性物质，包括多糖、多肽、蛋白、核酸、siRNA等均很难通过皮肤渗透吸收。因此，如何克服皮肤屏障，安全有效地将各种理化性质不同的生物大分子药物或活性物质经皮输送至病灶部位，是一项极具挑战性的工作，同时也是皮肤给药领域的研究难点和热点。
目前，促进药物或活性物质经皮吸收的方法大致可分为化学促渗方法和物理促渗方法。化学促渗方法主要包括化学促渗剂(如：DMSO、氮酮和吡咯烷酮类等)、多肽促渗剂(如：SPACE等)、纳米载体系统(如：脂质体、微乳、经皮胶和传递体等)等。化学促渗方法虽然具有价廉、起效迅速及使用方便等特点，但由于其促渗效果相对有限，而且有些促渗剂由于自身毒性问题，长期使用会破坏皮肤的屏障结构，引起皮肤刺激和过敏，甚至引起全身毒性反应，严重限制了其应用。物理促渗方法主要包括超声导入法、离子导入法、电穿孔法、热烧灼法、激光微钻法及微针法等，其中一些物理促渗方法虽然效果显著，但由于其对仪器设备的要求高、设计和生产成本较高、不易携带，同时由于其入侵性的给药方式，常造成刺痛、皮肤刺激和灼烧感等一系列问题，且只适用于小面积的皮肤给药，极大地限制了其应用。
微针技术是近年来兴起的一种新式物理促渗方式，以微创的方式可在皮肤表面形成大量的微米级孔道，微针的直径在50～200μm，长度在几百微米到几毫米不等，可穿过皮肤角质层，到达表皮层，甚至真皮层，却又不易触及位于真皮层的痛觉神经。与此同时，微针作用后的皮肤角质层可以形成大量的微型水孔隙通道，促使包括多糖、多肽、蛋白、激素、疫苗及其他生物活性成分在内的一系列药物、化妆品活性成分和纳米载体系统等进入体内，用于皮肤问题和各种疾病的治疗和预防，应用前景非常广阔，且鲜有副作用的报道。
然而，由于皮肤本身的弹性作用，微针在皮肤表面形成的微通道通常会在10～20分钟内自动闭合，从而导致药物、化妆品活性成分或纳米载体颗粒的有效渗透时间非常有限。当前，微针技术主要是以微针贴剂形式给药，长期使用可能会引起皮肤过敏，同时微针贴剂的给药面积固定且相对有限，虽然扩大给药面积可以增加药物的透过程度，但也会增加对皮肤的刺激性，降低患者用药的顺应性。因此，一般只适用于剂量小且活性强的药物运输，比如胰岛素或者疫苗类产品。另外，微针末端的尖锐度和微针排布的密集度取决于其生产和刻蚀工艺，对其制备材质、制备工艺与产业化要求较高，且微针通常为阵列排布，对于鼻翼等非平坦区域难以发挥作用。
海绵骨针(Sponge spicules)是海绵体内起骨架支撑作用的硅质或钙质纤维状物，具有多种结构形态，包括单轴、双轴、三轴和多轴等。研究发现，海绵骨针具有良好的光学特性和力学性能，目前关于海绵骨针的研究多集中在海绵骨针的光学特性、纳米结构和仿生学等领域。然而对于那些天然具有较高的机械强度、末端尖锐的海绵骨针，可能具有类似于微针作用的研究与开发的较少。我们创造性地研究了海绵骨针可以作为一种类微针的皮肤物理促渗剂，且相比于微针，其具有更多的优势，比如：使用剂量、使用方式和使用面积等灵活多变；并可长时间滞留于皮肤角质层并形成大量持续存在的微通道，从而更好地促进生物大分子药物或活性成分的经皮吸收；等等。
但是该方法也存在一定的局限性，较适用于一些分子量相对较小且稳定性较好的药物或化妆品活性成分，对于那些分子量大或者稳定性差的生物大分子(>50KDa)，其促渗效果仍相对有限。因此，开发一种更有效的促渗途径将是本发明的目的所在。
发明内容
本发明的目的在于克服现有技术的不足之处，提供了一种经皮吸收组合物及其 在制备经皮吸收制剂中的用途，该经皮吸收组合物包括海绵骨针和纳米颗粒，通过海绵骨针与搭载有药物和/或化妆品的纳米颗粒的协同作用，进而大幅促进药物或化妆品活性成分等一系列生物大分子的经皮吸收。
本发明解决其技术问题所采用的技术方案之一是：
一种经皮吸收组合物，包括海绵骨针和纳米颗粒，所述纳米颗粒中含有药物和/或化妆品。
一实施例中：所述纳米颗粒包括搭载有药物和/或化妆品的纳米载体、药物和/或化妆品的纳米化颗粒。其中，搭载有药物和/或化妆品的纳米载体是指将药物和/或化妆品包裹在纳米颗粒内部或将药物和/或化妆品吸附在纳米颗粒上；药物和/或化妆品的纳米化颗粒是指将药物、化妆品直接粉碎成纳米级别的颗粒，特别是针对中药类的药物、化妆品。本发明涉及的纳米颗粒，除有特别说明外，均可按照本领域常规制备方法制备。
一实施例中：所述纳米载体包括纳米脂质体、固体脂质纳米粒、纳米囊、纳米球、聚合物胶束、纳米混悬剂。其中，纳米脂质体是以磷脂、胆固醇等类脂质构成的双分子层为膜材包合而成的微粒，粒径可在1nm～1μm，具有单室脂质体、多室脂质体、大多孔脂质体等形式；固体脂质纳米粒是由多种室温下为固态的类脂材料如脂肪酸、脂肪醇及磷脂等制成的固体颗粒；纳米囊、纳米球是由聚乳酸、聚丙交酯乙交酯、壳聚糖、明胶等生物降解高分子材料制备得到，也可用非降解性的乙基纤维素、丙烯酸树脂等制备得到；聚合物胶束是例如聚乳酸-聚乙二醇嵌段共聚物、壳聚糖、聚乳酸-羟基乙酸(PLGA)嵌段共聚物等水溶性嵌段共聚物或接枝共聚物在水中溶解后自发形成的高分子胶束；纳米混悬剂是在表面活性剂和水等附加剂存在下将药物粉碎加工制成。
一实施例中：所述纳米脂质体包括普通纳米脂质体(CL)、柔性纳米脂质体(FL)、醇质体。其中，柔性纳米脂质体是在普通纳米脂质体的制备过程中加入表面活性物质制备得到，具有高度的变形能力；醇质体是在普通纳米脂质体的制备过程中加入较高浓度的醇制成。
一实施例中：所述海绵骨针来源于蜂海绵(Haliclona sp.)。
一实施例中：所述海绵骨针应达到可用于皮肤给药的纯度级别，纯度不低于90％，例如为95％或以上，98％或以上，99％或以上等，最好，还应形态均一、结构完整。
一实施例中：所述海绵骨针以海绵骨针溶液的形式与纳米颗粒联合，该海绵骨 针溶液为缓冲液、去离子水、双蒸水或生理盐水配制而成，其中海绵骨针的质量浓度为0.01～100％，例如0.01％、0.05％、0.1％、0.5％、1％、5％、10％、20％、40％、60％、80％、100％。所述缓冲液例如为摩尔浓度为0.01～0.2M，pH值为4～9的PBS磷酸盐缓冲液。
本发明解决其技术问题所采用的技术方案之二是：
上述经皮吸收组合物在制备经皮吸收制剂中的用途。
一实施例中：所述经皮吸收制剂为海绵骨针、纳米颗粒直接制成，例如将海绵骨针和纳米颗粒分别按照本发明提供的方法制备得到，或者按照其他药物生产、化妆品生产的相关工艺制备得到，或将海绵骨针和纳米颗粒混合后按照药物生产、化妆品生产的相关工艺制备得到；或者，该经皮吸收制剂为海绵骨针、纳米颗粒分别添加辅料后按照药物生产、化妆品生产的相关工艺制备得到，或将海绵骨针、纳米颗粒、辅料混合，按照药物生产、化妆品生产的相关工艺制备得到。
一实施例中：其使用方法包括：将经皮吸收制剂中的海绵骨针直接涂抹于清洁后的皮肤，再涂抹纳米颗粒。进一步的，将经皮吸收制剂中的海绵骨针直接涂抹于清洁后的皮肤后，可以配合手动或电动按摩方式，控制按摩的力度和作用时间，而后用缓冲液、去离子水、双蒸水或生理盐水洗去残留在皮肤表面的海绵骨针，再涂抹纳米颗粒。
一实施例中：其使用方法包括：将经皮吸收制剂直接涂抹于清洁后的皮肤。也可以进一步配合手动或电动按摩方式，控制按摩的力度和作用时间，促进吸收。
本发明所述的药物可以为药物单体、或药物单体的药学上可接受的盐，也可以为至少两种具有相同或不同药效的药物单体的组合、或种具有相同或不同药效的药物单体与药物单体的药学上可接受的盐的组合、或至少两种具有相同或不同药效的药物单体的药学上可接受的盐的组合。
本发明所述的“药物上可接受的盐”指的是能够保留药学活性和母体化合物性质的盐，例如包括可药用的金属盐、铵盐、有机胺加成盐、氨基酸加成盐等；其中可药用的金属盐例如包括钠盐、钾盐、镁盐、钙盐、铝盐、锌盐等；可药用的铵盐例如包括铵盐等；可药用的有机胺加成盐例如包括醇胺盐以及吗啉、哌啶等的加成盐等；可药用的氨基酸加成盐例如包括赖氨酸盐、精氨酸盐、甘氨酸盐、苯丙氨酸盐、天冬氨酸盐、谷氨酸盐等；并不以此为限。
本发明所述的化妆品可以为单组分或具有相同或不同功效的多组分的组合，例 如具有保湿、美白、抗氧化、抗皱、抗衰老等功效。
本发明所述的辅料应为药学上或化妆品制备工艺上可接受的、符合相关法规的辅料，例如包括稀释剂、溶剂、赋形剂、吸收剂、润湿剂、黏合剂、崩解剂、润滑剂、增溶剂、乳化剂、助悬剂、表面活性剂、成膜剂、抛射剂、抗氧剂、矫味剂、芳香剂、杀菌剂、防腐剂等。
本技术方案与背景技术相比，它具有如下优点：
本发明的经皮吸收组合物将海绵骨针与搭载药物、化妆品的纳米颗粒联合应用，在克服皮肤角质层屏障的同时，可以利用纳米颗粒的缓控释特性延长药物或化妆品活性成分的释放、提高其稳定性，降低其毒副作用和皮肤刺激性等，进而大幅促进药物或化妆品活性成分等一系列生物大分子更为高效、稳定和安全的经皮吸收。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为海绵骨针在显微镜下的外形与结构图。
图2为实施例1中ANTS-Fucoidan的对照组和单独海绵骨针组的对比结果图(包括A皮肤各层的分布柱状图，B对照组组织切片的荧光图及C骨针组组织切片的荧光图，其中，B和C的标尺为100μm，下同)，其中ANTS-Fucoidan浓度为10mg/mL，骨针溶液浓度为100mg/mL(相当于质量浓度10％)，溶剂为0.2M PBS(pH 7.4)，按摩用量为100μL，下同。
图3为实施例1中ANTS-Fucoidan的对照组和海绵骨针组协同柔性纳米脂质体组的对比结果图(包括A皮肤各层的分布柱状图，B对照组组织切片的荧光图及C骨针协同柔性纳米脂质体组组织切片的荧光图)，其中柔性脂质体90G含量为4％，表面活性剂聚氧乙烯(20)油醚含量为1.2％，下同。
图4为实施例1中ANTS-Fucoidan的对照组、海绵骨针组和海绵骨针协同柔性纳米脂质体组在皮肤总吸收量的对比结果图。
图5为实施例2中FITC-Hyaluronic acid的对照组和单独海绵骨针组的对比结果图(包括A皮肤各层的分布柱状图，B对照组组织切片的荧光图及C骨针组组织切片的荧光图)，其中FITC-Hyaluronic acid浓度为1mg/mL，骨针溶液浓度为100mg/mL(相当于质量浓度10％)，溶剂为0.2M PBS(pH 7.4),按摩用量为100μL，下同。
图6为实施例2中FITC-Hyaluronic acid的对照组和海绵骨针组协同普通纳米 脂质体的对比结果图(包括A皮肤各层的分布柱状图，B对照组组织切片的荧光图及C骨针协同普通纳米脂质体组组织切片的荧光图)，其中普通纳米脂质体90G含量为4％，下同。
图7为实施例2中FITC-Hyaluronic acid的对照组和海绵骨针组协同柔性纳米脂质体的对比结果图(包括A皮肤各层的分布柱状图，B对照组组织切片的荧光图及C骨针协同柔性纳米脂质体组组织切片的荧光图)，其中柔性脂质体90G含量为4％，表面活性剂聚氧乙烯(20)油醚含量为1.2％，下同。
图8为实施例2中FITC-Hyaluronic acid的对照组、海绵骨针组、海绵骨针协同普通纳米脂质体组以及海绵骨针协同柔性纳米脂质体组在皮肤总吸收量的对比结果图。
图9为实施例2中FITC-Hyaluronic acid的普通纳米脂质体组和海绵骨针组协同普通纳米脂质体的对比结果图(包括A皮肤各层的分布柱状图，B普通纳米脂质体组组织切片的荧光图及C骨针协同普通纳米脂质体组组织切片的荧光图)。
图10为实施例2中FITC-Hyaluronic acid的柔性纳米脂质体组和海绵骨针组协同柔性纳米脂质体的对比结果图(包括A皮肤各层的分布柱状图，B柔性纳米脂质体组组织切片的荧光图及C骨针协同柔性纳米脂质体组组织切片的荧光图)。
图11为实施例2中FITC-Hyaluronic acid的微针组和海绵骨针组的对比结果图(包括A皮肤各层的分布柱状图，B微针组组织切片的荧光图及C骨针组组织切片的荧光图)。
图12为实施例2中FITC-Hyaluronic acid的微针协同柔性纳米脂质体组和海绵骨针组协同柔性纳米脂质体的对比结果图(包括A皮肤各层的分布柱状图，B微针协同柔性纳米脂质体组组织切片的荧光图及C骨针协同柔性纳米脂质体组组织切片的荧光图)。
图13为360h内海绵骨针两种按摩方法与对照组及微针组的经皮水分丢失对比结果图。
图14为本发明采用的来源于蜂海绵的海绵骨针以及与来源于钙质海绵、荔枝海绵、山海绵的海绵骨针的形态对比(包括A高纯度的蜂海绵骨针，B低纯度的蜂海绵骨针，C钙质海绵骨针，D荔枝海绵骨针，E山海绵骨针，图中标尺均为100μm)。
图15为不同种属、不同形态的海绵骨针的促渗功效考察结果。
图16为实施例10中荔枝海绵骨针与高纯度的蜂海绵骨针分别作用后 FITC-Hyaluronic acid在皮肤各层的吸收情况的对比结果图(包括A皮肤各层的分布柱状图，B荔枝海绵骨针组组织切片的荧光图及C蜂海绵骨针组组织切片的荧光图)。
图17为实施例10中荔枝海绵骨针与高纯度的蜂海绵骨针分别协同柔性纳米脂质体后FITC-Hyaluronic acid在皮肤各层的吸收情况的对比结果图(包括A皮肤各层的分布柱状图，B荔枝海绵骨针协同柔性纳米脂质体组组织切片的荧光图及C蜂海绵骨针协同柔性纳米脂质体组组织切片的荧光图)。
图18为高纯度和低纯度的蜂海绵骨针的皮肤刺激实验结果示意图(包括A高纯度蜂海绵骨针刺激皮肤0h，B低纯度蜂海绵骨针刺激皮肤0h，C高纯度蜂海绵骨针刺激皮肤24h，D低纯度蜂海绵骨针刺激皮肤24h，E高纯度蜂海绵骨针刺激皮肤48h，F低纯度蜂海绵骨针刺激皮肤48h，G为高纯度蜂海绵骨针刺激皮肤96h，H低纯度蜂海绵骨针刺激皮肤96h，I高纯度蜂海绵骨针刺激皮肤168h，J低纯度蜂海绵骨针刺激皮肤168h，K高纯度蜂海绵骨针刺激皮肤240h，L低纯度蜂海绵骨针刺激皮肤240h)。
图19为高纯度蜂海绵骨针及低纯度蜂海绵骨针刺激皮肤后，皮肤屏障功能恢复随时间变化对比图。
具体实施方式
下面通过实施例具体说明本发明的内容：
实施例1：
(1)猪皮的前期处理：取新鲜猪皮，除去皮下脂肪层，将猪毛剃至长度不长于2mm，立即使用或冻存于-20℃～-80℃备用。
(2)柔性纳米脂质体的制备：将磷脂90G(100mg/ml)、表面活性剂聚氧乙烯(20)油醚(100mg/ml)和甲醇/氯仿＝1:1按一定的比例加入至圆形烧瓶中，通过旋转蒸发仪蒸干，使之在圆形烧瓶底表面形成均匀的膜。再加入1～5ml的ANTS-Fucoidan(岩藻多糖)药物溶液，通过振荡/超声等步骤进行水化。使用进口脂质体专用挤压装置，挤压21次，最后转移至新的EP管中，即得1～100mg/ml的ANTS-Fucoidan柔性纳米脂质体溶液，待用。
(3)海绵骨针溶液的配制：在海绵骨针中加入一定量的摩尔浓度为0.01～0.2M，pH为6.5～7.5的PBS磷酸盐缓冲液、去离子水、生理盐水或双蒸水等对皮肤无一定刺激性的溶剂，使海绵骨针的质量浓度达到0.01～100％，得海绵骨针溶液。
(4)体外透皮实验：用φ40nm的圆形打孔器钻取同样直径大小的猪皮，安装 至Franz扩散透皮装置上，采用离体皮肤经皮电阻试验测定海绵骨针溶液作用前后皮肤的电导变化情况。海绵骨针作用前，离体猪皮的电导不高于10μA，则说明皮肤角质层屏障功能完好，可用于接下来的实验。海绵骨针作用后，离体猪皮的电导增至40～150μA，则说明皮肤角质层屏障经海绵骨针不同程度的破坏。然后分别加入200μL含1～100mg/ml的ANTS-Fucoidan(平均分子量为60KDa)溶液或ANTS-Fucoidan柔性纳米脂质体溶液，使药物溶液均匀的覆盖在皮肤表面。于37℃，600r/min，透皮16h后取出猪皮。采用定量和定性两种方法同时检测海绵骨针对ANTS-Fucoidan药物的促渗效果。
(5)定量法：采用胶带剥离法依次剥离第1～10层角质层、分离活性表皮层并将真皮层部分切碎，分别浸于4ml PBS/甲醇＝1:1溶液中，室温条件下，200r/min，萃取8～24h。采用全波长酶标仪根据ANTS的检测波长(激发波长：350nm和发射波长：520nm)分别读取角质层、活性表皮层、真皮层以及接收池中ANTS-Fucoidan的吸收情况。结果表明，与对照组相比，海绵骨针组中ANTS-Fucoidan在皮肤各层的经皮总吸收量从0.01％增加至4.83％，参见附图2；海绵骨针协同柔性纳米脂质体组中ANTS-Fucoidan在皮肤各层的经皮总吸收量可大幅增加至24.76％，参见附图3。
(6)定性法：采用冷冻包埋切片法将离体猪皮的给药部位用φ为5mm的圆形打孔器钻取同样直径大小的组织块，迅速包埋至OCT中，在包埋组织的不同深度部位分别切出厚度为20μm的薄片，用中性树胶封片。而后在共聚焦显微镜下分别观察对照组、海绵骨针组以及海绵骨针协同柔性纳米脂质体组ANTS-Fucoidan在皮肤各层的分布情况。具体参见附图2、3和4。
海绵骨针在显微镜下的外形与结构参见图1；实施例1中ANTS-Fucoidan的对照组和单独海绵骨针组的对比结果图(包括皮肤各层的分布柱状图和组织切片的荧光图)参见图2；实施例1中ANTS-Fucoidan的对照组和海绵骨针组协同柔性纳米脂质体组的对比结果图参见图3；实施例1中ANTS-Fucoidan的对照组、海绵骨针组和海绵骨针协同柔性纳米脂质体组在皮肤总吸收量的对比结果图参见图4。
实施例2：
(1)猪皮的前期处理：同实施例1。
(2)普通纳米脂质体的制备：将磷脂90G(100mg/ml)和甲醇/氯仿＝1:1按一定的比例加入至圆形烧瓶中，通过旋转蒸发仪蒸干，使之在圆形烧瓶底表面形成均匀的膜；再加入1～5ml的FITC-Hyaluronic acid(透明质酸)药物溶液，通过振 荡/超声等步骤进行水化，使用进口脂质体专用挤压装置，挤压21次，最后转移至新的EP管中，即得1～100mg/ml的FITC-Hyaluronic acid普通纳米脂质体溶液，待用。
(3)柔性纳米脂质体的制备：类似于实施例1。
(4)海绵骨针溶液的配制：同实施例1。
(5)体外透皮实验：类似于实施例1。分别加入150μL含1～100mg/ml的FITC-Hyaluronic acid(平均分子量为250KDa)溶液或FITC-Hyaluronic acid普通纳米脂质体溶液或FITC-Hyaluronic acid柔性纳米脂质体溶液，使药物溶液均匀的覆盖在皮肤表面。于37℃，600r/min，透皮16h后取出猪皮。采用定量和定性两种方法同时检测海绵骨针对FITC-Hyaluronic acid药物的促渗效果。
(6)定量法：类似于实施例1。采用全波长酶标仪根据FITC的检测波长(激发波长：490nm和发射波长：530nm)分别读取角质层、活性表皮层、真皮层以及接收池中FITC-Hyaluronic acid的吸收情况。结果表明，与对照组相比，海绵骨针组中FITC-Hyaluronic acid在皮肤各层的经皮总吸收量从1.20％增加至6.92％，参见附图5；海绵骨针协同普通纳米脂质体组中FITC-Hyaluronic acid在皮肤各层的经皮总吸收量增加至9.01％，参见附图6；而海绵骨针协同柔性纳米脂质体组中FITC-Hyaluronic acid在皮肤各层的经皮总吸收量大幅增加至37.89％，参见附图7。
(7)定性法：类似于实施例1。在共聚焦显微镜下分别观察对照组、海绵骨针组、海绵骨针组协同普通纳米脂质体组以及海绵骨针协同柔性纳米脂质体组FITC-Hyaluronic acid在皮肤各层的分布情况。具体参见附图6、7和8。
实施例2中FITC-Hyaluronic acid的对照组和单独海绵骨针组的对比结果图参见图5；实施例2中FITC-Hyaluronic acid的对照组和海绵骨针组协同普通纳米脂质体的对比结果图参见图6；实施例2中FITC-Hyaluronic acid的对照组和海绵骨针组协同柔性纳米脂质体的对比结果图参见图7；实施例2中FITC-Hyaluronic acid的对照组、海绵骨针组、海绵骨针协同普通纳米脂质体组以及海绵骨针协同柔性纳米脂质体组在皮肤总吸收量的对比结果图参见图8；实施例2中FITC-Hyaluronic acid的海绵骨针组协同普通纳米脂质体组与单独普通纳米脂质体组的对比结果图参见图9；将实施例2的FITC-Hyaluronic acid的海绵骨针组协同柔性纳米脂质体组与单独柔性纳米脂质体组的对比结果图参见图10。
结果显示，海绵骨针协同普通纳米脂质体组的效果优于对照组，也优于单独海 绵骨针组、单独普通纳米脂质体组，说明海绵骨针与普通纳米脂质体协同增效，显著提高了经皮吸收效果。而且，海绵骨针协同柔性纳米脂质体组的效果优于对照组，也优于单独海绵骨针组、单独柔性纳米脂质体组，说明海绵骨针与柔性纳米脂质体协同增效，显著提高了经皮吸收效果，且其协同效果更优于海绵骨针协同普通纳米脂质体组。
另外，将本发明的海绵骨针与传统的微针(Dermaroller)方式进行了对比。FITC-Hyaluronic acid的微针组与实施例2中海绵骨针组的对比结果图参见图11；FITC-Hyaluronic acid的协同柔性纳米脂质体微针组和实施例2中海绵骨针协同柔性纳米脂质体组的对比结果图参见图12。结果说明，海绵骨针的效果明显优于传统微针。
实施例2的海绵骨针配合手动按摩和电动按摩两种按摩方法，与微针组的360h内经皮水分丢失对比结果参见图13，说明海绵骨针与微针相比，能够长时间滞留于皮肤角质层并形成大量持续存在的微通道，从而促进生物大分子药物或活性成分的经皮吸收。
实施例3：
(1)猪皮的前期处理：同实施例1。
(2)固体脂质纳米粒的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同固体脂质纳米粒相对其他组，具有明显的促渗效果。
实施例4：
(1)猪皮的前期处理：同实施例1。
(2)纳米囊的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同纳米囊相对其他组，具有明显的促渗效果。
实施例5：
(1)猪皮的前期处理：同实施例1。
(2)纳米球的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同纳米球相对其他组，具有明显的促渗效果。
实施例6：
(1)猪皮的前期处理：同实施例1。
(2)聚合物胶束的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同聚合物胶束相对其他组，具有明显的促渗效果。
实施例7：
(1)猪皮的前期处理：同实施例1。
(2)纳米混悬剂的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同纳米混悬剂相对其他组，具有明显的促渗效果。
实施例8：
(1)猪皮的前期处理：同实施例1。
(2)醇质体的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同醇质体相对其他组，具有明显的促渗效果。
实施例9：
(1)猪皮的前期处理：同实施例1。
(2)纳米化颗粒的制备：参照本领域常规技术制备。
(3)海绵骨针溶液的配制：同实施例1。
(4)体外透皮实验：参照实施例1进行。结果显示，海绵骨针协同纳米化颗粒相对其他组，具有明显的促渗效果。
实施例10
图14为本发明采用的来源于蜂海绵(Haliclona sp.)的海绵骨针的高纯度与低纯度，与来源于钙质海绵、荔枝海绵、山海绵的海绵骨针的形态对比。从图中可看出，高纯度的蜂海绵骨针(图14A)与低纯度的蜂海绵骨针(图14B)均呈双尖形， 高纯度的蜂海绵骨针形态更为均一、结构完整、杂质更少。而钙质海绵骨针(图14C)呈三尖形；荔枝海绵骨针(图14D)呈球形；山海绵骨针(图14E)呈单尖形。
参照实施例1的体外透皮实验，将上述来源于不同种属、具有不同形态的海绵骨针进行促渗功效考察。结果如图15所示，在浓度相等的情况下，高纯度(纯度99.5％)的蜂海绵骨针在作用前后的皮肤电导增加比率远高于钙质海绵骨针(纯度95.1％)、荔枝海绵骨针(纯度93.2％)、山海绵骨针(纯度96.7％)及低纯度的蜂海绵骨针(纯度69.9％)，说明高纯度的蜂海绵骨针相比钙质海绵骨针、荔枝海绵骨针、山海绵骨针及低纯度的蜂海绵骨针，具有更加明显的促渗效果。
参照实施例2的方法，对比荔枝海绵骨针与高纯度的蜂海绵骨针分别作用后FITC-Hyaluronic acid在皮肤各层的吸收情况。如图16所示，蜂海绵骨针组的促渗效果更好。
参照实施例2的方法，对比荔枝海绵骨针与高纯度的蜂海绵骨针分别协同柔性纳米脂质体后FITC-Hyaluronic acid在皮肤各层的吸收情况。如图17所示，蜂海绵骨针协同柔性纳米脂质体组中FITC-Hyaluronic acid在皮肤各层的经皮总吸收量为37.89％，而荔枝海绵骨针协同柔性纳米脂质体组中FITC-Hyaluronic acid在皮肤各层的经皮总吸收量为4.76％，说明蜂海绵骨针协同柔性纳米脂质体组的促渗效果更好。
实施例11
将高纯度和低纯度的蜂海绵骨针进行皮肤刺激实验。
实验方法：将豚鼠剃毛，取高纯度(99.5％)和低纯度(69.9％)蜂海绵骨针溶液(100mg/mL相当于质量浓度10％)各100μL对豚鼠背部两侧对称处按摩两分钟，并在按摩后，24h、48h、96h、168h和240h分别进行经皮水分丢失检测并拍照记录。
结果如图18、图19所示。高纯度骨针按摩后皮肤在96h后基本复原，无感染迹象；而低纯度骨针按摩后伤口明显发红，有感染迹象，复原速度变慢，在168h后才基本复原。皮肤本身有免疫体系，修复越快意味着受外界病原体侵害的几率越小。高纯度蜂海绵骨针刺激后，皮肤恢复速度更快，表明高纯度的蜂海绵骨针安全性更好。
实施例12
柔性脂质体过200nm膜挤出，粒径大小为168.13±2.99nm；柔性脂质体过100 nm膜挤出，粒径大小为130.57±0.65nm。
测试方法：取1mL注射器，分别加入1mL纯水、普通脂质体、柔性脂质体，外加500g压力(台秤测量)，计算其完全透过100nm膜的时间，以纯水为对照，计算样品与纯水通过时间的比率以考查脂质体的变形能力。
测量结果：普通脂质体过100nm膜通过时间与纯水通过时间比率为156.71％±4.32％；柔性脂质体过100nm膜通过时间与纯水通过时间比率为139.27％±2.06％。说明柔性脂质体的变形性更好，因而促渗效果越好。而粒径80～150nm的柔性脂质体协同海绵骨针的促渗效果最好。
进一步结合图6至图10可以看出，海绵骨针协同柔性纳米脂质体组的皮肤总吸收量相比海绵骨针协同普通纳米脂质体组的皮肤总吸收量的提高程度，大于柔性纳米脂质体组的皮肤总吸收量相比普通纳米脂质体组的皮肤总吸收量的提高程度，这也说明海绵骨针与柔性纳米脂质体产生了协同作用。
以上所述，仅为本发明较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。

Claims (10)

  1. 一种经皮吸收组合物，其特征在于：包括海绵骨针和纳米颗粒，所述纳米颗粒中含有药物和/或化妆品。
  2. 根据权利要求1所述的经皮吸收组合物，其特征在于：所述纳米颗粒包括搭载有药物和/或化妆品的纳米载体、药物和/或化妆品的纳米化颗粒。
  3. 根据权利要求2所述的经皮吸收组合物，其特征在于：所述纳米载体包括纳米脂质体、固体脂质纳米粒、纳米囊、纳米球、聚合物胶束、纳米混悬剂。
  4. 根据权利要求3所述的经皮吸收组合物，其特征在于：所述纳米脂质体包括普通纳米脂质体、柔性纳米脂质体、醇质体。
  5. 根据权利要求1所述的经皮吸收组合物，其特征在于：所述海绵骨针来源于蜂海绵Haliclona sp.。
  6. 根据权利要求1所述的经皮吸收组合物，其特征在于：所述海绵骨针纯度不低于90％。
  7. 根据权利要求1所述的经皮吸收组合物，其特征在于：所述海绵骨针以海绵骨针溶液的形式与纳米颗粒联合，该海绵骨针溶液为缓冲液、去离子水、双蒸水或生理盐水配制而成，其中海绵骨针的质量浓度为0.01～100％。
  8. 一种权利要求1至7中任一项所述的经皮吸收组合物在制备经皮吸收制剂中的用途。
  9. 根据权利要求8所述的用途，其特征在于：所述经皮吸收制剂为海绵骨针、纳米颗粒直接制成，或为海绵骨针、纳米颗粒及辅料制成。
  10. 根据权利要求8所述的用途，其特征在于：其使用方法包括：将经皮吸收制剂中的海绵骨针直接涂抹于清洁后的皮肤，配合或不配合按摩方式，而后洗去或不洗去残留在皮肤表面的海绵骨针，再涂抹纳米颗粒；或将经皮吸收制剂直接涂抹于清洁后的皮肤，配合或不配合按摩方式。
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