WO2014029143A1 - Système d'introduction transdermique de médicament à base d'extrait de plante et procédé transdermique associé - Google Patents

Système d'introduction transdermique de médicament à base d'extrait de plante et procédé transdermique associé Download PDF

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WO2014029143A1
WO2014029143A1 PCT/CN2012/081306 CN2012081306W WO2014029143A1 WO 2014029143 A1 WO2014029143 A1 WO 2014029143A1 CN 2012081306 W CN2012081306 W CN 2012081306W WO 2014029143 A1 WO2014029143 A1 WO 2014029143A1
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Prior art keywords
plant extract
transdermal
preparation
mediated drug
oil
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PCT/CN2012/081306
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English (en)
Chinese (zh)
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陆毅祥
张平静
朱远源
陈建新
彭微
李铁军
冯文建
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百奥迈科生物技术有限公司
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Publication of WO2014029143A1 publication Critical patent/WO2014029143A1/fr

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    • 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
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/342—Alcohols having more than seven atoms in an unbroken chain
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
    • 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
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • Plant extract-mediated drug transdermal introduction system and transdermal method thereof Plant extract-mediated drug transdermal introduction system and transdermal method thereof
  • the present invention relates to a plant extract-mediated drug transdermal delivery system and a transdermal method therefor. Background technique
  • Abnormal pigmentation of the skin due to excessive and uneven secretion of melanin may cause spots or plaques on the face and back of the hand, such as: pregnancy spots, acne marks, birthmarks, moles, freckles, sunburn and age spots.
  • a transdermal absorption enhancer refers to a substance that promotes penetration of a drug through the stratum corneum and diffusion of the epidermis. Promoters are chemically classified into surfactants, lipid solvents, hydrophilic solvents, and macrocyclic compounds (Pfister W R et al, Pharm Tech, 1990, 14 (9): 132). At present, transdermal enhancers that have been researched and applied more include natural accelerators and synthetic accelerators (Fang Shiping, Chinese Journal of Hospital Pharmacy, 2000, 20(12): 750-752)
  • Natural accelerators include: 1) terpenoids. Such as mint (Menthol (Krishnaiah YS et al, Pharm DevTech nol, 2002, 7 (3): 305), menthol, peppermint oil), borneol (Zhu Jianping, Chinese Journal of Pharmaceutical Sciences, 1990, 34 (2): 104 ), Duchenene; 2) Volatile oil or essential oil, such as eucalyptus oil (Chen Hongqing, Progress in Pharmacy, 2000, 24(4): 235), Cinnamon oil (Shen Qi et al, Chinese Journal of Hospital Medicine, 2001, 21 (4) ): 197), Cnidium volatile oil, Fengxiang oil (Li Wei, Journal of Shanghai Medical University, 1998, 25(5): 365), turpentine (Li Juan et al., Journal of China Pharmaceutical University, 1999, 30(5): 343 ), galangal oil (Shen Qi et al, Chinese herbal medicine, 2000, 23 (11): 697), clove volatile oil (Z
  • Natural penetration enhancers are natural plant extracts, have a good penetration-enhancing effect, and are less irritating, and have great value for development and utilization, and have become a hot spot in the research of penetration enhancers in recent years.
  • RNAi RN A interference
  • siRNA small interfering RNA
  • RISC RNA-induced silencing complex
  • the technical problem to be solved by the present invention is to provide a plant extract-mediated drug transdermal introduction system and a transdermal method, which enable biomacromolecules to pass through the skin's natural barrier (stratum corneum) to the basal layer of the skin to exert its therapeutic effect. effect.
  • the present invention provides a plant extract-mediated drug transdermal delivery system, comprising: 1) a transdermal agent prepared from at least one plant extract; 2) a biomacromolecules Or its preparation.
  • the plant extract is a vegetable volatile oil.
  • the plant volatile oil is a mixture of any one or more of angelica volatile oil, eucalyptus oil, eucalyptus oil, clove oil, cinnamon oil, turpentine oil and citric oil.
  • the plant extract is a terpenoid.
  • the terpenoid is a mixture of any one or more of peppermint oil, borneol and menthol.
  • the transdermally-introducing agent comprises 0 to 98 parts by weight of jojoba oil, 1 to 100 parts by weight of angelica volatile oil,
  • the biomacromolecule is a nucleic acid molecule, a protein molecule, a polypeptide molecule or an insulin molecule.
  • the biomacromolecule is a nucleic acid molecule
  • the biomacromolecular preparation is a nucleic acid preparation.
  • the nucleic acid preparation includes a nucleic acid molecule and a preparation compatible therewith.
  • the preparation compatible with the nucleic acid molecule is a lipid or an alcohol.
  • the nucleic acid molecule is a mixture of functional RNA and any one or more of the structural forms or mimetics and DNA comprising the modification and the modified structural form or mimetic thereof.
  • the functional RNA is a mixture of any one or more of siRNA, miRNA, small ligand RNA (sliRNA) and RNA aptamer.
  • nucleic acid preparation is a cosmetic emulsion comprising a nucleic acid molecule, comprising the following components in weight percent:
  • Ion-free water is added to 100%.
  • nucleic acid preparation is a makeup containing a nucleic acid molecule
  • Hyaluronic acid 0.01-0.05%
  • Ion-free water is added to 100%.
  • the invention also provides a plant extract-mediated drug transdermal method, characterized in that the above-mentioned plant extract-mediated drug transdermal introduction system is used, and the specific steps are as follows: 1) using the transdermal introduction first The agent is permeabilized, and then the biomacromolecule or a preparation thereof is transdermally; or 2) the biomacromolecule or a preparation thereof is uniformly mixed with the transdermal agent, and then a composite formulation is prepared to be transparent. skin.
  • the composite formulation in the method 2) comprises the following components in weight percent: Angelica essential oil 1-20%
  • Hyaluronic acid 0.01-0.05%
  • the composite formulation in the method 2) comprises the following components in weight percent: Angelica essential oil 1-20%;
  • Hyaluronic acid 0.01-0.05%
  • the invention also provides the use of the above plant extract mediated drug transdermal delivery system for the preparation of a skin health product.
  • the skin health product is a cosmetic.
  • the cosmetic is a cosmetic having whitening and freckle function.
  • the cosmetic is a whitening and freckle makeup containing siRNA regulating the expression of a melanin-related gene.
  • the invention also provides the use of the above plant extract mediated drug transdermal method for the preparation of a skin health product.
  • the skin health product is a cosmetic.
  • the cosmetic is a cosmetic having whitening and freckle function.
  • the cosmetic is a whitening and freckle makeup containing siRNA regulating the expression of a melanin-related gene.
  • the plant extract-mediated drug transdermal introduction system and the transdermal method thereof provided by the invention can be applied to skin health products, such as cosmetics, so that biomacromolecules penetrate into the skin to achieve a better therapeutic effect.
  • Figure 1 is a transdermal photograph of a mouse
  • Figure 2 is a comparison diagram of the effect of transdermal delivery of different transdermal agents
  • Figure 3 is a comparison of the effects of different concentrations of Angelica sinensis oil and jojoba oil compound formula on nucleic acid transdermal
  • Figure 4 is a comparison of the effect of the composite formula transdermal agent combined with the nucleic acid emulsion formula I on the transdermal effect of nucleic acid
  • Figure 6 is a comparison of the effect of the transdermal formulation of the composite formula with the nucleic acid emulsion formula II for transdermal delivery of nucleic acids
  • Figure 8 is a comparison of the effects of different transdermal drug delivery agents combined with nucleic acid emulsion formulation I for transdermal delivery of nucleic acids;
  • Figure 9 is a comparison diagram of the effect of transdermal administration of a composite formulation (transdermal introducer + nucleic acid molecule / nucleic acid preparation). detailed description
  • mice Experimental Animal Center of Nantong University, 4 to 6 weeks old, weighing 18 ⁇ 20g, male and female random.
  • Cy3-labeled siRNA (Cy3-siRNA) (Beaucom Biotech Co., Ltd.).
  • the PBS solution was used as a transdermal agent as a control group.
  • the interval is 10min. Wipe the area with the transdermal agent with a clean cotton swab to remove the skin. A residual transdermal introducer of the surface.
  • a 5 mL centrifuge tube cap was capped, and 200 ⁇ M of the preparation was aspirated from a small hole of a 5 mL centrifuge tube cap with an ImL syringe to cover the mouse skin. The mice were placed in the dark place and observed every half an hour. Observe whether the centrifuge tube and the mouse skin are firmly adhered, whether there is leakage, and if there is leakage, re-stick the leak, make up the preparation, and record.
  • the remaining preparation in the centrifuge tube was aspirated, placed in a new centrifuge tube, and stored at -80 °C.
  • the centrifuge tube of the back of the mouse was removed, and the skin of the mouse was washed with physiological saline, and washed at least 10 times each time with 1 mL.
  • the mice were sacrificed by the neck-breaking method, and the skin of the mice was carefully lifted with an ophthalmologist.
  • the skin of the mice was cut along the lines of the centrifuge tube, and the water was removed and stored at -80 ° C until use.
  • Frozen sections of skin tissue were prepared according to the method of the American Leica cryostat, and the skin was cut to a thickness of 5 ⁇ m.
  • mice Experimental Animal Center of Nantong University, 4 to 6 weeks old, weighing 18 ⁇ 20g, male and female random.
  • Cy3-labeled siRNA (Cy3-siRNA) (Beaucom Biotech Co., Ltd.).
  • transdermal enhancer is the same as step 2.1 in embodiment 1.
  • 2.1.2 Dissolve 4 mg of siRNA in 10 mL of 0.1% PBS containing 25% glycerol and mix for later use.
  • mice were randomly divided into 3 groups of 2 mice each:
  • a comparison of the effect of transdermal delivery of nucleic acids for different transdermal agents the white part of which is the distribution of Cy3 labeled siRNA in the cortex, wherein a and b are PBS negative control groups, c, d
  • e, f is the azone-promoting group.
  • the siRNA of the PBS negative control group was deposited on the surface of the skin, and the Angelica sinensis oil penetration group and the azone exposure group showed significant siRNA entry into the dermis layer.
  • mice Experimental Animal Center of Nantong University, 4 to 6 weeks old, weighing 18 ⁇ 20g, male and female random.
  • Cy3-labeled siRNA (Cy3-siRNA) (Baimax Biotech Co., Ltd.).
  • the preparation method of the transdermal enhancer is the same as the step 2.1 in the first embodiment, except that the angelica essential oil and the jojoba oil are used.
  • the mixture replaces Angelica essential oil.
  • mice were randomly divided into 6 groups, 2 mice each, with jojoba oil as the base oil, and 10%, 20%, 50% and 100% of the essential oils of Angelica essential oil:
  • Fig. 3 the effect of nucleic acid transdermal coating for different concentrations of angelica essential oil and jojoba oil compound formulation is shown in Fig. 3.
  • the white part of the figure shows the distribution of Cy3 labeled siRNA in the cortex.
  • a and b are PBS negative control group
  • c and d are 100% jojoba oil to promote the control group
  • e is 10% angelica essential oil +90% jojoba oil penetration group
  • g, h is 20 % Angelica essential oil + 80% jojoba oil promoted through the group
  • i, j is 50% Angelica essential oil + 50% jojoba oil promoted through group
  • k 1 is 100% Angelica essential oil to promote the group.
  • siRNA of the PBS negative control group was deposited on the skin surface, and the 100% jojoba oil-permeation control group did not differ from the PBS negative control group, and the depth of siRNA entering the skin increased with the increase of the concentration of angelica essential oil. This indicates that the penetration of siRNA is concentration dependent on Angelica essential oil.
  • mice Experimental Animal Center of Nantong University, 4 to 6 weeks old, weighing 18 ⁇ 20g, male and female random.
  • the preparation method of the transdermal enhancer is the same as the step 2.1 in the first embodiment, except that the mixture of ingredients in 1.3 is used instead of the angelica essential oil.
  • the oil phase and the water phase in Table 3 were respectively heated to 85 °C, homogenized, and kept for 30 minutes ; the temperature was lowered to 75 °C, and the oil phase was added to the water phase under stirring, and stirred uniformly; rapid stirring, under vacuum Homogenize at 75 °C for 3 min ; cool to 45 °C. Add the components numbered 17, 18, 19 in Table 3, stir for 20 min, and cool to room temperature.
  • the non-ionized water is heated to 85 ° C, the temperature is kept for 30 minutes, then cooled to 45 ° C, and the serial number is added to Table 4 under stirring.
  • mice were randomly divided into 8 groups, each treating 2 mice:
  • mice 8 ( ⁇ L 10% chloral hydrate was intraperitoneally injected for anesthesia. After the mice were completely anesthetized, the mice were placed flat on medical gauze, and the back of the mouse was cut with an eye clipping skin of about 1.5 C. Mxl.5cm, can not cut the skin of the mouse. Cut the bottom of the centrifuge tube at 1cm along the 5mL centrifuge tube, take the end of the tube of the centrifuge tube, and repair the edge of the tube. Drain the lOuL medical glue and apply it to the mouth of the 5mL centrifuge tube. Edge, then press the tube onto the back skin of the mouse for 10 s.
  • the interval was 10 min. Wipe the area where the transdermal agent was applied with a clean cotton swab to remove the residual transdermal agent on the skin surface. Apply a 0.2 mg/ml fluorescently labeled siRNA emulsion to the back skin with a clean cotton swab and apply evenly. The mice were then placed in the dark.
  • the remaining preparation in the centrifuge tube was aspirated, placed in a new centrifuge tube, and stored at -80 °C.
  • the centrifuge tube of the back of the mouse was removed, and the skin of the mouse was washed with physiological saline, and washed at least 10 times each time with 1 mL.
  • the mice were sacrificed by the neck-breaking method, and the skin of the mice was carefully lifted with an ophthalmologist.
  • the skin of the mice was cut along the lines of the centrifuge tube, and the water was removed and stored at -80 ° C until use.
  • Frozen sections of skin tissue were prepared according to the method of the American Leica cryostat, and the skin was cut to a thickness of 5 ⁇ m.
  • Figure 4 is a comparison diagram of the effects of a compound transdermal agent combined with a nucleic acid emulsion I for transdermal delivery of nucleic acids, wherein a and b are In the PBS negative control group, cd was the BW-01 penetration group, ef was the BW-02 penetration group, and gh was the BW-03 penetration group.
  • Figure 5 is a comparison diagram of the effects of the compound transdermal agent combined with the nucleic acid cream I for transdermal nucleic acid, wherein ab is
  • c d was the BW-01 penetration-promoting group
  • e f was the BW-02 penetration-promoting group
  • g h was the BW-03 penetration-promoting group.
  • the white part of the figure shows the distribution of Cy3-labeled siRNA in the cortex, and the compound transdermal introducers BW-01 BW-02 and BW-03 can effectively promote the absorption of siRNA.
  • the nucleic acid emulsion I promotes the transdermal penetration depth of the nucleic acid is superior to the nucleic acid cream I.
  • mice Experimental Animal Center of Nantong University, 4 6 weeks old, weighing 18 20g, male and female random.
  • the preparation method of the transdermal enhancer is the same as the step 2.1 in the first embodiment, except that the mixture of ingredients in 1.3 is used instead of the angelica essential oil.
  • the preparation method is the same as the step in the embodiment 4. 2.1.2.1
  • mice were randomly divided into 8 groups, and 2 mice were treated in each group:
  • Fig. 6 is a comparison diagram of the effects of a compound transdermal agent combined with a nucleic acid emulsion I for transdermal nucleic acid, wherein a and b are PBS negative control groups, c and d are BW-04 penetration groups, and e and f are BW-05. Promote the group, g, h is the BW-06 promoting group.
  • FIG. 7 is a comparative diagram of the effect of a compound transdermal agent combined with a nucleic acid cream II for transdermal nucleic acid, wherein a and b are PBS negative control groups, c and d are BW-04 promoting groups, and e and f are BW- 05 promoted the group, g, h for the BW-06 promoting group.
  • the white part of the figure shows the distribution of Cy3-labeled siRNA in the cortex.
  • the compound transdermal agents BW-04, BW-05, and BW-06 can effectively promote the absorption of siRNA.
  • the nucleic acid emulsion formula I promotes the transdermal depth of the nucleic acid to be superior to the nucleic acid cream formulation.
  • mice Experimental Animal Center of Nantong University, 4 to 6 weeks old, weighing 18 ⁇ 20g, male and female random.
  • transdermal introducer eucalyptus oil, eucalyptus oil, clove oil, cinnamon oil, turpentine, peppermint oil, citric acid oil, angelica essential oil, borneol (5% borneol dissolved in 75% ethanol), menthol (5% Menthol is dissolved in 75% ethanol) (Jiangxi Cedar Natural Pharmaceutical Oil Co., Ltd.).
  • mice were intraperitoneally injected with 8 ( ⁇ L 10% chloral hydrate for anesthesia. After the mice were completely anesthetized, the mice were placed flat on medical gauze, and the back of the mouse was cut with an ophthalmic clipping skin of about 1.5 C mxl .5 cm. Can not cut the skin of mice.
  • 2.2 Transdermal introduction agent to promote penetration 8 ( ⁇ L 10% chloral hydrate for anesthesia. After the mice were completely anesthetized, the mice were placed flat on medical gauze, and the back of the mouse was cut with an ophthalmic clipping skin of about 1.5 C mxl .5 cm. Can not cut the skin of mice.
  • the interval was 10 min. Wipe the area where the introduction agent (and its control PBS solution) was applied with a clean cotton swab to remove the residual introduction agent (and its control PBS solution) on the skin surface. Apply a 0.2 mg/ml fluorescently labeled siRNA emulsion to the back skin with a clean cotton swab and apply evenly. The mice were then placed in the dark.
  • the remaining nucleic acid preparation in the centrifuge tube was aspirated, placed in a new centrifuge tube, and stored at -80 °C.
  • the centrifuge tube on the back of the mouse was removed, and the skin of the mouse was washed with physiological saline, and washed at least 10 times each time with 1 mL.
  • the mice were sacrificed by cervical dislocation. The skin of the mice was carefully lifted with ophthalmology. The skin of the mice was cut along the lines of the centrifuge tube, and the water was removed and stored at -80 °C until use.
  • Frozen sections of skin tissue were prepared according to the method of the American Leica cryostat, and the skin was cut to a thickness of 5 ⁇ m.
  • FIG. 8 the effect of transfecting nucleic acid emulsions with different transdermal agent-incorporating nucleic acid emulsion formula I is shown in FIG.
  • the middle white part is the distribution of Cy3 labeled siRNA in the cortex, wherein ab is the eucalyptus oil promoting group, cd is the eucalyptus oil promoting group, ef is the clove oil promoting group, gh is the cinnamon oil promoting group, ij
  • k 1 is the peppermint oil promoting group, mn is the citric oil-promoting group, op is the angelica essential oil promoting group, qr is the borneol promoting group, st is the menthol promoting group, u V is PBS negative control group.
  • the compound transdermal agent can effectively promote the absorption of siRNA, and all of the ten transdermal agents have a transdermal effect, wherein Angelica sinensis, eucalyptus oil, and peppermint oil have better permeation effect.
  • Example 7 Angelica sinensis, eucalyptus oil, and peppermint oil have better permeation effect.
  • mice Experimental Animal Center of Nantong University, 4 6 weeks old, weighing 18 20g, male and female random.
  • Olivem 1000 cete stearyl oleate, sorbitan
  • cetostearyl alcohol cetyl alcohol, stearyl alcohol
  • oil phase 5 PEG-100 stearate 2-5g
  • mice were randomly divided into 4 groups of 3 mice each:
  • the oil phase and the water phase in Table 10 were respectively heated to 85 °C, and homogenized, and kept for 30 minutes ; the temperature was lowered to 75 °C, and the oil phase was added to the water phase under stirring, and stirred uniformly; rapid stirring, under vacuum Homogenize at 75 °C for 3 min ; cool to 45 °C. Add the components numbered 18, 19, 20 in Table 10, stir for 20 min, and cool to room temperature.
  • the oil phase and the water phase in Table 11 were respectively heated to 85 ° C, and homogenized, kept for 30 min ; the temperature was lowered to 75 V, and the oil phase was added to the water phase under stirring, and stirred uniformly; rapid stirring, under vacuum 75 °C was homogenized for 3 min ; cooled to 45 °C.
  • the components numbered 18, 19, 20 in Table 11 were added, stirred for 20 min, and cooled to room temperature.
  • the preparation method is the same as step 2.1.2.1 in the fourth embodiment. 2.1.4 Preparation of nucleic acid emulsion ⁇
  • the nucleic acid emulsion prepared in Example 5 was used.
  • mice were intraperitoneally injected with 8 ( ⁇ L 10% chloral hydrate for anesthesia. After the mice were completely anesthetized, the mice were placed flat on medical gauze, and the back of the mouse was cut with an eye clipping skin of about 1.5 C mxl.5 cm. Can not cut the skin of mice.
  • nucleic acid-containing emulsion compound formula and the nucleic acid cream composite formulation to the back skin with a clean cotton swab, and apply evenly, while using the nucleic acid emulsion formula I (same as in Example 11) and the nucleic acid emulsion formula II (same as in the example 12) as a negative control. Operate as described above. The mice were placed in the dark after treatment.
  • the remaining preparation in the centrifuge tube was aspirated, placed in a new centrifuge tube, and stored frozen at -80 °C.
  • the centrifuge tube of the back of the mouse was removed, and the skin of the mouse was washed with physiological saline, and washed at least 10 times each time with 1 mL.
  • the mice were sacrificed by cervical dislocation, and the skin of the mice was carefully lifted with an ophthalmology.
  • the skin of the mice was cut along the lines of the centrifuge tube, and the water was removed and stored at -80 ° C until use.
  • Frozen sections of skin tissue were prepared according to the method of the American Leica cryostat, and the skin was cut to a thickness of 5 ⁇ m.
  • a comparison of the effects of transdermal administration of a composite formulation (transdermal introducer + nucleic acid molecule/nucleic acid preparation), the white part of which is the distribution of Cy3-labeled siRNA in the cortex, wherein a, b are nucleic acids In the emulsion compound formula group, c and d are the nucleic acid cream compound formula group, e and f are the nucleic acid emulsion formula I control group, and g and h are the nucleic acid emulsion formula II control group. As can be seen from Fig. 9, both the nucleic acid emulsion composite formulation and the nucleic acid cream composite formulation are effective for transdermal siRNA.

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Abstract

La présente invention concerne un système d'introduction transdermique de médicament à base d'extrait de plante et un procédé transdermique associé. Le système d'introduction transdermique comprend un agent d'introduction transdermique préparé à partir d'au moins un extrait de plante, et des macromolécules biologiques ou une préparation les comprenant. Le procédé transdermique comprend : dans un premier temps l'utilisation d'un agent d'introduction transdermique pour promouvoir la pénétration, puis la réalisation de la pénétration transdermique des macromolécules biologiques ou de la préparation les contenant ; ou le mélange uniforme des macromolécules biologiques ou de la préparation les contenant avec l'agent d'introduction transdermique pour préparer une préparation composite pour la pénétration transdermique. La présente invention concerne en outre une application du système d'introduction de médicament transdermique à base d'extrait de plante susmentionné dans la préparation de produits de soins pour la peau.
PCT/CN2012/081306 2012-08-23 2012-09-12 Système d'introduction transdermique de médicament à base d'extrait de plante et procédé transdermique associé WO2014029143A1 (fr)

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CN2012103026269A CN102793639A (zh) 2011-12-16 2012-08-23 一种植物提取物介导的药物透皮导入系统及其透皮方法
CN201210302626.9 2012-08-23

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CN105560077B (zh) * 2015-12-31 2018-12-18 上海宇昂水性新材料科技股份有限公司 化妆品用促透剂
CN107823637B (zh) * 2017-11-29 2019-01-11 安徽中医药大学 一种蛭肽蛋白乳膏剂及其制备方法和应用
CN111135120B (zh) 2018-11-06 2021-04-20 万华化学集团股份有限公司 一种水性聚氨酯功能型面膜基质及其应用
CN109223666B (zh) * 2018-12-04 2021-05-25 施莱新研(杭州)生物科技有限公司 一种植物提取物组合物及其在护肤品中的应用
CN111743852B (zh) * 2019-03-29 2022-10-28 傅柏舜 使大分子药物经皮肤通透的组合物

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