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WO2021130541A1 - Composition d'administration transdermique d'arnsi et son utilisation - Google Patents

Composition d'administration transdermique d'arnsi et son utilisation Download PDF

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Publication number
WO2021130541A1
WO2021130541A1 PCT/IB2020/020080 IB2020020080W WO2021130541A1 WO 2021130541 A1 WO2021130541 A1 WO 2021130541A1 IB 2020020080 W IB2020020080 W IB 2020020080W WO 2021130541 A1 WO2021130541 A1 WO 2021130541A1
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Prior art keywords
sirna
skin
liposomes
cfl
flexible
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English (en)
Chinese (zh)
Inventor
陈铭
梁雪娇
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Xiamen University
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Xiamen University
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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/25—Silicon; Compounds thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • a siRNA transdermal delivery composition and its use Technical Field belongs to the technical field of transdermal drug delivery preparations, and specifically relates to a siRNA transdermal delivery composition and its use. Background technique
  • RNA interference is a specific gene silencing mechanism triggered by small interfering RNA (siRNA), which uses short double-stranded RNA with 21 to 23 nucleotides in a highly sequence-specific manner Inhibit gene expression.
  • siRNA small interfering RNA
  • RNAi therapy has been proven to treat skin diseases caused by abnormal gene expression, including hair loss, psoriasis, allergic skin disease, skin cancer, congenital pneumonia and hyperpigmentation, etc.
  • the local application of RNAi therapy can avoid the first-pass metabolism and side effects involved in systemic administration, while local administration can directly act on the skin lesions, improving patient compliance, etc. .
  • siRNA is a hydrophilic and negatively charged biological macromolecule ( ⁇ 13 kDa)
  • the first obstacle to delivery is the outermost stratum corneum (SC) of the skin, mainly due to the "brick and cement" structure and lipophilicity of the stratum corneum.
  • SC stratum corneum
  • various penetration enhancement strategies and technologies have been developed and utilized, such as microneedles, chemical penetration enhancers and nanocarrier systems.
  • SHS as a new type of silicon microneedles, can be used alone or in combination with flexible liposomes to improve the transdermal absorption of hydrophilic macromolecules.
  • SHS can penetrate the stratum corneum of the skin and create a large number of long-lasting microchannels (up to 72 h) in the stratum corneum. Applying 10 mg of SHS at 1.77 cm 2 can produce about 850 micropores per mm 2.
  • the second obstacle to the local delivery of siRNA is the skin cell membrane. Many methods have been adopted to overcome this challenge and promote the internalization of siRNA, such as electroporation Pores, lipid complexes and heat shock, etc.
  • encapsulating the siRNA into a nanocarrier is a strategy to protect the siRNA from degradation to the greatest extent.
  • a siRNA transdermal delivery composition including sponge spicules, flexible liposomes and the siRNA.
  • the flexible liposome and the siRNA are in the form of flexible liposomes carrying siRNA, or a mixed form of flexible liposomes and siRNA, that is, non-carrying form, preferably flexible liposomes carrying siRNA form.
  • the sponge spicules are bee sponge spicules, which are derived from bee sponge Haliclonasp.
  • the purity of the sponge spicule is preferably not less than 90%.
  • the sponge spicules are in the form of a sponge spicule solution, which is prepared by buffer, deionized water, double distilled water or physiological saline, wherein the mass concentration of the sponge spicules is 0.01 ⁇ 100%.
  • the flexible liposomes include ordinary flexible liposomes and cationic flexible liposomes.
  • the flexible liposome of the present invention is prepared by adding surface active substances (such as sodium cholate, sodium deoxycholate, Tween, Span, polyoxyethylene oleyl ether, etc.) during the preparation of ordinary liposomes , Has a high degree of deformability.
  • Flexible liposomes can be classified into cationic flexible liposomes, anionic flexible liposomes, and neutral flexible liposomes according to the charge they carry.
  • the cationic flexible liposomes of the present invention are positively charged flexible liposomes.
  • the cationic flexible liposomes of the present invention can be prepared by phospholipids with cations ((2,3-dioleoyl-propyl)-trimethylamine (DOTAP), 2,3-dioleoyloxypropyl-l-bromo At least one of trimethylamine (DOTMA), dimethyl dioctadecyl ammonium bromide (DDAB), dioleoylphosphatidylethanolamine (DOPE), etc.) and a surfactant.
  • DOTAP 2,3-dioleoyl-propyl)-trimethylamine
  • DOTMA 2,3-dioleoyloxypropyl-l-bromo
  • DOTMA trimethylamine
  • the ordinary flexible liposomes described in the present invention are other flexible liposomes other than cationic flexible liposomes, for example, they may be neutral flexible liposomes.
  • the ordinary flexible liposomes of the present invention can be prepared by soybean lecithin, egg yolk lecithin, etc. and surfactants.
  • the phospholipid concentration of the ordinary flexible liposome is 3 ⁇ 5%.
  • the membrane material of the ordinary flexible liposome includes soybean lecithin and a surfactant.
  • the mass ratio of soybean lecithin and surfactant is 4:1 ⁇ 1.5.
  • the phospholipid concentration of the cationic flexible liposome is 0.02% ⁇ 1.5%, preferably 0.04% ⁇
  • the membrane material of the cationic flexible liposome includes DOTAP and a surfactant.
  • the mass ratio of DOTAP and surfactant is 1:1 ⁇ 1.5.
  • the surfactant is polyoxyethylene 20 oleyl ether.
  • the particle size of the ordinary flexible liposome is 90 ⁇ 110 nm, (; the potential is -10 ⁇ 0 mV, and the potential decreases after carrying siRNA.
  • the cationic flexible liposome The particle size is 90 ⁇ 110 nm, and the potential is 30 ⁇ 40 mV. After carrying siRNA, the G potential is reduced to 20 ⁇ 30 mV or -35 ⁇ -25 mV.
  • the third technical solution adopted by the present invention to solve its technical problems is: The use of an siRNA transdermal delivery composition in gene knockout.
  • the fourth technical solution adopted by the present invention to solve its technical problems is: The use of an siRNA transdermal delivery composition in the preparation of transdermal absorption preparations or cosmetics.
  • the transdermal absorption preparation or cosmetic is directly made of sponge spicules, flexible liposomes and siRNA, for example, spongy spicules, flexible liposomes and siRNA are prepared separately according to the method provided by the present invention, Or prepared according to other medical, pharmaceutical or cosmetic related processes, or prepared by mixing sponge spicules, flexible liposomes and siRNA according to medical, pharmaceutical or cosmetic related processes; or, the process Skin absorption preparations or cosmetics are sponge spicules, flexible liposomes and siRNA prepared by adding auxiliary materials respectively according to relevant medical, pharmaceutical or cosmetic processes, or mixing spongy spicules, flexible liposomes, siRNA and auxiliary materials , Prepared according to medical, pharmaceutical or cosmetic related processes.
  • the excipients of the present invention should be medically, pharmaceutically or cosmetically acceptable excipients that comply with relevant laws and regulations, such as diluents, solvents, excipients, absorbents, wetting agents, binders, and disintegrants , Lubricants, solubilizers, emulsifiers, suspending agents, surfactants, film-forming agents, propellants, antioxidants, flavors, fragrances, fungicides, preservatives, etc.
  • This technical solution has the following advantages:
  • the present invention combines SHS with different lipid vesicles, ordinary flexible liposomes (FL) and cationic flexible liposomes (CFL) to greatly enhance siRNA Skin permeability outside the body.
  • FIG. 1 is the liposome characterization in Example 2, where: a. liposome size, b. liposome potential, c. liposome flexibility.
  • Figure 2 shows the penetration rate of GAPDH-siRNA in the skin under different topical treatments in the in vitro transdermal penetration experiment of Example 3 (all liposomes in the figure carry siRNA) (* means p ⁇ 0.05, ** means p ⁇ 0.0l, *** means /? ⁇ 0.001 ).
  • Figure 3 is a fluorescence image of siRNA skin delivery under a confocal microscope in the in vitro transdermal penetration experiment of Example 3 (all liposomes in the figure carry siRNA), in which: (8) control group; (b) SHS massage; (c) Topically use CFL (l %)@siRNA; (d) Topically use CFL (0.05%)@siRNA; (e) Topically use SHS and FL@ siRNA; (f) Topically use SHS and CFL (l%)@siRNA ; (g) Local combined use of dermaroller and CFL (0.05%)@siRNA; (h) Local combined use of SHS and CFL (0.05%)@siRNA.
  • Figure 4 is the fluorescence image of liposome-carrying FAM-siRNA transfection in L929 cells in Example 4.
  • CFL(0.05%)@siRNA A, a): Add 1.5 ( J CFL(0.05%) and 30 pmol FAM-siRNA mixture to each well
  • CFL(l%)@siRNA(B, b) Add 1.5 ( JCFL (1 %) and 30 pmol FAM-siRNA mixture to each well
  • FL@ siRNA (C, c) Add 1.5 ( J FL and 30 pmol FAM-siRNA mixture to each well
  • siRNA( D, d) 30 pmol FAM-siRNA.
  • FIG. 5 shows the effect of liposomes carrying FAM-siRNA on L929 cells in Example 4 GAPDH protein knockout rate (*** means /? ⁇ 0.001).
  • Figure 6 shows the cytotoxicity of liposomes to L929 cells in Example 4, where: (8)Adding different doses After CFL (0.05%), CFL (1%) and FL, the cell growth inhibition rate.
  • (b) Cell growth status after adding different doses of liposomes.
  • Figure 7 shows the knockout rate of GAPDH protein in the local treatment in vivo in Example 5. Among them: A: 3D simulation diagram of GAPDH protein knockout rate; B: Top view of Figure A. The final concentration of GAPDH-siRNA administration in all groups was 25nmol/ml.
  • Injection + CFL(0_05%)@siRNA This group is 100 ( J GAPDH-siRNA (3.75nmol) mixture, the group tested the GAPDH protein knockout rate in the skin of three different treatment positions, namely the skin at the injection center, the skin 0.5 cm from the injection center, and 1.0 cm from the injection center Skin.
  • SHS + CFL(0.05 %)@siRNA This group is 1000 GAPDH-siRNA
  • Example 1 Preparation of cationic flexible liposomes (CFL) from liposomes
  • the preparation of cationic flexible liposomes (CFL) adopts a film hydration method: 1% DOTAP ((2, 3 -dioleoyl -Propyl) -trimethylamine) + 1.2% surfactant (BRU® O20, polyoxyethylene 20 oleyl ether) in a round-bottomed flask in a solvent commonly used to prepare flexible liposomes (such as chloroform, ether, etc.) After steaming, a lipid film is formed on the inner wall of the round-bottomed fla
  • the hydration solution is passed through the lipid film with a 100 nm pore diameter polycarbonate film.
  • CFL(l%)@siRNA Use CFL(1%) as a solvent to dissolve siRNA, and then mix with ultrasound (20 min) to prepare siRNA-carrying CFL(1%), denoted as CFL(l%)@siRNA.
  • CFL(0.05%)@ siRNA Use CFL(0.05%) as a solvent to dissolve siRNA, and then mix with ultrasound (20 min) to prepare CFL(0_05%)@ siRNA.
  • Preparation of FL@ siRNA Use FL as a solvent to dissolve siRNA, then mix with ultrasound (20 min) to prepare FL@ siRNA.
  • Example 2 Characterization of liposomes Malvern Zetasizer Nano ZS90 instrument (Malvern Instruments, UK) was used to characterize the particle size and potential of cationic flexible liposomes and ordinary flexible liposomes. Under a pressure of 0.25 MPa, 1 ml of liposomes were extruded through a 100 nm polycarbonate membrane to determine the deformability of different lipid vesicles.
  • CFL@ siRNA shows a similar particle size distribution, but the potential of CFL(0.05%)@siRNA becomes electronegative (-31.4+1.1 mV) c ordinary flexible liposomes (FL or FL@
  • the average diameter of siRNA, Figure la) is about 102.5 nm, and the G potential is neutral, about -2.2 mV.
  • Lipid Body flexibility results show that the optimized CFL (0.05%, 94.08% ⁇ 1.01%) has better deformability than the original CFL (1%, 56.03% ⁇ 1.98%) and FL (4%, 61.79% ⁇ 0.48%) (/? ⁇ 0.001).
  • Example 3 In vitro transdermal permeation of siRNA. This example uses isolated pig skin as a skin model for experiments.
  • the pig skin needs to be pre-treated, and the subcutaneous fat tissue on the pig skin is carefully removed with a scalpel, and then the hair on the pig skin is shaved with an electric shaver to make the length less than 5 mm.
  • Use ultra-pure water Wash the pigskin after the above treatment and store it at -20 ° (: for later use. Thaw the skin at room temperature before use.
  • Use a round punch with a diameter of 40 mm to drill a pig skin of the same diameter Installed on the Franz diffusion transdermal device, using the isolated skin percutaneous resistance test to measure the electrical conductance of the skin to ensure the integrity of the skin barrier.
  • the effective penetration area of the Franz diffusion cell is 1.77 cm 2 , and the receptor volume is 12 ml.
  • PBS pH 7.4, 0.2 M
  • SHS is: through a household electric massager (Codos KP-3000) (Applying about 0.3N force, rotating speed about 300 rpm/min) SHS (5 mg / cm 2 ) was applied topically to the skin for 2 minutes. Then the skin was washed 3 times with PBS (0.2 M), In order to remove the residual SHS on the skin.
  • the drug penetration time of each group is 16 hours. Each group is repeated at least three times.
  • Example 4 Liposome cytotoxicity and in vitro cell transfection. L929 cells were seeded into a 96-well plate and cultured in a cell incubator for 24 h (5% CO 2 , 37 ° C). Remove the medium in each well and replace with 100M fresh medium.
  • the cells were incubated with different doses of liposomes (5.0M/well, 2.5M/well, 1.0ul/well, 0.50/well, 0.10/well) at 37 ° C for another 24 hours. Then the MTT method was used to determine the survival rate of the cells under different liposome doses. Inoculate L929 cells into a 24-well plate and culture in a cell incubator for 24 h (5% CO 2 , 37 ° C). When the cell density is about 70%-80%, perform cell transfection experiments.
  • this example also measured the expression of GAPDH protein in L929 cells to further verify the cell transfection effect (Figure 5).
  • CFL(0.05%)@siRNA can lead to GAPDH protein knockout rate of 41.09% ⁇ 5.14% after 68 hours of transfection, which is much higher than CFL(l%)@siRNA (8.38% ⁇ 2.08%), FL@ siRNA (3.48) % ⁇ 2.25%) and siRNA alone (6.07% ⁇ 1.62%) knockout rate of GAPDH protein.
  • the relationship between the cytotoxicity of CFL (0.05%), CFL (1%) and FL and the additive dose was determined by MTT method.
  • mice were anesthetized by intraperitoneal injection of 1500 chloral hydrate (4%), the hair on the back of the mice was trimmed, and a hollow cylinder with an area of 1.77 cm 2 was glued on the exposed skin area of the back of the mice using 3M Vetbond Then use SHS (5 mg/cm 2 ) to massage the bare skin for 2 minutes under an applied force of 0.3 N, and finally wash the treated area 3 times with PBS (0.2 M) to remove SHS. Then, for local combined application 100
  • the mixed solution of the solution (see Example 1 for the preparation method) was applied to the treatment area non-sealed.
  • 150 The siRNA (3.75 nmol) solution is applied to the treatment area in a closed manner.
  • 150 pi negative control siRNA (3.75 nmol) solution was applied to the treatment area in a closed manner.
  • the mice were sacrificed by overexposure to pyrolysis. The mouse skin tissue was collected from the treatment area, and the KDalert GAPDH assay kit was used to determine the GAPDH protein expression level, and calculate the protein knockout effect in vivo (each group contains 3 replicates).
  • the combined use of SHS and CFL shows the best transdermal penetration enhancement effect on siRNA in vitro; CFL (0.05%) has lower toxicity to cells and higher protein knockout rate; in vivo results show The combined use of SHS and CFL (0.05%) can have a comparable protein knockout rate with the skin of the subcutaneous injection center, but it has a better area.
  • CFL (0.05%) is the optimal concentration to cooperate with SHS, and the combined use of SHS and CFL (0.05%) is the most effective combination method for local application of RNAi, and it is expected to become a promising delivery system for RNAi therapy. .
  • the above are only preferred embodiments of the present invention, so the scope of implementation of the present invention cannot be limited accordingly.
  • the present invention discloses a siRNA transdermal delivery composition and its use.
  • the present invention combines bee sponge spicules with The combination of ordinary flexible liposomes and cationic flexible liposomes can enhance the skin permeability of siRNA in vitro.
  • the combined use of bee sponge spicules and cationic flexible liposomes shows the best transdermal penetration enhancement effect for siRNA, and is expected to become a promising delivery system for RNAi therapy, opening up new ideas for local delivery of siRNA for the treatment of skin diseases Opportunities, have good industrial usability.

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  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne une composition d'administration transdermique d'ARNsi et son utilisation. Dans la composition, les spicules de l'éponge Haliclona sp. sont utilisées en combinaison avec des liposomes souples classiques et des liposomes souples cationiques, permettant ainsi de renforcer la perméation cutanée in vitro de l'ARNsi. L'utilisation conjointe de spicules d'éponge Haliclona sp. et de liposomes souples cationiques présente le meilleur effet d'amélioration de la perméation transdermique pour l'ARNsi, potentiellement capable de devenir un système d'administration prometteur pour une thérapie par ARNsi, et d'ouvrir de nouvelles opportunités pour l'application d'une administration locale d'ARNsi dans le traitement de maladies de la peau.
PCT/IB2020/020080 2019-12-24 2020-12-24 Composition d'administration transdermique d'arnsi et son utilisation Ceased WO2021130541A1 (fr)

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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
CN110882219B (zh) * 2019-12-24 2021-04-20 厦门大学 一种siRNA经皮递送组合物及其用途
CN114557964B (zh) * 2022-03-17 2024-03-12 西安艾领克生物科技有限公司 一种可载rna的阳离子梭型柔性脂质体及其制备方法和应用

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