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Formation of cyclosporin a/cyclodextrin nanoparticles

A technology of cyclosporine and cyclodextrin, which can be used in cyclopeptide components, medical preparations of inactive components, sensory diseases, etc., can solve the problems of itchy conjunctiva, low drug bioavailability, blurred vision, etc.

Inactive Publication Date: 2018-05-11
奥库里斯公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The second hurdle is the rapid turnover rate of the tear fluid and the consequent decrease in the concentration of dissolved drug molecules
[0005] A third hurdle is slow drug penetration across membrane barriers (i.e. cornea and / or conjunctiva / sclera)
However, the use of oils and surfactants for topical delivery of cyclosporine A has low drug bioavailability and can cause blurred vision, burning sensation, itching, and conjunctival irritation

Method used

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  • Formation of cyclosporin a/cyclodextrin nanoparticles
  • Formation of cyclosporin a/cyclodextrin nanoparticles
  • Formation of cyclosporin a/cyclodextrin nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] The effect of cyclodextrin on the solubility of cyclosporin A in water was studied. Excess drug was added to aqueous solutions containing up to 20% (w / v) cyclodextrin. The solution was sonicated in a sealed glass vial at 40-50°C for 45-60 minutes, then allowed to cool to room temperature (22-23°C). A small amount of solid drug was then added to each vial, which was resealed and allowed to equilibrate under constant stirring and protected from light at room temperature for 7 days. When the solution had reached equilibrium, it was filtered through a 0.45 μm membrane filter and analyzed by high pressure liquid chromatography. The apparent complexation constant (K 1:1 ) (Higuchi, T., Connors, K.A., 1965. Phase solubility techniques. Advanced Analytical Chemistry of Instrumentation 4, 117-212). Complexation efficiency (CE) is determined from the slope of a phase solubility diagram (a plot of the total solubility of a drug against the total CD concentration in mol / l), wher...

Embodiment 2

[0091] Determination of the cyclosporin A moiety present in cyclosporin A / cyclodextrin aggregates in aqueous eye drop media. Prepare 0.05% (w / v) cyclosporine by dissolving benzalkonium chloride (20 mg) and edetate disodium dehydrate (100 mg) in 70 ml of a 1.4% (w / v) aqueous solution of polyvinyl alcohol Mycocin A eye drops aqueous micron suspension. Then 50 mg of cyclosporin A and measured amounts of different cyclodextrins (i.e. pure α-cyclodextrin, pure γ-cyclodextrin or a mixture of α-cyclodextrin and γ-cyclodextrin) were added to the solution, and shake until a homogeneous suspension is obtained. The volume was then adjusted to 100.0 ml with a 1.4% (w / v) aqueous solution of polyvinyl alcohol and heated in an autoclave at 121° C. for 20 minutes in a sealed vessel. The suspension was cooled to room temperature under sonication. Then, the suspension was removed from the sonicator and allowed to equilibrate at room temperature with constant stirring for 7 days, protected fr...

Embodiment 3

[0111] Particle size characterization of eye drop formulations was performed by dynamic light scattering (DLS). Each formulation was filtered through a 0.45 μm membrane filter (to exclude particles larger than 0.45 μm) prior to measurements performed at 25 °C, 180° scattering angle and 780 nm laser beam, and each measurement was performed in triplicate . Visualizing the particle size using an optical microscope without sample filtration gives a better idea of ​​how many particles are in the suspension and how big they are. Table 6 shows the size distribution data from DLS measurements.

[0112] Table 6

[0113] DLS results for size analysis of cyclosporin A / cyclodextrin complexes for formulations F1-F10, data reported as hydrodynamic diameter (d), population width and intensity distribution (%I) in the nanoscale range

[0114]

[0115]

[0116] DLS measurements of formulations F1 , F2 and F3 gave 2 or 3 size clusters based on the intensity distribution, with an averag...

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Abstract

Methods of forming cyclosporin / cyclodextrin complex nanoparticles and microparticles, and administration of the nano- and micro-suspension formed to an eye of a human or animal in the form of aqueouseye drops suitable to elicit or enhance tear formation and for treatment of diseases of the eye and surrounding areas. The aqueous eye drop composition contains cyclosporin and a mixture of alpha-cyclodextrin and gamma-cyclodextrin as well as one or more stabilizing polymers. Alpha-cyclodextrin solubilizes cyclosporin while gamma-cyclodextrin promotes formation of cyclosporin / cyclodextrin complexaggregates. The polymers stabilize the aqueous nano- and micro-suspension.

Description

Background technique [0001] The present invention relates to novel aqueous eye drop compositions, wherein the active ingredient is cyclosporin A (cyclosporin A). [0002] Topical eye drops are the preferred mode of drug delivery to the eye due to their convenience and safety compared to other routes of ophthalmic drug administration such as intravitreal injection and implantation (Le Bourlais, C., Acar , L., Zia, H., Sado, P.A., Needham, T., Leverge, R., 1998. Ophthalmic drug delivery systems—Recent advances. Progress in Retinal and Eye Research 17, 33-58). Drugs are transported from the ocular surface into the eye and surrounding tissues primarily by passive diffusion, where, according to Fick's law, the drug is driven through a gradient of dissolved drug molecules into the eye. Passive diffusion of drugs into the eye is hampered by three major obstacles (Gan, L., Wang, J., Jiang, M., Bartlett, H., Ouyang, D., Eperjesi, F., Liu, J., Gan ,Y.,2013.Recent advances in topical o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K47/69A61K9/50A61K9/51
CPCA61K38/13A61K9/0048A61K47/6951A61P27/04A61K47/6907A61K47/6939A61K9/10A61K9/1641A61K9/1652A61K9/1682
Inventor T·罗夫特森
Owner 奥库里斯公司
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