WO2013045729A1 - Nanogels de cyclodextrines - Google Patents

Nanogels de cyclodextrines Download PDF

Info

Publication number
WO2013045729A1
WO2013045729A1 PCT/ES2012/070638 ES2012070638W WO2013045729A1 WO 2013045729 A1 WO2013045729 A1 WO 2013045729A1 ES 2012070638 W ES2012070638 W ES 2012070638W WO 2013045729 A1 WO2013045729 A1 WO 2013045729A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogel
cyclodextrins
nanogels
cyclodextrin
water
Prior art date
Application number
PCT/ES2012/070638
Other languages
English (en)
Spanish (es)
Inventor
Carmen Alvarez Lorenzo
Angel Concheiro Nine
Maria Dolores MOYA ORTEGA
Thorstein LOFTSSON
Original Assignee
Universidade De Santiago De Compostela
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidade De Santiago De Compostela filed Critical Universidade De Santiago De Compostela
Publication of WO2013045729A1 publication Critical patent/WO2013045729A1/fr

Links

Classifications

    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/16—Cyclodextrin; Derivatives thereof

Definitions

  • the present invention relates to the development of hydrogels, more specifically it relates to the development of cyclodextrin hydrogels of nanometric size.
  • Cyclodextrins are cyclic oligomers consisting of units of ⁇ -D-glucose in a variable number, generally 6 (a-), 7 ( ⁇ -), or 8 ( ⁇ -cyclodextrin). Cyclodextrins have a toroidal structure with a hydrophobic internal surface and a hydrophilic external face (Düchene and Wouessidjewe, Pharm. Technol. 14: 22-30, 1990). This conformation gives them the ability to form complexes with substances of diverse nature (Uekama, Chem. Pharm. Bull. 52: 900-915, 2004). Complex formation has been used for decades to modify the solubility, stability and volatility of active drugs and molecules.
  • hydrogels that are characterized by their ability to incorporate water.
  • hydrogels constituted by cyclodextrins are known for the preparation of which have been carried out procedures that involve a) the previous formation of an aerobic or vinyl derivative of cyclodextrin capable of reacting with other acrylic or vinyl monomers (Siemoneit, U., Schmitt, C, Alvarez-Lorenzo, C, Luzardo, A., Otero-Espinar, F., Concheiro, A., Blanco-Méndez, J. Acrylic / cyclodextrin hydrogels with enhanced drug loading and sustained relée capability. Int. J. Pharm.
  • Patent application WO2006 / 089993 A2 describes a process for obtaining hydrogels of cyclodextrins or their derivatives and water-soluble cellulose ethers or their water-soluble derivatives, or cyclodextrins or their derivatives and guar gums or their derivatives, using as crosslinking molecules that They contain two or more glycidyl ether groups in their structure.
  • hydrogels as drug carriers are only possible if they are presented as multiparticulate systems consisting of nanogels smaller than 200 nm in size (Raemdonck, K; Demeester, J; De Smedt, S. Advanced nanogel engineering for drug delivery, SoftMatter 5, 707-715, 2009; JungKwon Oha, Ray Drumright, Daniel J. Siegwart, KrzysztofMatyjaszewski. The development of microgels / nanogels for drug delivery applications. Polym. Sci. 33 (2008) 448-477).
  • the nanogels could be obtained from monolithic structures, by spraying or crushing, but this procedure ("top-bottom” approach) is difficult to implement in practice and the resulting particles have irregular shapes and their size dispersion is wide.
  • the procedures that allow the formation of nanogels directly from their constituents (“bottom-up” approach) are more suitable for nanogels of controlled size and mainly spherical shape (JungKwon Oha, Ray Drumright, Daniel J. Siegwart, KrzysztofMatyjaszewski. The development of microgels / nanogels for drug delivery applications. Prog. Polym. Sci. 33 (2008) 448-477).
  • a recently published procedure refers to the synthesis of nanogels by polymerization-precipitation of vinyl cyclodextrin monomers together with other acrylic or vinyl comonomers in water at 70 ° C and ultrafiltration (Markus J. Kettel, Fiete Dierkes, Karola Schaefer, Martin Moeller, Andrij Pich. Aqueous nanogels modified with cyclodextrin. Polymer 52 (2011) 1917-1924).
  • This procedure requires in a first stage the previous preparation of cyclodextrin vinyl derivatives, followed, in a second stage, of the copolymerization with other acrylic or vinyl monomers.
  • the authors of the invention have developed nanometric size gels, which solve the limitations of the corresponding monolithic hydrogels, since they are useful for applications for which the monolithic ones cannot be used.
  • the invention provides nanometric gels that possess well differentiated properties from the corresponding monolithic hydrogels.
  • the size of the gels of the invention provides a high specific surface which facilitates the exchanges of matter with the medium in which they are located and makes it possible for them to pass through cell membranes by endocytosis and elude recognition by the mononuclear phagocytic system.
  • the invention is directed to a hydrogel characterized by an average hydrodynamic diameter of less than 1 micrometer, comprising a matrix of cyclodextrins, where the cyclodextrins are linked together through a spacer to which they are joined by an ether group. or amino.
  • a particular embodiment of the invention relates to a hydrogel as defined above which additionally comprises a water-soluble polymer.
  • the cyclodextrins that constitute the hydrogel of the invention confer a high capacity for the incorporation of drugs, active substances and biological or toxic molecules with very diverse structures and physicochemical properties.
  • the hydrogel as defined above may further comprise an active ingredient, a biological molecule, or a toxic molecule.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrogel as defined above and at least one pharmaceutically acceptable excipient.
  • the invention is directed to a cosmetic composition
  • a cosmetic composition comprising the hydrogel as defined above.
  • the invention is directed to a phytosanitary composition
  • a phytosanitary composition comprising the hydrogel as defined above.
  • the invention also provides a suitable process for the preparation of the nanogels of the invention that is based on an approximation from the materials that constitute them, and not on crushing the corresponding monolithic hydrogels. This procedure has the advantage of preparing the nanogels in a single step, integrating the cross-linking and emulsification phase, and also allows the control of the structure and morphology of the nanogels.
  • the invention relates to a process for the preparation of the hydrogel as defined above comprising: a) preparing an aqueous solution comprising one or more cyclodextrins, a crosslinking agent having two or more functional groups which are capable of reacting with the hydroxyl groups of the cyclodextrins to form ether groups or with amino groups of the cyclodextrins to form amino groups, and an acidic or basic substance, and optionally a water-soluble polymer,
  • step d) mix the emulsion obtained in step c) with water.
  • the process further comprises adding an active ingredient or a biological molecule.
  • the invention relates to the use of the hydrogel as defined above to prepare a medicament.
  • the invention relates to the use of the hydrogel as defined above, in systems capable of sequestering toxic substances, molecules produced by living organisms, pollutants or liquid waste.
  • Figure 1 Microscopy micrograph of electron transmission of ⁇ -cyclodextrin nanogels before undergoing the lyophilization process.
  • Figure 2 Microscopy micrograph of electron transmission of ⁇ -cyclodextrin and hydroxypropylmethylcellulose nanogels before undergoing the lyophilization process.
  • Figure 3. Infrared spectra of of yCO (1), HPpCD (2), HPMC (3), agar-agar (4), YCDo, o.5 (5), YCD-HPMC 2 , I (6), HPpCD 0 , or. 5 (7) and HPpCD-agari > 0 . 5 (8) in the region 1600-800 cm "1.
  • Figure 4 Diffusion profiles of 3-MBA from a solution without nanogels or available in ⁇ -cyclodextrin or ⁇ -cyclodextrin and hydroxypropylmethylcellulose ogels.
  • FIGS. 5A, 5B and 5C Dexamethasone assignment profiles obtained from a dexamethasone solution (Dex code), a dexamethasone solution to which free ⁇ -cyclodextrin (yCD code) was incorporated, and ⁇ -cyclodextrin and FIPMC nanogels prepared with different proportions of Span 80 in the organic phase (0%, code and CD-HPMC 2 , or; 0.5%, code and CD-HPMC 2 , 0 5 ; 1.0%, code and CD-HPMC 2>1 ; 2.0%, code and CD-HPMC 2; 2 ).
  • Dex code dexamethasone solution
  • yCD code free ⁇ -cyclodextrin
  • FIPMC nanogels prepared with different proportions of Span 80 in the organic phase (0%, code and CD-HPMC 2 , or; 0.5%, code and CD-HPMC 2 , 0 5 ; 1.0%, code and CD-HPMC 2>1 ; 2.0%, code and CD
  • hydrogel refers to a network of hydrophilic polymer chains, which can be crosslinked by different methods, and which contains a high proportion of water. Hydrogels can be presented macroscopically or confined in smaller dimensions. Nanogel is understood as a submicron size hydrogel (Jung Kwon Oha, Ray Drumright, Daniel J. Siegwart, Krzysztof Matyj aszewski. The development of microgels / nanogels for drug delivery applications. Prog. Polym. Sci. 33 (2008) 448- 477).
  • the present invention is directed to a hydrogel characterized by an average hydrodynamic diameter of less than 1 micrometer, comprising a matrix of cyclodextrins, where the cyclodextrins are linked together through a spacer to which they are joined by a group ether or amino.
  • the nanogels of the invention are capable of incorporating high proportions of water without dissolving.
  • One of the objectives of the invention is to provide nanogels useful in the transport and release of drugs and which are also capable of targeting specific tissues or cells.
  • the hydrogel as described above has an average hydrodynamic diameter between 1 nm and 400 nm.
  • the nanogel of the invention has an average hydrodynamic diameter between 1 nm and 200 nm.
  • Nanoparticles are solid particles between 1 and 1000 nm in size (Encyclopedia of Pharmaceutical Technology, J. Swarbrick and JC Boylan. Vol. 10. Marcel Dekker Inc., New York, p. 165) which, depending on their internal structure, differ in two groups: nanocapsules and nanospheres.
  • the nanocapsules consist of a cavity surrounded by a polymer layer; and the nanospheres are continuous matrix systems (F. Rocha Formiga, E. Ansorena, A. Estella-Hermoso De Mendoza, E. Imbuluzqueta, D.
  • cyclodextrins in the present invention refers to natural cyclodextrins, synthetic and semi-synthetic cyclodextrins, such that this term includes for example, without this being a limitation, cyclodextrins of 6, 7, and 8 members (known as alpha , beta, and gamma, respectively), cyclodextrins with more than 8 members (known as large cyclodextrins) and cyclodextrin derivatives. Cyclodextrin derivatives are understood as cyclodextrins substituted in some of their hydroxyl groups by functional groups, for example those listed in the following table:
  • Cyclodextrin derivatives also include their pharmaceutically acceptable salts.
  • the amino derivatives of cyclodextrins can be obtained by the procedure described in Nature Protocols, 2008, 3, 691-697.
  • the cyclodextrins are crosslinked, so that a cyclodextrin is linked to one or more spacers to which other cyclodextrins are in turn, thus forming a matrix.
  • the cyclodextrins and the spacer are covalently linked through an ether or amino group.
  • the spacer comprises a carbon skeleton that is selected from linear, branched, optionally substituted alkyl, aryl, aryl, and polyether chains.
  • the spacer is a polyether.
  • Alkyl refers to a linear or branched, cyclic or acyclic hydrocarbon chain consisting of carbon and hydrogen atoms, without unsaturation, from 1 to 12, preferably from one to eight, more preferably from one to four carbon atoms , optionally substituted.
  • Aryl refers to an aromatic hydrocarbon of 6 to 10 carbon atoms, such as phenyl or naphthyl, optionally substituted by an alkyl or oxyalkyl group, which may in turn be substituted.
  • Arylalkyl refers to one or more aryl groups attached to the rest of the molecule by an alkyl radical, for example, benzyl, 3- (phenyl) -propyl, etc.
  • Polyether refers to a chain with one or more ether groups.
  • the polyether is an unsaturated alkyl, or an arylalkyl, in which one or more ether groups are intercalated in the alkyl chain, and which is optionally substituted by a functional group selected from hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C 1-C6 alkyloxy, and OR 3 , where R 3 is a C 1-C 4 alkyl optionally substituted by hydroxyl, C 1-C 6 alkyl, C 1-C 6 hydroxyalkyl or glycidyl ether.
  • the polyether has the formula - (CHRi-CHR 2 0) n-, where n has a value between 1 and 100, preferably between 1 and 50, more preferably between 1 and 10, Ri and R 2 can be the same or different and are selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, hydroxyalkyl C1-C6, alkyloxy C1-C6 alkyl, and OR 3 , where R 3 is a C1-C4 alkyl optionally substituted by hydroxyl , C1-C6 alkyl, C1-C6 hydroxyalkyl or glycidyl ether.
  • the nanogel spacers of the invention come from crosslinking agents that possess two or more functional groups that are capable of reacting with the hydroxyl groups of the cyclodextrins to form ether groups or with amino groups of the cyclodextrins to form amino groups.
  • Said functional groups are known to the person skilled in the art and some examples, without being limited to them, are the following: 1,2-epoxyethane group, glycidyl ether, primary alkyl halide, primary alkyl tosylate, etc.
  • the group capable of reacting with the hydroxyl or amino groups of the cyclodextrins is a glycidyl ether group.
  • the crosslinking agent comprises an optionally substituted polyether, and two or more glycidyl ether groups.
  • Glycidyl ethers have the advantage that they have a very low toxicity. Their wide safety margins, together with the absence of repoductive and endocrine effects and of carcinogenic effects, make them suitable as components of containers that are kept in prolonged contact with food (Poole et al, Food Additives & Contaminants 21: 905- 919, 2004).
  • the RETI culantes agents with glycidyl ether groups also known as epoxides, oxirane or alkene oxides;...
  • the crosslinking agents are selected from among diglycidylether, ethylene glycol glycidylether, di eti 1 engl ic ol di gl i ci di 1 ether, p oli eti 1 engl i col di gl i ciledter, polyglycerol polyglycidyl ether, propylene glycol glycidyl ether, glyceroldiglycidylether, glyceroltriglycidylether, or bisphenol A diglycidyl ether.
  • the dry weight ratio of cyclodextrin is between 1 and 95%, and the dry weight ratio of the crosslinking agent is between 99% and 5% of the total dry hydrogel weight of the invention. as described above. In a more particular embodiment, the dry weight ratio of cyclodextrin is between 4 and 70%, and the dry weight ratio of the crosslinking agent is between 96% and 30% of the total weight of the dried hydrogel.
  • the nanogels of the invention can incorporate water soluble polymers.
  • water-soluble polymer is meant any natural, semi-synthetic or synthetic macromolecule that can be dispersed in aqueous medium forming colloidal solutions or systems.
  • water-soluble polysaccharides are suitable for modulating the affinity of nanogels for drugs and for modulating transfer profiles.
  • the polysaccharides are constituted by carbohydrates that have reactive hydroxyl groups similar to those of cyclodextrins, so comparatively to other polymers, they have the advantage of being able to react with the crosslinking agent in a similar way as cyclodextrins do, which facilitates obtaining homogeneous frameworks.
  • the water-soluble polymer is a water-soluble polysaccharide or its derivatives.
  • a water-soluble polysaccharide or its derivatives.
  • the water-soluble polysaccharide is selected from the group consisting of dextrans, alginates, starch, glycogen, chitosan, guar gums, agar-agar, water-soluble cellulose gums and cellulose ethers, and their pharmaceutically acceptable salts.
  • the water soluble cellulose ethers are selected from methyl cellulose (MC), hydroxyethylmethyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethylhydroxyethyl cellulose (EHC) N-cellulose ), quaternary ammonium salts of hydroxyethylcellulose with trimethylammonium substituent (Polyquaternium 10), and copolymers of hydroxyethyl cellulose and dimethyl diallyl ammonium chloride (Polyquaternium 4).
  • MC methyl cellulose
  • HEMC hydroxyethylmethyl cellulose
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropylmethyl cellulose
  • HEC hydroxyethyl cellulose
  • EHC ethylhydroxyethyl cellulose N-cellulose
  • guar derivatives For example, s gom a guar derivatives, their hydroxypropylated or carboxyhydroxypropylated esters, their cationic derivatives (Ecopol) and the products resulting from depolymerization of guar gums.
  • Ecopol cationic derivatives
  • the water-soluble polymer is a neutral or ionizable acrylic polymer with the condition of being soluble in aqueous medium.
  • the acrylic polymer is interpenetrated in cyclodextrin intermingling, it is not covalently bound to cyclodextrins or spacers.
  • the water-soluble acrylic polymer is selected from the group consisting of polyacrylic acid, poly-N-isopropylacrylamide, methacrylic acid and ethyl acrylate copolymers, methacrylic acid copolymers, methyl acrylate and methyl methacrylate, and copolymers. of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate.
  • the dry weight ratio of cyclodextrin is between 1% and 95%; the dry weight ratio of water-soluble polymer is between 0.05% and 95%; and the dry weight ratio of the crosslinking agent is between 98.95% and 4% of the total dry hydrogel weight of the invention as described above.
  • the dry weight ratio of cyclodextrin is between 4 and 70%, the dry weight ratio of water soluble polymer is between 0.1% and 20%; and the dry weight ratio of the crosslinking agent is between 96% and 30%) of the total weight of the dried hydrogel.
  • the invention relates to a hydrogel as described above, selected from the group of the following hydrogels consisting of:
  • the nanogels object of the present invention are suitable for associating active ingredients or biological molecules regardless of their solubility characteristics. The ability to associate will depend on the corresponding molecule.
  • active ingredient refers to any substance that is used in the treatment, cure, prevention or diagnosis of a disease or that is used to improve the physical and mental well-being of humans and animals, as well as that compound that is intended to destroy, prevent action, counteract or neutralize, any harmful organism, or any substance that is used as cosmetic or hygiene, as well as that compound that is intended to regenerate tissues or tissue engineering.
  • biological molecules any molecule synthesized in a living organism, such as, for example, proteins, carbohydrates, lipids, nucleic acids, amino acids, etc.
  • the biological molecule is selected from peptides, proteins, lipid compounds. or lipophilic, saccharide compounds, nucleic acid or nucleotide compounds such as oligonucleotides, polynucleotides or combinations of the aforementioned molecules.
  • the active ingredient or the biological molecule possesses antifungal, antiseptic or anti-inflammatory activity, or is a molecule of interest in tissue engineering, regenerative, cosmetic or hygiene medicine.
  • the active ingredient is an anti-inflammatory.
  • the active ingredient is a steroidal anti-inflammatory.
  • the proportion of active ingredient or biological molecule incorporated will depend in each case on the nature of the active ingredient or biological molecule to be incorporated, the indication for which it is used and the efficiency of administration.
  • the nanogel of the invention is in lyophilized form.
  • the nanogels of the invention are suitable as active ingredient release systems or biological molecules for ophthalmic treatments.
  • the nanogel of the invention is used in the preparation of a medicament for the treatment of ophthalmic diseases.
  • the ophthalmic diseases to which the invention is directed are those that affect the ocular surface, as well as those that affect the internal structures of the eye.
  • An example of ophthalmic diseases to which the invention is directed, but not limited to them, are severe, acute and chronic allergies, inflammatory processes involving the eyes such as ophthalmic herpes zoster, ulceris, iridocyclitis, chorioretinitis, posterior diffuse uveitis and chorioiditis, optic neuritis, sympathetic ophthalmia, inflammation of the anterior segment, allergic conjunctivitis, keratitis, corneal and marginal allergic ulcers, bacterial infections, viral infections, degenerations such as macular degeneration, blepharitis, conjunctivitis, glaucoma, benign or malignant tumors, retinopathies, etc.
  • the invention is directed to a sterile aqueous solution comprising a hydrogel as described above.
  • the sterile aqueous solution comprises between 2 mg / mL and 100 mg / mL of the hydrogel.
  • the invention is directed to a method for treating ophthalmic diseases which comprises administering to the mammal in need an effective amount of the pharmaceutical composition as described above or the sterile aqueous solution as described above.
  • the invention relates to a method for treating any of the ophthalmic diseases described above which comprises administering to the mammal in need an effective amount of the pharmaceutical composition as described above or the accused solution as described above.
  • the nanogels of the invention, with or without active ingredient or biological molecules incorporated, can be used as such or as base components of pharmaceutical forms, medicaments and sanitary products for the treatment of pathological or physiological conditions in humans, animals and plants.
  • compositions according to the invention are suitable for transdermal, oral, oral, rectal, ocular, nasal, otic, vaginal, or parenteral implant administration.
  • They can also be used as sequestering agents for biological or toxic substances in living organisms, for example cholesterol, glucose or bile acids, or in the environment.
  • the nanogels of the invention are also very suitable for controlling the release of drugs or active substances, incorporated into the nanogels.
  • the compositions provide different transfer rates depending on their qualitative and quatitative composition, and the physicochemical properties of the drug, especially its water solubility and its affinity for the cyclodextrin cavity.
  • They can also serve to direct drugs to specific areas in living beings, through changes associated with environmental conditions, in the degree of swelling of the nanogel or in the affinity of the drug for the components of the nanogel.
  • the process of the invention takes place under mild conditions, high temperatures and drastic conditions are avoided, and so that it is possible to incorporate active ingredients or biological molecules without damaging their integrity and without danger of degradation.
  • the process of the invention has the advantage that it does not require prior modification of the structure of the cyclodextrin or of the water-soluble polymer, nor the use of a mold to form the nanogel.
  • the process of the invention allows the size and shape of the nanogel to be modulated by controlling the emulsion droplet formation process of step c) and by the proportion of system components.
  • the invention also relates to a process for the preparation of the hydrogel as defined above comprising: a) preparing an aqueous solution comprising one or more cyclodextrins, a crosslinking agent having two or more functional groups that they are capable of reacting with the hydroxyl groups of the cyclodextrins to form ether groups or with amino groups of the cyclodextrins to form amino groups, and an acidic or basic substance, and optionally a water-soluble polymer,
  • step d) mix the emulsion obtained in step c) with water.
  • step a) The preparation of the aqueous solution of step a) is possible in several ways without variations in the result obtained.
  • the addition of said polymer to the water can be done before or after dissolving the cyclodextrin.
  • the crosslinking agent in solid, liquid or aqueous solution.
  • the acidic substance may be an organic or inorganic acid, for example triluoroacetic acid, p-toluenesulfonic acid, camforsulfonic acid, acetic acid, ionic acid exchange resin, Lewis acid, etc.
  • the basic substance includes organic and inorganic bases for example potassium or sodium carbonate, cyanides, hydrides, primary, secondary amines, sodium or potassium methoxide, sodium or potassium ethoxide, etc.
  • the aqueous solution prepared in step a) is incubated for a period of between 1 and 60 minutes, more preferably between 5 and 45 minutes. In a particular embodiment, the incubation of the aqueous solution prepared in step a) is carried out at a controlled temperature between 5 ° C and 80 ° C, more preferably between 20 ° C and 60 ° C.
  • step a) the crosslinking is initiated but without giving rise to an increase in viscosity that prevents subsequent emulsification with the organic phase.
  • an organic solution is prepared.
  • organic phases are, although the invention is not limited to these, chlorobenzene, chloroform, cyclohexane, dichloromethane, hexane, tetrahydrofuran, toluene, octanol, heptanol.
  • a surface active agent refers to a molecule composed of a hydrophobic part and a hydrophilic moiety. These molecules therefore have amphiphilic properties, which means that in an organic water / solvent mixture, they migrate to the surface between the water and the organic solvent. Thus, the hydrophilic head is maintained in the aqueous phase and the hydrophobic tail interacts with the organic solvent by altering the surface properties of the water / solvent interface and allowing the formation of an emulsion, as well as its stabilization.
  • the surface active agent is selected from the group consisting of long chain hydroxylic derivatives of 8 to 18 carbon atoms (fatty alcohols), ethoxylated carboxylic acids, ethoxylated amides, ethoxylated glycerides, glycol esters and derivatives, monoglycerides , polyglyceryl esters, esters and ethers of polyalcohols, sorbitan / sorbitol esters, phosphoric acid esters, ethoxylated derivatives of fatty alcohols and polyethylene glycol ethers.
  • the surfactant is a sorbitan ester.
  • the sorbitan ester is selected from the group consisting of sorbitan mono-, di-, tri- or sesqui-oleate, mono-, di-, tri- or sesqui-sorbitan sorbitan, mono-, sorbitan di-, tri- or sesqui-palmitate, sorbitan mono-, di-, tri- or sesqui-stearate and sorbitan mono-, di-, tri- or sesqui-isostearate, as well as combinations of the foregoing.
  • the weight ratio of surface active agent added in step b) is between 0% and 5%, preferably between 0% and 3%.
  • step c) the mixture is homogenized for a time between 1 second and 2 minutes, preferably between 30 and 60 seconds.
  • This homogenization can be carried out by vigorous stirring, for example, using a high performance homogenizing stirrer.
  • the volume of the organic phase of stage b) is equal to or greater than the volume of aqueous phase resulting from stage a).
  • the mixture of step c) is stirred for a period of time between 5 minutes and 5 hours, preferably between 10 minutes and 50 minutes.
  • said stirring is carried out at a controlled temperature between 5 ° C and 80 ° C, preferably between 40 ° C and 70 ° C.
  • stage d) the emulsion obtained in stage c) is diluted with a volume of water between an equal volume and up to 10 times greater than that of the mixture of stage a).
  • the dilution mixture is incubated for 10 minutes to 10 hours, preferably 1 hour to 5 hours.
  • said incubation is performed under a controlled temperature between 5 ° C and 80 ° C. Through this process the crosslinking ends and it is possible to evaporate the organic solvent.
  • the method further comprises a stage e) after stage d) comprising the dialysis of the mixture.
  • the process further comprises a step f) after step e) comprising lyophilization of the mixture
  • the process further comprises a stage g) after stage f) comprising rehydration of the nanogels.
  • the process further comprises adding an active ingredient or a biological molecule.
  • the incorporation of the active ingredient or biological molecule can be carried out by one of the following processes: i) direct immersion of a hydrogel of the invention, as described above, in a solution or in a suspension of the active ingredient or of the biological molecule, at a temperature between 0 and 100 ° C and at atmospheric pressure, optionally using ultrasound, ii) in an autoclave at a temperature between 100 and 130 ° C, or, iii) addition of active ingredient or from the biological molecule to the aqueous phase a).
  • the invention relates to a nanogel obtainable by the method described above.
  • nanogel obtainable by the procedure described above becomes relevant in the tests carried out as set forth in the examples herein.
  • These nanogels have a high capacity to incorporate drugs, active substances, biological or toxic molecules with very diverse structures and physical-chemical properties that form inclusion complexes with cyclodextrins of The nanogels
  • the nanogels form stable colloidal systems: dispersed in aqueous medium, have high physical stability, resisting centrifugation at 5000 rpm for 10 min without precipitating.
  • the size and shape of the nanogels can be modulated by controlling the formation process of the emulsion droplets.
  • the shape of the nanogels of the invention is spherical and the size distribution of the nanogels in the colloidal system is narrow. All these characteristics can be modulated through an adequate selection of the variety and / or the proportion of cyclodextrin / s and of the water-soluble polymers or their derivatives that accompany it / s.
  • compositions can be used as components of pharmaceutical forms, cosmetic preparations or "trap" systems to capture molecules of living organisms or of the environment, without raising problems of biocompatibility or environmental impact.
  • ⁇ -Cyclodextrin (yCD, W8) and 2-hydroxypropyl-p-cyclodextrin (HPpCD, W7 HP, Mw 1309.24 Da) were from Wacker (Barcelona, Spain), 2-hydroxypropyl-y-cyclodextrin (HPyCD, W8 HP, Mw 1576 Da) was from PURAC biochem BV (Gorinchem, The Netherlands), hydroxypropyl methylcellulose (HPMC, Methocel K4M Premium EP) from Colorcon Ibérica SL (Barcelona, Spain), Guinama agar (Valencia, Spain), ethylene glycol diglycidyl ether (EGDE, 50% w / w in water) from Fluka (St.
  • EGDE ethylene glycol diglycidyl ether
  • Example 1 Procedure for obtaining nanogels based on ⁇ -cyclodextrin or HPPCD.
  • a solution of 20% (w / w) ⁇ -cyclodextrin or HPpCD was prepared in 0.2M NaOH. Then, 10 mL of a 50% (w / w) ethylene glycol glycidyl ether solution in water was added to 10 mL of solution, so that the final concentration of crosslinking agent was 14.28%. The solution was stirred for 25 minutes at 60 ° C to start the crosslinking reaction.
  • the organic phase consisting of a solution of 2% Span 80 (w / w) in dichloromethane at 20 ° C was prepared separately.
  • the aqueous solution of cyclodextrin-ethylene glycol glycidyl ether was added to 20 ml of the organic phase and the whole was subjected to the action of a high performance homogenizing stirrer (8000 rev./min; Ultra-Turrax T25, Janke & Kunkel, INK-Labortechnik , Germany) for 30 seconds. Then, the emulsion was kept under stirring (magnetic stirrer 300 rev./min) for 30 min in a thermostatic bath at 60 ° C.
  • the emulsion was poured into 100 ml of distilled water and kept under stirring (magnetic stirrer 300 rev./min) for 210 min in a thermostated bath at 60 ° C, to complete the formation of the nanogels.
  • the colloidal system containing the nanogels were taken and dialyzed for 72 hours using 12-14 kDa dialysis tubes. After dialysis, the colloidal system containing the nanogels was dried by lyophilization (VirTis Genesis freeze-dryer, USA). Once lyophilized, the nanogels were easily redispersed in water resulting in a colloidal system with a particle size similar to that recorded before lyophilization (40-500 nm).
  • Figure 1 shows the electron transmission microscopy photomicrograph (Philips CM-12 TEM apparatus, FEI Company, The Netherlands) of the nanogels before undergoing the lyophilization process.
  • the sizes of the nanogels were determined using dynamic light scattering equipment using an ALV-5000 F optical system equipped with a Nd: YAG laser (400 mW) connected to a CW diode pump (400 mW) operated at 532 nm ( Coherent Inc., Santa Clara, CA, USA). The average size was 151.36 nm.
  • Example 2 Procedure for obtaining nanogels based on ⁇ -cyclodextrin and a water-soluble polymer.
  • a solution of 1% (w / w) or 2% (w / w) K4M HPMC in 0.2M NaOH or 1% (w / w) or 2% (w / w) agar in 0.2 NaOH will be prepared M. Then, 10 grams of ⁇ -cyclodextrin or HPpCD were added to 10 mL of this solution and, after homogenization, 4 mL of a 50% (w / w) solution of ethylene glycol glycidyl ether in water. The solution was stirred for 25 minutes at 60 ° C to start the crosslinking reaction.
  • the aqueous solution of HPMC-cyclodextrin-ethylene glycol glycidyl ether was added to 20 ml of the organic phase and the whole was subjected to the action of a high performance homogenizing agitator (8000 rev./min; Ultra-Turrax T25, Janke & Kunkel, INK-Labortechnik, Germany)) for 30 seconds. Then, the emulsion was kept under stirring (magnetic stirrer 300 rev./min) for 30 min in a thermostatic bath at 60 ° C.
  • the emulsion was poured into 100 ml of distilled water and kept under stirring (magnetic stirrer 300 rev./min) for 210 min in a thermostated bath at 60 ° C, to complete the formation of the nanogels.
  • the colloidal system containing the nanogels were taken and dialyzed for 72 hours using 12-14 kDa dialysis tubes. After dialysis, the colloidal system containing the nanogels was dried by lyophilization. Once lyophilized, the nanogels were easily redispersed in water resulting in a colloidal system with a particle size similar to that recorded before lyophilization (40-500 nm).
  • Figure 2 shows the electron transmission microscopy photomicrograph (Philips CM-12 TEM apparatus, FEI Company, The Netherlands) of the nanogels before undergoing the lyophilization process.
  • the sizes of the nanogels were determined using dynamic light scattering equipment using an ALV-5000 F optical system equipped with a Nd: YAG laser (400 mW) connected to a CW diode pump (400 mW) operated at 532 nm ( Coherent Inc., Santa Clara, CA, USA). The average size was 93.68 nm.
  • nanogels were obtained as shown in Table 1.
  • the nanogel formulations obtained are identified using the code cyclodextrin-polysaccharide xj where the cyclodextrin is ⁇ -CD or HPpCD, the polysaccharide is HPMC or agar, "x" is the concentration of HPMC or agar (0%, 1% or 2 %) in the aqueous phase and "y” is the concentration of Span 80 in the organic phase (0%, 0.5% or 2%) as used in the preparation of the hydrogel as described in examples 1 and 2.
  • Table 1 The data of the surfactant concentration, preparation process performance (Rto), results of the dynamic light scattering (DLS) analysis of the nanogels suspension, area of each peak, hydrodynamic radius, and distribution of data are collected. mass.
  • the stability of the nanogels obtained as aqueous dispersions was also studied, after centrifugation at 5000 rpm. for 10 minutes or 10,000 r.p.m. for 30 minutes to assess the tendency of nanogels to precipitate, thus simulating an aging process during storage. It was observed that centrifugation at 5000 rpm. for 10 minutes it did not cause precipitation of the nanogels. While centrifugation at 10,000 rpm. for 30 minutes it led to small precipitated amounts that were more intense in the nanogels to which FIPMC was incorporated than in the case of the nanogels constituted solely by cyclodextrins. In all cases, after stirring the precipitate, it was redispersed again.
  • Infrared spectra or ⁇ -CD nanogels were taken in a range between 400 and 4000 cm “1 , on a Brucker IFS 66V FT-IR spectrophotometer (using the potassium bromide technique). These spectra are shown in the figure 3. The formation of ether groups between the crosslinking agent and cyclodextrins is evidenced in the infrared (IR) spectra when comparing the starting species against the cross-linked cyclodextrins.
  • the prepared hydrogels capture water in a proportion of between 200% and 1000%) by weight of water with respect to the dry weight of the hydrogel.
  • Example 3 Control of the cession of 3-methylbenzoic acid (3-MBA) from ⁇ -cyclodextrin nanogels and d e n a n o g e l e s d e ⁇ -cyclodextrin and hydroxypropyl methylcellulose.
  • Lyophilized nanogels were dispersed in 3-MBA solutions (0.08 mg / ml) to obtain a dispersion of 2% w / v nanogels, which was maintained at 20 ° C for 60 hours.
  • the assignment of 3-MBA from nanogel dispersions was evaluated using vertical diffusion cells, using cellophane membrane (MWCO 3500, 0.785 was 2 ) as a separation barrier between the donor compartment and the receptor compartment. The tests were carried out at 37 ° C using 2 ml of nanogel dispersion and 5.5 ml of purified water, subjected to magnetic stirring at 300 rpm, as the receiving medium.
  • a solution of 3-MBA (0.08 mg / ml) without nanogels was also tested under the same conditions.
  • Example 4 Control of the transfer of dexamethasone from ⁇ -cyclodextrin nanogels and ⁇ -cyclodextrin and hydroxypropylmethylcellulose nanogels.
  • Example 4.1 Dexamethasone loading.
  • Lyophilized nanogels were dispersed in saturated dexamethasone solutions (0.14-0.16 mg / ml) to obtain a dispersion of 2% w / v nanogels, which was maintained at 20 ° C for 16 hours or 7 days.
  • dexamethasone from nanogel dispersions was evaluated using vertical diffusion cells, using cellophane membrane (MWCO 12-14 kDa, 1.77 was 2 ) as a separation barrier between the donor compartment and the receptor compartment. The tests were carried out at 37 ° C using 2 ml of nanogel dispersion and 12 ml of pH 7.4 phosphate buffer as a receptor medium, which was kept under magnetic stirring at 300 rpm. The saturated dexamethasone solution without nanogels was also tested under the same conditions. At pre-established time intervals, 150 ⁇ samples were taken from the receiving medium and replaced by fresh medium The concentration of dexamethasone in the receptor medium was determined by HPLC.
  • Example 5 Formulation of a dexamethasone eye drops based on cyclodextrin nanogels
  • Nanogels YCD-HPMCi were incorporated! (up to 4% w / v) to an aqueous hydroalcoholic solution (ethanol: water 50:50 v / v) of saturated dexamethasone and kept in an ultrasonic bath at 25 ° C for 60 minutes (Cole-Parmer Instrument Company 8892E -DTH, Niles, Illinois). Then the solvent medium is rotovapped (RII, Buchi, Switzerland) to obtain dry nanogels YCD-HPMCi,! loaded with dexamethasone.
  • Nanogels YCD-HPMCi,! loaded with dexamethasone were added (up to 4% w / v) to a 1.5% aqueous solution of dexamethasone (w / v) in 10% HPyCD (w / v), ethylenediamine tetraacetic acid (EDTA) 0.1% (w / v), 0.02% (w / v) benzalkonium chloride, 0.1% (w / v) HPMC K4M and 0.6% (w / w) sodium chloride and the pH was adjusted to 7.40 ⁇ 0.05.
  • the formulation was autoclaved at 121 ° C for 20 min and allowed to equilibrate for 5 days at room temperature under constant stirring.
  • the total dexamethasone concentration in the dexamethasone / HPyCD / nanogels formulation was 25.7 ⁇ 2.6 mg / ml, the osmolarity 299 ⁇ 31 mOsm / kg and the viscosity 31.4 ⁇ 3.9 cP.
  • Example 6 In vivo studies
  • Example 6.2 Study in vitreous humor.
  • rabbits were sacrificed by intravenous administration of T61 0.3 ml kg "1 (Intervet Germany). Approximately 0.05 ml of aqueous humor were taken using a syringe with a 30 gauge needle and inserting it into the anterior chamber in the limbus. The samples were kept frozen at -70 ° C until analysis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials Engineering (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des nanogels de cyclodextrines et un procédé d'obtention de nanogels de cyclodextrines par réticulation/émulsification/évaporation de la pnase organique de cyclodextrines ou de leurs dérivés, ou de cyclodextrines ou leurs dérivés et de polymères hydrosolubles ou leurs dérivés en utilisant en tant qu'agent de réticulation, des molécules contenant au moins deux groupes glycidyléther dans la structure. L'invention concerne également les compositions obtenues pouvant incorporer des produits pharmaceutiques et des substances actives formant des complexes d'inclusion avec des cyclodextrines, leur utilisation en tant que composants de systèmes à libération contrôlée, par exemple des formes pharmaceutiques transdermiques, des formes transmucosales, buccales, rectales, oculaires, otiques ou vaginales, et des implants parentéraux, permettant d'administrer des médicaments ou des substances actives à des humains, des animaux ou des plantes, ou en tant que composants de préparations cosmétiques. L'invention concerne enfin l'utilisation des compositions comme agents séquestrants dans l'extraction de molécules toxiques ou biologiques d'organismes vivants, ou de substances contaminantes des eaux.
PCT/ES2012/070638 2011-09-29 2012-08-31 Nanogels de cyclodextrines WO2013045729A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201131575A ES2371898B2 (es) 2011-09-29 2011-09-29 Nanogeles de ciclodextrina.
ESP201131575 2011-09-29

Publications (1)

Publication Number Publication Date
WO2013045729A1 true WO2013045729A1 (fr) 2013-04-04

Family

ID=45374460

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2012/070638 WO2013045729A1 (fr) 2011-09-29 2012-08-31 Nanogels de cyclodextrines

Country Status (2)

Country Link
ES (1) ES2371898B2 (fr)
WO (1) WO2013045729A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2740287C1 (ru) * 2019-08-30 2021-01-12 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) 3д-матриксная структура для доставки лекарственных препаратов
WO2021006845A3 (fr) * 2019-07-09 2021-03-11 Akdeniz Universitesi Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4535152A (en) * 1983-02-14 1985-08-13 Chinoin, Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Water soluble cyclodextrin polymers substituted by ionic groups and process for the preparation thereof
US4596795A (en) * 1984-04-25 1986-06-24 The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
ES2310948A1 (es) * 2005-02-25 2009-01-16 Universidade De Santiago De Compostela Procedimiento de obtencion de hidrogeles de ciclodextrinas con glicidileteres, las composiciones obtenidas y sus aplicaciones.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4535152A (en) * 1983-02-14 1985-08-13 Chinoin, Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Water soluble cyclodextrin polymers substituted by ionic groups and process for the preparation thereof
US4596795A (en) * 1984-04-25 1986-06-24 The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
ES2310948A1 (es) * 2005-02-25 2009-01-16 Universidade De Santiago De Compostela Procedimiento de obtencion de hidrogeles de ciclodextrinas con glicidileteres, las composiciones obtenidas y sus aplicaciones.

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RODRIGUEZ-TENREIRO, C. ET AL.: "Estradiol sustained release from high affinity cyclodextrin hydrogels", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 66, 2007, pages 55 - 62, XP005938637, DOI: doi:10.1016/j.ejpb.2006.09.003 *
RODRIGUEZ-TENREIRO, CARMEN ET AL.: "New cyclodextrin hydrogels cross-linked with diglycidylethers with a high drug loading and controlled release ability", PHARMACEUTICAL RESEARCH, vol. 23, no. 1, January 2006 (2006-01-01), pages 121 - 130, XP019370956, DOI: doi:10.1007/s11095-005-8924-y *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021006845A3 (fr) * 2019-07-09 2021-03-11 Akdeniz Universitesi Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament
RU2740287C1 (ru) * 2019-08-30 2021-01-12 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) 3д-матриксная структура для доставки лекарственных препаратов

Also Published As

Publication number Publication date
ES2371898A1 (es) 2012-01-11
ES2371898B2 (es) 2012-06-13

Similar Documents

Publication Publication Date Title
Di Colo et al. Effect of chitosan and of N-carboxymethylchitosan on intraocular penetration of topically applied ofloxacin
Barclay et al. Review of polysaccharide particle-based functional drug delivery
Dmour et al. Natural and semisynthetic polymers in pharmaceutical nanotechnology
Mourya et al. Trimethyl chitosan and its applications in drug delivery
Nurunnabi et al. Polysaccharide based nano/microformulation: An effective and versatile oral drug delivery system
JP5469458B2 (ja) 高分子ミセルクラスタ及びそれらの薬剤への使用
Salústio et al. Advanced technologies for oral controlled release: cyclodextrins for oral controlled release
US8759322B2 (en) Hyaluronic acid derivative and pharmaceutical composition thereof
WO2008136536A1 (fr) Gel hybride comprenant un dérivé de l'acide hyaluronique réticulé chimiquement, et composition pharmaceutique l'utilisant
Alhaique et al. Polysaccharide-based self-assembling nanohydrogels: An overview on 25-years research on pullulan
Bongiovì et al. Imatinib-loaded micelles of hyaluronic acid derivatives for potential treatment of neovascular ocular diseases
EP3890732A1 (fr) Formulations injectables
JP2014129408A (ja) 眼薬物送達用の新規生体材料ならびにその製造および使用方法
Imran et al. Application and use of Inulin as a tool for therapeutic drug delivery
Khare et al. Mucoadhesive polymers for enhancing retention in ocular drug delivery: a critical review
CN111686075B (zh) 一种以纳米胶束为交联剂的原位水凝胶组合物及其应用
ZA200102918B (en) Formulations of fexofenadine.
US20080008755A1 (en) Pharmaceutical formulation of cholanic acid-chitosan complex incorporated with hydrophobic anticancer drugs and preparation method thereof
Sahni et al. Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applications
Nayak et al. Hyaluronic acid (hyaluronan): pharmaceutical applications
US20230102859A1 (en) Natural origin stabilizer for oil in water emulsions
Kumar et al. Polysaccharide nanoconjugates for drug solubilization and targeted delivery
Zhang et al. Therapeutic carrier based on solanesol and hyaluronate for synergistic tumor treatment
WO2013045729A1 (fr) Nanogels de cyclodextrines
AU743204B2 (en) Controlled release of ophthalmic compositions

Legal Events

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

Ref document number: 12835115

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12835115

Country of ref document: EP

Kind code of ref document: A1