WO2011124380A1 - Chitosan beads and filler comprising such beads - Google Patents
Chitosan beads and filler comprising such beads Download PDFInfo
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- WO2011124380A1 WO2011124380A1 PCT/EP2011/001736 EP2011001736W WO2011124380A1 WO 2011124380 A1 WO2011124380 A1 WO 2011124380A1 EP 2011001736 W EP2011001736 W EP 2011001736W WO 2011124380 A1 WO2011124380 A1 WO 2011124380A1
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- chitosan
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- beads
- chitosan beads
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K8/0204—Specific forms not provided for by any of groups A61K8/0208 - A61K8/14
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K8/0241—Containing particulates characterized by their shape and/or structure
- A61K8/025—Explicitly spheroidal or spherical shape
-
- 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
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/736—Chitin; Chitosan; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
-
- 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
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/30—Characterized by the absence of a particular group of ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/54—Polymers characterized by specific structures/properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/60—Particulates further characterized by their structure or composition
- A61K2800/65—Characterized by the composition of the particulate/core
- A61K2800/654—The particulate/core comprising macromolecular material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/70—Biological properties of the composition as a whole
- A61K2800/72—Hypo-allergenic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention pertains to chitosan beads consisting of chitosan cross- linked with citrate ions.
- the present invention furthermore pertains to a filler comprising such chitosan-citrate beads.
- the filler is a dermal filler.
- the dermal filler is for the treatment of wrinkles and/or folds.
- the filler is for use in the treatment of a medical condition.
- the filler provided in the present invention may further comprise one or more active pharmaceutical ingredients. Further, the present invention pertains to a process for preparing the filler as claimed herein.
- Collagen is a natural protein of connective tissue.
- Hyaluronic acid is a polysaccharide and is naturally found in many tissues of the body.
- the unfavorable effect of fillers comprising hyaluronic acid is the short-lasting result and the need for multiple injections for an observable effect. Thereby swellings can occur, which decay in 1-3 days.
- treatments with collagen and hyaluronic acid based fillers are costly and painful due to the prerequisite of multiple injections and allergy tests. Further reported complications for the fillers is poor syringeability due to high viscosity, aggregation of the particles in the packaging and non-homogeneous distribution of the particles at the injection site.
- Chitosan and its derivatives are very well known natural substances and have been employed in the formulation of controlled release systems, i.e. microcapsules and similar colloidal delivery systems. This is documented in several publications, e.g. M. Prabaharan “Review Paper: Chitosan derivatives as promising materials for controlled drug delivery” Journal of Biomaterials Applications, 2008; 23; 5 and in O. Gaserod et al. "Microcapsules of alginate-chitosan - I A quantitative study of the interaction between alginate and chitosan" Biomaterials 19 (1998), 1815-1825; and in Cai et al.
- Biodegradable chitosan scaffolds containing microspheres as carriers for controlled transforming growth factor- ⁇ delivery for cartilage tissue engineering Chinese Medical Journal 2007; 120 (3); 197-203.
- Several methods and reagents have been tested for their ability to crosslink chitosan and to form microspheres. Reaction of chitosan with alginate under different conditions resulted in the formation of microcapsules that had an alginate-chitosan complex membrane including either an alginate or a chitosan core, depending on the reaction conditions (Gaserod et al., loc. cit.). Chitosan microspheres were prepared from chitosan and sodium tripolyphosphate solution (Cai et al., loc. cit.).
- WO 2008/103594 describes the use of chitosan and its derivatives as biomaterial for the treatment, repair and/or enhancement of bodily tissue insufficiencies of the vocal chords, muscles, ligaments and cartilage. According to the invention the use of the biomaterial produces a filling effect. Also disclosed are chitosan or chitosan-derivative gels, which optionally include chitin microspheres. In a fist step of the chitin microsphere preparation, chitosan microspheres were obtained by spray-drying a chitosan solution in acetic acid / ethanol.
- citrate for the cross-linking of chitosan.
- citrate was added to an emulsion of chitosan in acetic acid- containing solution, only irregular microparticles were formed, and microspheres could only be obtained when gelatin was added and co-emulsified (Shu, X. Z. and Zhu, K. J., "Chitosan/gelatin microspheres prepared by modified emulsification and ionotropic gelation", J. Microencapsulation 2001; 18; 237).
- microspheres were obtained by dropping a solution containing chitosan and gelatin into a cold oil in order to obtain coagulation of gelatin, prior to cross-linking with citrate (Shu, X. Z. and Zhu, K. J., "Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure", Int. J. Pharm. 2002; 233; 217).
- chitosan microspheres denotes microspheres comprising cross-linked chitosan and gelatin.
- the first object of the present invention is to provide chitosan-citrate beads that are free from gelatine.
- the second object of the present invention is a novel filler, which is injected below the dermis, thereby leaving no scar, rapidly restoring volume at the application site and sustaining the volume augmentation, and which does not contain collagen, which can cause allergic reactions, thereby not requiring pre-testing, such as allergic skin testing. It is also important that the particles remain evenly distributed after the injection to avoid palpable mass after the carrier is resorbed in the body. Thus, it is an object of the present invention to provide a novel filler exhibiting a long-lasting effect and far less side effects.
- Another object of the present invention is to provide a novel filler composition, which, unlike conventional fillers, which contain collagen or hyaluronic acid as a major component, is not easily degraded by human enzymes or absorbed in the body, thus ensuring stable longer-lasting volume augmentation, and is cheaper than conventional fillers.
- One further object of the instant invention is to provide a filler exhibiting a more improved syringeability as the conventional fillers, avoidance of aggregation of the particles in the packaging and non-homogeneous distribution of the particles at the injection site.
- chitosan beads which consist essentially of chitosan and citrate ions, and a filler comprising such chitosan beads or chitosan beads comprising chitosan and citrate ions.
- the chitosan employed in the chitosan beads and/or filler according to the instant invention has a molecular weight distribution from about 50 kD to about 5000 kD.
- the chitosan employed is deacetylated to a degree from about 60% to about 100%. In a particular embodiment, the chitosan employed is deacetylated to a degree from about 70% to about 90%.
- the chitosan beads according to the instant invention, and/or the filler according to the instant invention comprise chitosan beads that have a mass median diameter of less than or equal to about 1500 pm determined by microscopical analysis.
- the chitosan beads have a mass median diameter of between about 20 and 1000 pm, more particularly between about 20 and 500 pm, and most particularly between about 30 and 300 pm.
- the present invention pertains to chitosan beads and/or a filler wherein chitosan beads and/or the filler may further comprise one or more active pharmaceutical ingredient selected from the group of anesthetics, analgesics, anti-microbials, anti-inflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, antithrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- the one or more active pharmaceutical ingredient may be entrapped, bound to or encapsulated in the chitosan beads.
- the chitosan beads and/or the filler may further comprise one or more pharmaceutical excipients selected from antioxidants, viscosity enhancers / modifiers, hydrating agents, bulking substances, tonicity agents, preservatives and surface active agents, or a mixture thereof.
- the chitosan beads including those of the herein claimed filler, are stable in form, the form stability being determined microscopically by recording the changes in spherical shape.
- the mass median diameter of the chitosan beads remains constant, i.e. within +/- 20% of the starting value for the mass median diameter, for a period of at least 6 months, particularly at least 12 months, more particularly at least 24 months, and most particularly at least 36 months, at 25°C ⁇ 2°C and 60 % ⁇ 5% relative humidity determined by laser diffraction technique.
- the chitosan beads and/or the filler claimed herein has a shelf-life at 25°C ⁇ 2°C and 60 % ⁇ 5% relative humidity of at least 6 months, particularly at least 12 months, more particularly at least 24 months, and most particularly at least 36 months.
- the chitosan beads including those of the filler, according to the instant invention have an elasticity greater 5%, a tensile strength lower 5 N, and/or a deformability greater 90%. Deformability and elasticity are determined according to the method described by Edwards-Levy et. al. (Biomaterials 20 (1999) 2069-2084) using a texture analyzer.
- the chitosan beads are for use as drug-delivery vehicles.
- the filler is for use for aesthetic purposes.
- the filler is for use as a dermal filler.
- the dermal filler is for the treatment of, or for the use in the treatment of, wrinkles and/or folds.
- the filler is for the treatment of, or for the use in the treatment of, a medical condition, including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), or a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet, perioral wrinkles, breast and acne scars.
- a medical condition including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), or a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to
- the filler is used for the treatment of, or for the use in the treatment of, acne scars, such as by filling areas of acne scars.
- the present invention further pertains to a method of treating a medical condition, including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), or a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet, perioral wrinkles and acne scars, wherein said method comprises a step of administering a filler as claimed in the present invention to a patient in need thereof
- the present invention further pertains to a method of using a filler according to the present invention in plastic, cosmetic, dental or general surgery, in ophthalmology, in orthopedics, as products for preventing tissue adhesions, or in urology, wherein said method comprises a step of administering a filler as claimed in the present invention to a patient in need thereof.
- the present invention pertains to a process (i.e. a method, such as a manufacturing method) for preparing chitosan beads and/or the filler as claimed herein, wherein the process comprises a step of dropping a chitosan solution into an aqueous solution containing citrate anions.
- the pH of the aqueous solution containing citrate anions is adjusted to a value from about 6 to about 11.
- the concentration of the citrate ions in the process for preparing said filler is below about 2.0 M.
- the concentration of the citrate ions in the process for preparing the chitosan beads and/or the filler is between about 0.01 M and about 1.0 M.
- the concentration of chitosan in the process for preparing chitosan beads and/or the filler is at maximum about 5.0 wt-% (w/w%) relative to the total weight of the composition, particularly between about 0.5 wt-% and 4 wt-%, more particularly between about 0.5 wt-% and 3 wt-%, and most particularly between about 0.5 wt-% and 2 wt-%.
- the viscosity of the chitosan solution in the process for preparing chitosan beads and/or the filler is in the range from about 50 mPa * s to about 2000 mPa * s measured by a falling ball viscometer at 20°C, particularly between about 100 mPa * s and about 1700 mPa * s, more particularly between about 500 mPa * s and about 1500 mPa*s, and most particularly between about 750 mPa * s and about 1250 mPa * s.
- the pH of the chitosan solution is between about pH 1 and about pH 6, more particularly between about pH 1 and pH 5.
- the aqueous solution containing citrate ions further comprises one or more active pharmaceutical ingredients selected from the group of anesthetics, analgesics, anti-microbials, antiinflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- the present invention pertains to a kit comprising a filler as provided herein and an injection device.
- the injection device could be a syringe or an electronic injection device.
- the present invention pertains to an injection device comprising the filler provided herein.
- the injection device could be a prefilled syringe or an electronic injection device.
- the invention relates to a method, wherein the chitosan beads cross-linked with citrate ions are redissolved after implantation, to the extent necessary, by the injection of a solution containing divalent or trivalent cations.
- the present invention relates to chitosan beads, which consist essentially of chitosan and citrate, i.e. chitosan cross-linked with citrate ions.
- bearing or "beads” as used in the present invention relates to spherical particles.
- chitosan beads which consist essentially of chitosan and citrate refers to beads that are formed from chitosan and citric acid, or a citrate salt in the presence of an acid, and wherein the resulting chitosan beads do not contain more than about 5% impurities, such as acid anions other the citrate, and/or citrate salts, particularly not more than about 2%, and even more particularly not more than 1%.
- the term “impurities” includes both (i) impurities present in the starting materials used for forming the beads, and (ii) any other substances that may otherwise provide an auxiliary function in the formation of cross-linked structures, including acid anions other the citrate, or other polymeric molecules, such as gelatine, or inert fillers.
- impurities does not include, however, any solvent, solvent mixture or solution, that may be entrapped in the chitosan beads.
- the term “impurities” does not include any active pharmaceutical ingredient or other substance, that is incorporated in the beads of the present invention, wherein the beads act as a vehicle for such active pharmaceutical ingredient or other substance.
- the present invention relates to chitosan beads, wherein the three- dimensional network of chitosan cross-linked with citrate ions forming the bead structure consists essentially of chitosan and citrate, i.e. wherein that three- dimensional network of chitosan cross-linked with citrate ions forming the bead structure does not contain more than 5% impurities, particularly not more than about 2%, and even more particularly not more than 1%.
- the present invention relates to a filler comprising such chitosan beads and/or chitosan beads, wherein the chitosan beads comprise chitosan and citrate ions.
- filling as used in the instant invention relates to compositions which are administered for augmentation, repair or strengthening of tissue, or for filling a bodily cavity, in a mammal.
- mammal refers to a human or an animal taken from the list of farm animals like horses, cattle, pigs, camels, chicken, turkey, or pets like dogs or cats.
- chitosan as used in the instant invention relates to a linear polysaccharide composed of randomly distributed 3-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit) and/or salts thereof.
- the chitosan is selected from the group of chitosan glycolate, chitosan lactate, chitosan acetate, chitosan succinate, N-(aminoalkyl) chitosan, succinyl chitosan, quateraminated chitosan, octanoyl chitosan, acetyl chitosan, thiol chitosan, trimethyl chitosan, carboxymethylchitosan, trimethyammonium chitosane, N-diethyl methyl chitosan, N-methyl chitosan, carboxymethyl chitosan, N-carboxyethyl chitosan, glycol chitosan, N-(2- hydroxy)propyl-3-trimethylammonium chitosane or mixtures thereof.
- the chitosan is produced by deacetylation of chitin from the exoskeleton of crustaceans and cell walls of fungi or manufactured by biotechnological and/or enzymatic methods
- the chitosan employed is deacetylated to a degree from about 60% to about 100%.
- a commercially available example for such a chitosan is Chitopharm ® from the company Cognis, such as Chitopharm S: degree of deactylation 81%, MW 50-1000 kDa, or Chitopharm L: degree of deactylation 80%, MW 500-5000 kDa.
- the chitosan exhibits a molecular weight distribution from about 50 kD to about 5000 kD.
- a commercially available example for such a chitosan is Chitopharm ® L from the company Cognis.
- molecular weight distribution refers to a range or distribution of the molecular weights of a population of molecules, which are not homogeneous with respect to molecular size and weight, and which thus can best be described by a range of molecular weights characterized by a lower and an upper limit, where such range covers about at least 60%, particularly at least 70%, more particularly at least 80%, and most particularly at least 90% of all molecular weights present in a given sample.
- the chitosan beads are present in the filler at a concentration from about 10% (v/v) to about 95% (v/v) of total volume of the filler, as determined by determining the bead volume after sedimentation of the bead suspension in a graduated cylinder. In one embodiment, the chitosan beads are present in the filler at a concentration from about 25% to about 95% of total volume of the filler. In one further embodiment, the chitosan beads are present in the filler at a concentration from about 50% to about 95% of total volume of the filler. In another embodiment, the chitosan beads are present in the filler at a concentration from about 75% to about 95% of total volume of the filler.
- the chitosan beads are present in the filler at a concentration from about 85% to about 90% of total volume of the filler.
- the amount of chitosan beads present in the filler varies according to the size of the beads, size of the injection needle and the location of treatment.
- the chitosan beads prepared according to the process of the instant invention are flexible and elastic in terms of their physical properties, thus enabling an improved syringeability.
- the chitosan beads exhibit a particle size, measured as mass median diameter by microscopical analysis or with laser diffraction, of less than or equal to about 1500 pm.
- the chitosan beads have a mass median diameter of between about 20 and 1000 pm, more particularly between about 20 and 500 pm, and most particularly between about 30 and 300 pm.
- the particle size can be reduced by employing known techniques, such as Air jet/Air stripping method, Jet cutter method, Vortex bowl atomizer, Vibrating nozzle device, Electrostatic device, Emulsification ("water in oil”) approach, low mid and high pressure homogenization approaches.
- the size of the particle is adjusted according to the location of treatment. After the filler is injected the size of the chitosan beads provides fixation at the injection location and prevents undesirable migration to other parts of patient's body.
- the filler may comprise a medium in which the chitosan beads are suspended.
- Said medium may be sterile water, phosphate- buffer saline (PBS), ringer solution, isotonic saline solution (0.9%), trometamol, citrate, carbonate, acetate, borate, amino acids, diethylamine, glucono delta lactone, glycine, lactate, maleic, methanesulfonic, monoethanolamine, tartrate buffer of choice or any combination thereof.
- PBS phosphate- buffer saline
- ringer solution ringer solution
- isotonic saline solution 0.8%
- trometamol citrate
- carbonate carbonate
- acetate borate
- amino acids diethylamine
- glucono delta lactone glycine
- lactate lactate
- maleic, methanesulfonic monoethanolamine
- tartrate buffer of choice or any combination thereof.
- Said buffer may be citrate buffer.
- the filler according to the present invention does not comprise a chitosan gel.
- the chitosan beads and/or filler as claimed in the instant invention may further comprise one or more active pharmaceutical ingredient selected from the group of anesthetics, analgesics, anti-microbials, anti-inflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- active pharmaceutical ingredient selected from the group of anesthetics, analgesics, anti-microbials, anti-inflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- active pharmaceutical ingredient refers to all structures, which are pharmacologically active, thus resulting in a pharmacological effect in mammal and all known chemical forms thereof. Examples are, but not limited to, conjugates, isomers, esters, derivatives, metabolites, residues, salts or prodrugs thereof.
- Anesthetics may be, but are not limited to, local anesthetics based on esters (Procaine, Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine, Dimethodcaine, Larocaine, Propoxycaine, Proparacaine, Tretracaine) or local anesthetics based on amides (Lidocaine, Articaine, Bupivacaine, Carticaine, Cinchocaine, Etidocaine, Levobupivacaine, Mepivacaine, Piperocaine, Prilocaine, Ropivacaine, Trimecaine).
- a suitable concentration for the anesthetic is from about 0.01% to 6% based on the total weight of the composition and the agent selected.
- Analgesics may be, but are not limited to, paracetamol, ibuprofen, diclofenac, naproxen, aspirin, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulid.
- Antimicrobials may be, but are not limited to, antibiotics (amikacin, gentamycin, neomycin, tobramycin, kanamycin, meropenem, imipenem, cefaclor), antivirals (abacavir, aciclovir, amantadine, boceprevir, cidofovir, darunavir, edoxudine, famciclovir, ganciclovir, imunovir, inosine, interferon, lamivudine, nexavir, oseltamivir, penciclovir, ribavirin, rimantadine, viramidine, zidovudine) and antifungals (Miconazole, ketoconazole, itraconazole, clotrimazole, econazole, fluconazole, voriconazole, abafungin, naftifine, caspofungin, micafungin, benzo
- Anti-inflammatory drugs may be, but are not limited to, zinc salts, including zinc salts of polysaccharide acids, such as hyaluronic acid.
- the one or more active pharmaceutical ingredients are entrapped in the chitosan beads.
- living cells e.g. autologous stem cells, are entrapped in the chitosan beads.
- a polysaccharide is entrapped in the chitosan beads.
- proteins or peptides e.g. adhesion proteins, granulocyte-colony stimulating factors, erythropoietin, bone morphogenic protein, tissue plasminogen activator, are entrapped in the chitosan beads.
- the filler further comprises one or more pharmaceutical excipients selected from antioxidants, viscosity enhancers / modifiers, hydrating agents, bulking substances, tonicity agents, preservatives and surface active agents, or a mixture thereof.
- Antioxidants may be, but are not limited to, vitamin E, vitamin C, glutathione coenzyme Q, resveratrol, bisulfite sodium, butylated hydroxyl anisole/toluene, cysteinate, dithionite sodium, gentisic acid, glutamate, formaldehyde sulfoxylate sodium, metabisulfite sodium, monothiogylcerol, propyl gallate, sulfite sodium, thiogycolate sodium, flavonoids, catalase, lycopene, carotenes, lutein, superoxide dismutase and peroxidases or mixtures thereof.
- Viscosity enhancers may be, but are not limited to, glycerol, xanthene gum, polyethylene glycol (PEG), alginate, carbomers, cellulose derivatives, dextrans, and carrageenan, starches, gum, acacia, tragacanth, gelatin, polyvinylpyrrolidone, albumin, dextran or mixtures thereof.
- Surface active agents may be, but are not limited to, polysorbate 20, polysorbate 80, polysorbate 40, polysorbate 60, polysorbate 65, Pluronic F68, Cetrimoniumbromid, Cetylpyridiniumchlorid, Brij 72, Brij 30, Brij 35, deoxycholate, lecithine, tocopheryl polyethylene glycol succinate or mixtures thereof.
- Bulking substances or tonicity modifiers may be substances such as glycerol, lactose, mannitol, dextrose, sodium or potassium chloride, sodium sulphate and sorbitol, in general at a concentration up to 5% depending upon the chosen substance and the composition of the formulation.
- the chitosan beads are stable in form, such form stability being determined microscopically by recording the changes in spherical shape.
- the stability is further determined by measuring periodically the mass median diameter of the chitosan beads.
- the mass median diameter of the chitosan beads remains constant, i.e. within +/- 20% of the starting value for the mass median diameter, for a period of at least 6 months, particularly at least 12 months, more particularly at least 24 months, and most particularly at least 36 months, at 25°C ⁇ 2°C and 60 % ⁇ 5% relative humidity determined by laser diffraction technique.
- the filler has a shelf-life at 25°C ⁇ 2°C and 60 % ⁇ 5% relative humidity of at least 6 months, particularly at least 12 months, more particularly at least 24 months, and most particularly at least 36 months.
- the chitosan beads including those of the filler, according to the instant invention have an elasticity greater 5%, a tensile strength lower 5 N, and/or a deformability greater 90%. Deformability and elasticity are determined according to the method described by Edwards-Levy et. al. (Biomaterials 20 (1999) 2069-2084) using a texture analyzer.
- the filler of the instant invention is for use for aesthetic purposes.
- the filler is a dermal filler
- the dermal filler is for the treatment of wrinkles and/or folds.
- treatment of wrinkles and/or folds refers to non-medical treatments.
- Wrinkles that may be treated by employing the filler according to the instant invention include, but are not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet, perioral wrinkles and acne scars.
- the filler is for the treatment of, or for use in the treatment of, a medical condition, including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), and the treatment of a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet, perioral wrinkles and acne scars.
- a medical condition including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), and the treatment of a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines,
- the filler is for use in plastic, cosmetic, dental or general surgery, in ophthalmology, in orthopedics, for preventing tissue adhesions, or in urology.
- the present invention further pertains to methods of using the chitosan beads and/or the fillers of the present invention for aesthetic purposes, including the use as dermal filler, such as in the treatment of wrinkles and/or folds.
- the present invention further pertains to methods of using the chitosan beads and/or the fillers of the present invention for the therapeutic treatment of a patient in need thereof, such as in the treatment of lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), and the treatment of a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet and perioral wrinkles.
- GUD gastroesophageal reflux disease
- VUR vesico ureteral reflux
- a psychological condition caused by the appearance of an aesthetic deficiency including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to
- the present invention further pertains to a method of treating a medical condition, including lipoatrophy, gastroesophageal reflux disease (GERD), urine incontinence, vesico ureteral reflux (VUR), or a psychological condition caused by the appearance of an aesthetic deficiency, including, but not limited to, frown lines, medium depth wrinkles, such as nasolabial folds, lip augmentation, forehead wrinkles, glabellar lines, obvious mild to moderate nasal furrows and cheek wrinkles, crow's feet, perioral wrinkles and acne scars, wherein said method comprises a step of administering a filler as claimed in the present invention to a patient in need thereof [0093]
- the present invention further pertains to a method of using a filler according to the present invention in plastic, cosmetic, dental or general surgery, in ophthalmology, in orthopedics, as products for preventing tissue adhesions, or in urology, wherein said method comprises a step of administering a filler as claimed in
- the present invention further pertains to a process for preparing chitosan beads and/or a filler according to the invention, which comprises a step of dropping a chitosan solution into an aqueous solution containing citrate anions.
- the pH of the aqueous solution containing citrate anions is adjusted to a value from about 5 to about 10.
- the concentration of the citrate ions is below about 2.0 M.
- the concentration of citrate ions is between about 0.01 M and about 1.0 M.
- the concentration of chitosan in the process for preparing chitosan beads and/or the filler is at maximum about 5.0 wt-% (w/w%) relative to the total weight of the composition, particularly between about 0.5 wt-% and 4 wt-%, more particularly between about 0.5 wt-% and 3 wt-%, and most particularly between about 0.5 wt-% and 2 wt-%.
- the viscosity of the chitosan solution in the process for preparing chitosan beads and/or the filler is in the range from about 50 mPa*s to about 2000 mPa * s measured by a falling ball viscometer at 20°C, particularly between about 100 mPa * s and about 1700 mPa * s, more particularly between about 500 mPa * s and about 1500 mPa * s, and most particularly between about 750 mPa * s and about 1250 mPa*s.
- the aqueous solution containing citrate ions may further comprise one or more active pharmaceutical ingredient selected from the group of anesthetics, analgesics, antimicrobials, anti-inflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- active pharmaceutical ingredient selected from the group of anesthetics, analgesics, antimicrobials, anti-inflammatory drugs, growth factors, hormones, cosmeceuticals, vitamins, nutrients, stimulants, steroids, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, tranquilizers, muscle relaxants, antifungals, lipolytic agents and biorejunevation agents.
- the present invention further pertains to a kit comprising (a) the filler as disclosed herein, and (b) an injection device.
- the injection device comprises a 25- to 32-gauge needle. The size of the needle will be determined by the filler composition, the depth of the injection site and the injection volume.
- the injection device is disposable. In one embodiment, the injection device is made of sterile glass.
- the present invention further pertains to an injection device comprising chitosan beads and/or a filler as disclosed herein.
- the injection device may comprise a 25- to 32-gauge needle. The size of the needle will be determined by the filler composition, the depth of the injection site and the injection volume.
- the injection device is disposable. In one embodiment, the injection device may be made of sterile glass.
- the injection device and the chitosan beads and/or filler provided herein are both sterile and non-pyrogenic e.g. containing less than 10 EU (Endotoxin Unit, a standard measure) per dose or application.
- EU Endotoxin Unit
- Isotonicity of the chitosan beads and/or filler may be accomplished by employing sodium chloride, or other pharmaceutically acceptable agents such as dextrose.
- a pharmaceutically acceptable preservative may be employed to improve the shelf-life of the filler.
- the preservative may be, but is not limited to, benzalkonium chloride, thiomersal, parabens, chlorobutanol, benzethonium chloride, m-cresol, phenol, 2-phenoxyethanol, phenyl mercuric nitrate or benzyl alcohol.
- the suitable concentration of the preservative agent is from about 0.001 % to 5% based on the total weight of the composition and the agent selected.
- the invention relates to a method, wherein the chitosan beads cross-linked with citrate ions are redissolved after implantation, to the extent necessary, by the injection of a solution containing divalent or trivalent cations.
- the injection volume of the dispersed beads is between 0.1 and 100 ml, particular between 0.1 and 50 ml, more particular between 0.1 and 30, 0.1 and 20, or 0.1 and 10 ml, and most particular between 0.1 and 5, 0.1 and 2, or 0.1 and 1 ml.
- the volume can be higher than 100 ml if larger areas are augmented.
- Example 1 Manufacturing of chitosan beads and/or a filler comprising such beads
- Chitosan (Chitopharm L) is dispersed in deionized water. The appropriate amount of acid is added to the dispersion under constant stirring (0.05 mol per 10 g of chitosan). The dispersion is stirred until a clear solution is obtained. Having obtained a clear solution the pH of the obtained chitosan solution is stabilized from pH 1 to 5. With the help of a 30 Gauge syringe the chitosan solution is dropped into the following solutions having a pH from 5 to 11 and the obtained beads are let for 1 h in solution.
- the obtained chitosan beads were investigated by employing a microscope (Mikroskop Nikon Eclipse E600W).
- the following figure shows chitosan beads cross-linked with citrate ions and stored in citrate puffer.
- the beads are perfect in shape, i.e. being circular. Bead size is 1.0 to 1.5 mm.
- Chitosan is dispersed in deionized water. The appropriate amount of acid is added to the dispersion under a constant stirring. The dispersion is stirred until a clear solution is obtained. As a second solution, lidocaine hydrochloride USP (2% weight per weight) is dissolved in the chitosan solution. With the help of a 30 Gauge syringe the chitosan lidocaine solution is dropped into the following solutions having a pH from 1 to 5 and the obtained beads with lidocaine encapsulated are let for 1 h in solution.
- USP 2% weight per weight
- Example 3 Administration of the filler comprising chitosan beads
- Chitosan citrate beads were prepared according to the method described in example 1 at pH 8.5. Ten randomly chosen beads were selected for each experiment and the mean value and standard deviation were calculated.
- the rupture force as the initial force recognized when the piston reached the bead was calculated and the deformability expressed as the percentage of the total height of the sample that the piston reached before breakage.
- Tensile strength of the chitosan beads was 2.0 ⁇ 0.3 N, Deformability was 96 ⁇ 2%.
- Elasticity of the chitosan citrate beads was determined and calculated as the ratio of the force opposed by the bead after 10 s to the instantaneous resistance strength of the bead.
- the bead was placed under the piston, which went down at a rate of 2.0 mm/s until it reached 30% of the total height of the bead. Then, the piston stayed motionless at this position for 10 s and finally returned to its initial position.
- the elasticity of the beads was 7.2 ⁇ 1.7%.
Abstract
Description
Claims
Priority Applications (4)
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EP11714227A EP2555809A1 (en) | 2010-04-08 | 2011-04-07 | Chitosan beads and filler comprising such beads |
BR112012024887A BR112012024887A2 (en) | 2010-04-08 | 2011-04-07 | chitosan granules, filler, process for preparing chitosan granules, injection kit and disposal |
US13/639,004 US8865879B2 (en) | 2010-04-08 | 2011-04-07 | Chitosan beads and filler comprising such beads |
US14/481,135 US20140377368A1 (en) | 2010-04-08 | 2014-09-09 | Chitosan beads and filler comprising such beads |
Applications Claiming Priority (4)
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US32195010P | 2010-04-08 | 2010-04-08 | |
EP10003795 | 2010-04-08 | ||
US61/321,950 | 2010-04-08 | ||
EP10003795.1 | 2010-04-08 |
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US13/639,004 A-371-Of-International US8865879B2 (en) | 2010-04-08 | 2011-04-07 | Chitosan beads and filler comprising such beads |
US14/481,135 Continuation US20140377368A1 (en) | 2010-04-08 | 2014-09-09 | Chitosan beads and filler comprising such beads |
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WO2011124380A1 true WO2011124380A1 (en) | 2011-10-13 |
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PCT/EP2011/001736 WO2011124380A1 (en) | 2010-04-08 | 2011-04-07 | Chitosan beads and filler comprising such beads |
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US (2) | US8865879B2 (en) |
EP (1) | EP2555809A1 (en) |
BR (1) | BR112012024887A2 (en) |
WO (1) | WO2011124380A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013070926A1 (en) * | 2011-11-10 | 2013-05-16 | Allergan, Inc. | Methods for evaluating dermal filler compositions |
WO2017136935A1 (en) * | 2016-02-10 | 2017-08-17 | Prollenium Medical Technologies, Inc. | Dermal filler composed of macroporous chitosan microbeads and cross-linked hyaluronic acid |
WO2018083326A1 (en) | 2016-11-07 | 2018-05-11 | Croma-Pharma Gesellschaft M.B.H. | Hydrogen sulfide releasing polymer compounds |
WO2018099931A1 (en) * | 2016-12-01 | 2018-06-07 | Unilever Plc | Anti-perspirant composition comprising chitosan |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10231961B1 (en) | 2017-02-07 | 2019-03-19 | Genus Lifesciences Inc. | Pharmaceutical compositions and methods of using the same |
US10149843B1 (en) | 2017-02-07 | 2018-12-11 | Gneus Lifescineces Inc. | Pharmaceutical compositions and methods of using the same |
US10413505B1 (en) | 2017-02-07 | 2019-09-17 | Genus Lifesciences Inc. | Pharmaceutical compositions and methods of using the same |
CN116162181B (en) * | 2021-11-24 | 2024-04-12 | 珠海市自然之旅生物技术有限公司 | Chitosan-tricarboxylic acid derivative and preparation method and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005068282A (en) * | 2003-08-25 | 2005-03-17 | Wakamoto Pharmaceut Co Ltd | Method for producing chitosan fine particle |
DE102004019241A1 (en) | 2004-04-16 | 2005-11-03 | Cellmed Ag | Injectable cross-linked and uncrosslinked alginates and their use in medicine and aesthetic surgery |
CN101245326A (en) * | 2008-02-27 | 2008-08-20 | 江苏省农业科学院 | Concentration method for virus or bacteria |
WO2008103594A1 (en) | 2007-02-21 | 2008-08-28 | Cutanea Life Sciences, Inc. | Methods of use of biomaterial and injectable implant containing biomaterial |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100500793C (en) | 2008-03-07 | 2009-06-17 | 山东东岳化工有限公司 | Refrigerant capable of directly filling to substitute R22 |
-
2011
- 2011-04-07 BR BR112012024887A patent/BR112012024887A2/en not_active IP Right Cessation
- 2011-04-07 US US13/639,004 patent/US8865879B2/en not_active Expired - Fee Related
- 2011-04-07 WO PCT/EP2011/001736 patent/WO2011124380A1/en active Application Filing
- 2011-04-07 EP EP11714227A patent/EP2555809A1/en not_active Withdrawn
-
2014
- 2014-09-09 US US14/481,135 patent/US20140377368A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005068282A (en) * | 2003-08-25 | 2005-03-17 | Wakamoto Pharmaceut Co Ltd | Method for producing chitosan fine particle |
DE102004019241A1 (en) | 2004-04-16 | 2005-11-03 | Cellmed Ag | Injectable cross-linked and uncrosslinked alginates and their use in medicine and aesthetic surgery |
WO2008103594A1 (en) | 2007-02-21 | 2008-08-28 | Cutanea Life Sciences, Inc. | Methods of use of biomaterial and injectable implant containing biomaterial |
CN101245326A (en) * | 2008-02-27 | 2008-08-20 | 江苏省农业科学院 | Concentration method for virus or bacteria |
Non-Patent Citations (9)
Title |
---|
CAI ET AL.: "Biodegradable chitosan scaffolds containing microspheres as carriers for controlled transforming growth factor-B delivery for cartilage tissue engineering", CHINESE MEDICAL JOURNAL, vol. 120, no. 3, 2007, pages 197 - 203, XP009179742 |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2005, ISHIKAWA, HIROSHI: "Chitosan microparticles, their manufacture, and formation of chitosan films or fibers from them", XP002599725, retrieved from STN Database accession no. 2005:235211 * |
EDWARDS-L6VY, BIOMATERIALS, vol. 20, 1999, pages 2069 - 2084 |
M. PRABAHARAN: "Review Paper: Chitosan derivatives as promising materials for controlled drug delivery", JOURNAL OF BIOMATERIALS APPLICATIONS, vol. 23, 2008, pages 5 |
O. GASEROD ET AL.: "Microcapsules of alginate-chitosan - I A quantitative study of the interaction between alginate and chitosan", BIOMATERIALS, vol. 19, 1998, pages 1815 - 1825, XP004161454, DOI: doi:10.1016/S0142-9612(98)00073-8 |
SHU, X. Z., ZHU, K. J.: "Chitosanlgelatin microspheres prepared by modified emulsification and ionotropic gelation", J. MICROENCAPSULATION, vol. 18, 2001, pages 237 |
SHU, X. Z., ZHU, K. J.: "Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure", INT. J. PHARM., vol. 233, 2002, pages 217, XP002599820 |
X.Z. SHU , K.J. ZHU: "Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure", INTERNATIONAL JOURNAL OF PHARAMACEUTICS, vol. 233, 2002, pages 217 - 225, XP002599820 * |
X.Z.SHU AND K.J. ZHU: "Chitosan/gelatin microspheres prepared by modified emulsification and ionotropic gelation", J. MICROENCAPSULATION, vol. 18, no. 2, 2001, pages 237 - 245, XP002599726 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013070926A1 (en) * | 2011-11-10 | 2013-05-16 | Allergan, Inc. | Methods for evaluating dermal filler compositions |
WO2017136935A1 (en) * | 2016-02-10 | 2017-08-17 | Prollenium Medical Technologies, Inc. | Dermal filler composed of macroporous chitosan microbeads and cross-linked hyaluronic acid |
WO2018083326A1 (en) | 2016-11-07 | 2018-05-11 | Croma-Pharma Gesellschaft M.B.H. | Hydrogen sulfide releasing polymer compounds |
US11331338B2 (en) | 2016-11-07 | 2022-05-17 | Croma-Pharma Gesellschaft M.B.H. | Hydrogen sulfide releasing polymer compounds |
WO2018099931A1 (en) * | 2016-12-01 | 2018-06-07 | Unilever Plc | Anti-perspirant composition comprising chitosan |
Also Published As
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BR112012024887A2 (en) | 2016-06-21 |
US8865879B2 (en) | 2014-10-21 |
US20130090306A1 (en) | 2013-04-11 |
US20140377368A1 (en) | 2014-12-25 |
EP2555809A1 (en) | 2013-02-13 |
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