WO2001045645A1 - Biopolymere de chitosane utilise dans l'administration par voie topique d'agents actifs - Google Patents

Biopolymere de chitosane utilise dans l'administration par voie topique d'agents actifs Download PDF

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Publication number
WO2001045645A1
WO2001045645A1 PCT/US2000/035319 US0035319W WO0145645A1 WO 2001045645 A1 WO2001045645 A1 WO 2001045645A1 US 0035319 W US0035319 W US 0035319W WO 0145645 A1 WO0145645 A1 WO 0145645A1
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Prior art keywords
chitosan
skin
active agent
molecular weight
active
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PCT/US2000/035319
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English (en)
Inventor
Maurizio V. Cattaneo
Marie-France Demierre
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Ivrea, Inc.
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Priority to US10/221,307 priority Critical patent/US20030206958A1/en
Priority to JP2001546386A priority patent/JP2003524635A/ja
Priority to CA002394901A priority patent/CA2394901A1/fr
Publication of WO2001045645A1 publication Critical patent/WO2001045645A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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
    • A61K31/74—Synthetic polymeric materials
    • 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
    • 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
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • This invention relates to carrier bases for the topical delivery of active agents comprising high viscosity chitosan biopolymers.
  • Preferred carrier bases comprise chitosan having a molecular weight of at least 250,000 Dalton.
  • the invention also relates to carrier bases comprising high viscosity chitosan at a concentration of at least 2 weight%.
  • the present invention further provides a delivery system for therapeutic agents, such as retinoids, that overcomes many of the previously known problems associated with delivery systems for retinoids.
  • Skin connective tissue is comprised primarily of fibrillar collagen bundles and elastic fibers, along with extracellular matrix (ECM) molecules such as glycosaminoglycans (GAG), proteoglycans, glycoproteins, peptide growth factors.
  • ECM extracellular matrix
  • GAG glycosaminoglycans
  • proteoglycans glycoproteins
  • fibroblasts are the main cell types embedded within the ECM.
  • the predominant component of the ECM is hyaluronan (HA).
  • HA is the primordial and simplest of the GAGs, and the first ECM to be developed in the developing embryo. HA is thought to be largely a product of fibroblasts.
  • HA extracellular matrix
  • Age-related changes include a decrease in the number of fibroblasts, and connective tissue abnormalities such as ( 1) thinning of the collagen fiber bundles, (2) an increase in space between collagen fiber bundles, (3) an increase in collagen fiber bundle disorganization and (4) increase in depth of disorganization (Varani et al, 2000).
  • connective tissue abnormalities such as ( 1) thinning of the collagen fiber bundles, (2) an increase in space between collagen fiber bundles, (3) an increase in collagen fiber bundle disorganization and (4) increase in depth of disorganization (Varani et al, 2000).
  • the HA in the epidermal extracellular matrix has disappeared completely in aged skin (Neudeker et al, 2000).
  • Photoaged skin is characterized by the presence of elastotic material and damage to the collagen bundles. Clinically, photoaged skin appears thick and rough, with course wrinkles and mottled pigmentation (Lavker, 1995).
  • retinoids such as All-trans retinoic acid and retinol has been shown to stimulate collagen synthesis in naturally aged as well as photoaged skin (Varani et al, 2000; Griffiths et al., 1993). The active substance seems to be All-trans retinoic acid. However, the two retinoids All-trans retinoic acid and retinol are related. Indirect evidence exists that retinol transforms into All-trans retinoic acid in human skin (Kang et al, 1995). Retinoids appear to affect the quantity of collagen by increasing the number of collagen-producing fibroblasts, increasing collagen synthesis and/ or by reducing MMP levels in skin, thereby decreasing destruction of collagen (Varani et al.
  • retinoids do not seem capable of affecting the quality of the collagen being produced as evidenced by no change in the dermal connective tissue abnormalities after retinoic! treatment (Varani et al., 2000).
  • retinoid treatment induced measurable changes in the dermal fibroblast population, it did not alter age-associated connective tissue abnormalities such as correct collagen fiber deposition (Varani et al., 2000).
  • Retinoids are also used to treat other skin conditions such as acne, actinic keratosis, psoriasis, skin cancers and have been found to useful therapeutic agents in the chemoprevention of melanoma (Stam-Postuma, 1998; Halpern, 1994; Kligman, 1998).
  • the incidence of melanoma is increasing in the United States at a rate of about 2.7% annually, even as most other cancers are experiencing a decline in incidence.
  • melanoma is the seventh most commonly diagnosed cancer in U.S. men and women.
  • Chemoprevention is a strategy to prevent the development of melanoma through the administration of drugs.
  • the recognition of dysplastic nevi as markers of melanoma risk and intermediate steps of melanocytic tumor progression has significant implications for melanoma chemoprevention .
  • chemoprevention is an important strategy for the management of malignant melanoma (Halpern, 1994, 1998).
  • Chemoprevention entails the use of specific agents to block, reverse or suppress carcmogenesis and thereby prevent the development of primary or secondary cancers Melanocytic nevi, particularly dysplastic nevi confer a risk factor for the development of melanoma, with quantitative measures correlating directly with the magnitude of risk.
  • dysplastic nevi Having additional large non- dysplastic nevi increases the risk four-fold. Having just one dysplastic nevus was associated with approximately a 2-fold risk, while 10 or more conferred a 12-fold risk of melanoma. Furthermore, clinical and histopathologic features of melanoma have suggested five steps of melanoma progression: (1) common acquired and congenital nevi with structurally normal melanocytes, (2) dysplastic nevus with structural and architectural atypia, (3) early radial growth phase primary melanoma, (4) advanced vertical growth phase primary melanoma with competence for metastasis, and (5) metastatic melanoma (Sauter and Herlyn, 1998). The recognition of dysplastic nevi both as markers of melanoma risk and intermediate steps of melanocytic tumor progression has significant implication for melanoma chemoprevention.
  • ATRA topical tretinoin
  • 4-HPR systemic fenretinide
  • Retinoids are among the most promising chemopreventive agents with clinical effects of retinoid chemoprevention having been demonstrated in cancers of the head and neck, lung, cervix, ovaries and skin (Lotan, 1996; Sankaranarayanan and Mathew, 1996, Labrecque et al., 1999).
  • Topical application of tretinoin (all-trans retinoic acid, ATRA) has been shown to decrease melanocyte numbers and reduce melanocytic atypia in the treatment of photodamaged skin (Bhawan et al., 1996) and small pilot studies have demonstrated a significant effect of topical tretinoin on the appearance and histology of dysplastic nevi (Halpern et al., 1994, 1998; Stam-Posthuma et al., 1998).
  • ATRA binds and activates RARs
  • panagonist 9-cis-RA a novel retinoid
  • melanoma expresses all three of the RAR subtypes (Nagpal and Chandraratna, 1996).
  • topical delivery of retinoids increases the concentration of retinoids in the dermal compartment 10- to 100-fold (Lehman et al., 1988).
  • topical tretinoin (ATRA) induces irritation in 90% of patients (Gilchrest, 1997), and other side effects include patchy erythema, localized swelling, xerosis, and scaling. Irritation has been attributed, in part, by an overload of the tretinoin dependent pathways with non-physiological amounts of exogenous tretinoin in the skin. (Siegenthaler et al., 1994). This irritation may be the reason for discontinuation of treatment for close to 50% of patients (Stam-Posthuma et al., 1998). This high incidence of irritation, leading to poor compliance, can preclude its use.
  • these formulations utilize a non-biodegradable synthetic polymer as a carrier of the drug.
  • High molecular weight polymers (360,000 to 400,000 Dalton) have been shown to penetrate the stratum corneum (Brown et al., 1999).
  • the possibility of other polymers, such as the synthetic polymers described above, to penetrate the skin and enter the systemic circulation has been suggested by the authors after careful radiolabeled analysis of the tissue distribution and accumulation in various tissue organs of their target high molecular weight polymer after topical application (Brown et al., 1999).
  • it would be desirable to have a topical delivery system which is entirely biodegradable due to the likelihood of it entering the systemic circulation and accumulating in target tissues.
  • a controlled delivery system could make retinoid topical therapy a viable chemoprevention treatment for melanoma.
  • a controlled delivery vehicle for active agents used to treat skin ailments which would prevent the irritation seen in present treatments.
  • such a delivery system for retinoids would enable chronic use of topical retinoids for treating skin ailments, including for melanoma chemoprevention.
  • a controlled delivery system could make tretinoin topical therapy a viable chemoprevention treatment for melanoma in individuals with dysplastic nevi who are at high risk of developing melanoma.
  • Chitosan is a natural, biodegradable cationic polysaccharide derived by deacetylating chitin, a natural material extracted from fungi, the exoskeletons of shellfish and from algae and has previously been described as a promoter of wound healing (Balassa, 1972; Balassa, 1975).
  • Chitosan comprises a family of polymers with a high percentage of glucosamine (normally 70-99%) and N- acetylated glucosamine (1-30%) forming a linear saccharide chain of molecular weight from 10,000 up to about 1000,000 Dalton. Chitosan is polycationic.
  • Chitosan through its cationic glucosamine groups, interacts with anionic proteins such as keratin in the skin conferring bioadhesive characteristics.
  • anionic proteins such as keratin in the skin conferring bioadhesive characteristics.
  • the acetamino groups of chitosan are an interesting target for hydrophobic interactions and contribute to some degree to its bioadhesive characteristics.
  • Modified chitins and chitosans have been administered to humans in the form of dressings for wounded soft tissues and for the controlled delivery of drugs (Muzzarelli et al, 1986; 1999; Muzzarelli, 1993; 1996; Tokura and Azuma, 1992; Wada, 1995; Maekawa and Wada, 1990; Mita et al., 1989).
  • chitin-based biomaterials For the purpose of soft tissue healing the most relevant characteristics of chitin-based biomaterials are their biodegradability, biocompatibility and similarity to hyaluronan, beside their capacity to release glucosamine and N-acetyl-glucosamine monomers and oligomers (Muzzarelli, 1999).
  • Chitosan is insoluble in neutral to alkaline water and thus, it has to be exposed to acidic conditions to render it soluble.
  • Methods for solubilizing chitosan include the use of a slightly acid solution (pH ⁇ 6) containing acidic acid, glycolic acid, lactic acid, or other alpha-hydroxy acids.
  • Other methods include producing derivatives of chitosan which obviate the need for acids to solubilize chitosan.
  • U.S Patent No. 3,953,608 in Vanlerberghe and Sebag describes a method of making chitosan soluble in water at pH>7 by acylation of the chitosan using organic anhydrides.
  • Patent No. 4,929,722 describes, in particular, the method of making a chitin or chitosan salt or covalent derivative from highly crystalline, partially deacetylated chitin or chitosan.
  • Thes" ionic derivatives of chitosan called chitosonium polymers and covalent chitosan derivatives have been made by dispersing chitosan in an aqueous/ solvent mixture.
  • a controlled delivery system could make tretinoin topical therapy a viable chemoprevention treatment for melanoma. It would also be useful to have a controlled delivery system for the delivery of retinoids in which the carrier of the drug promotes connective tissue abnormalities in the damaged tissue, in order to increase the effectiveness of the treatment.
  • the present invention relates to a carrier base for the topical delivery of an active agent comprising a high viscosity chitosan biopolymer.
  • the carrier base comprises a high viscosity chitosan having a molecular weight of at least about 100,000 Dalton, more preferably at least about 250,000 Dalton and most preferably at least about 300,000 Dalton.
  • the chitosan has a concentration of at least about 2 weight% .
  • the carrier bases comprises a high viscosity chitosan biopolymer having a molecular weight of at least about 300,000 Dalton and at a concentration of at least 2 weight%.
  • the present invention also relates to a composition for the topical delivery of an active agent comprising a carrier base as described above and an active agent.
  • active agents include pharmaceutical actives and therapeutic actives.
  • Preferred pharmaceutical actives are those used for the treatment of skin diseases, e.g., retinoids, corticosteroids, non-steroidal anti- inflammatory drugs (NSAIDS), hormones, anti-fungal agents, anti-septic agents, local anaesthetics, kerolytic agents, and 5-FU.
  • useful therapeutic actives include, but are not limited to vitamins and moisturizing agents such as alpha- hydroxy acids, etc. as further described below.
  • the compositions contain more than one active agent, thus the compositions comprise at least one additional active agent, which can be either a pharmaceutical active or a therapeutic active.
  • a preferred composition comprises the carrier, retinoids and alpha-hydroxy acid.
  • the chitosan has a molecular weight of at least about 300,000 Daltons. In certain of these embodiments, the chitosan is present in a concentration greater than about 2%. These compositions are especially useful for obtaining the slow, sustained release of the active agent.
  • the chitosan has a molecular weight of about 10,000 to about 250,000 Dalton. In certain of these embodiments the chitosan is present in a concentration greater than about 5%, more preferably between about 5% up to about 8%.
  • the invention further relates to compositions for the topical delivery of retinoids comprising a carrier base and a retinoid, wherein the carrier base comprises a high viscosity chitosan.
  • the carrier base comprises a high viscosity chitosan having a molecular weight of at least about 100,000 Dalton, more preferably at least about 250,000 Dalton and most preferably at least about 300,000 Dalton.
  • the chitosan has a concentration of at least about 2 weight %.
  • the carrier bases comprises a high viscosity chitosan biopolymer having a molecular weight of at least about 300,000 Dalton and at a concentration of at least 2 weight %.
  • the invention provides for compositions of the present invention in the form of gels, creams and lotions. The manufacture of such gels, creams or lotions are known in the art.
  • the invention further relates to a method of controlling the release of an active agent from a carrier base, comprising as a carrier base a high viscosity chitosan; providing the active agent; and mixing the active agent and the chitosan.
  • the carrier base comprises a high viscosity chitosan having a molecular weight of at least about 100,000 Dalton, more preferably at least about 250,000 Dalton and most preferably at least about 300,000 Dalton.
  • the chitosan has a concentration of at least about 2 weight % .
  • the carrier base comprises a high viscosity chitosan biopolymer having a molecular weight of at least about 300,000 Dalton and at a concentration of at least 2 weight %.
  • the method further comprises the step of selecting a concentration of chitosan depending on the molecular weight of the chitosan provided so that a viscosity of at least about 100 cps is obtained.
  • the active agent comprises a pharmaceutical active, e.g., an agent that is used for the treatment of skin diseases.
  • pharmaceutical actives include, but are not limited to retinoids, such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS), hormones, antiviral, anti-histamines, anti- fungal agents, anti-septic agents, local anaesthetics, kerolytic agents, 5-FU, etc.
  • the active agent comprises a therapeutic active, e.g., vitamins, moisturizing agents such as alpha-hydroxy acids, etc., as further described below.
  • the composition contains more than one active agent, thus the compositions comprise at least one additional active agent, which can be either a pharmaceutical active or a therapeutic active.
  • the invention also relates to a method of treating skin diseases providing to the diseased skin a composition containing a high viscosity chitosan biopolymer and an active agent.
  • the high viscosity chitosan has a molecular weight of at least about 100,000 Dalton, more preferably at least about 250,000 Dalton and most preferably at least about 300,000 Dalton.
  • the chitosan has a concentration of at least about 2 weight % .
  • the high viscosity chitosan biopolymer has a molecular weight of at least about 300,000 Dalton and at a concentration of at least 2 weight %.
  • the active agent comprises a pharmaceutical active, e.g., an agent that is used for the treatment of skin diseases.
  • pharmaceutical actives include, but are not limited to retinoids, such as corticosteroids, non-steroidal anti- inflammatory drugs (NSAIDS), hormones, anti- viral, anti-histamines, anti- fungal agents, anti-septic agents, local anaesthetics, kerolytic agents, 5-FU, etc.
  • the active agent comprises a therapeutic active, e.g., vitamins, moisturizing agents such as alpha-hydroxy acids, etc., as further described below.
  • the compositions contains more than one active agent, thus the compositions comprises at least one additional active agent, which can be either a pharmaceutical active or a therapeutic active.
  • the methods of treating skin diseases comprises the compositions of the present invention, as described herein, in conjunction with other treatments for the disease. For example, in treating precancerous skin conditions, it may be useful to use the compositions of the present invention with standard treatments that use an anti-cancer drug, e.g., 5-FU for the treatment of actinic keratosis.
  • the invention further relates to compositions for the topical delivery of an active agent comprising a chitosan biopolymer and the active agent, wherein the chitosan has a molecular weight of at least about 300,000 Daltons and is present at a concentration less than about 2%, preferably less than about 1 weight %. These compositions are useful for increasing the transdermal delivery of the active agent.
  • the chitosan biopolymer comprises a chitosan having a molecular weight of at least about 100, 000 dalton.
  • the chitosan has a molecular weight ranging from about 250,000 daltons to about 1000,000, more preferably about 300,000 to about 1000,000, and most preferably from about 300,000 to about 800,000 Dalton.
  • the chitosan has a molecular weight from about 300,000 to about 800,000, at a concentration of at least about 2%.
  • the chitosan has a molecular weight from about 100,000 Daltons to about 300,000 and a concentration of at least about 5%.
  • the chitosan has a degree of deacetylation of from about 70% to about 90%.
  • the pharmaceutical active comprises a retinoid.
  • retinoids comprise retinoic acid or retinol.
  • the retinoic acid comprises all trans retinoic acid (ATRA).
  • Figure 1 is a graph that shows ATRA distribution with chitosan topical delivery.
  • Figure 2 shows the use of high molecular weight (HMW) chitosan to enhance transdermal delivery.
  • HMW high molecular weight
  • Figure 3 shows ATRA distribution using 3% HMW chitosan.
  • Figure 4 is a graph showing ATRA permeation with the high molecular weight chitosan (TD012).
  • Figure 5 is a graph that shows ATRA permeation of the high molecular weight chitosan and middle molecular weight chitosan (TM761).
  • Figure 6 shows the stability of ATRA gels of the present invention at 20°C.
  • Figure 7 shows the stability of retinol creams of the present invention at 40°C.
  • Figure 8 shows the stability of ATRA in HMW chitosan.
  • Figure 9 is a graph that shows that as the chitosan concentration increases from 1% to 3% this results in a more gradual release of retinoic acid from the chitosan matrix.
  • the methods of the present invention provide a system of incorporating active agents, e.g., pharmaceuticals, such as retinoids, into polymeric carriers to provide advantages, such as preferable tissue distribution of the drug, prolonged half life, controlled drug release and reduction of drug toxicity. More particularly, the present invention relates to the use of a chitosan carrier for the topical delivery of an active agent, e.g., retinoids, where the sustained release of the drug can be altered by varying the properties of the chitosan that is used as a carrier base for the drug.
  • active agents e.g., pharmaceuticals, such as retinoids
  • active agent refers to any substance that when introduced into the body has an affect on either the appearance of tissue to which it is applied, or alters the way the body functions.
  • pharmaceutical active refers to a drug, i.e. , a substance which when applied to, or introduced into the body, alters in some way body functions, e.g., altering cell processes.
  • Examples of pharmaceutical actives include, but are not limited to, agents that are used for the treatment of skin diseases, e.g., retinoids, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS), hormones, anti-viral agents, anti-fungal agents, anti-septic agents, local anaesthetics, anti- histamines, kerolytic agents, 5-FU, etc.
  • Other examples of such actives include, but are not limited to growth factors, recombinant human interleukin-2 and DNA, RNA and oligonucleotides and the like.
  • therapeutic active refers to a substance which either alters processes within the body, or alters the cosmetic appearance of the tissue of interest, e.g., skin, but is not technically considered a drug.
  • therapeutic actives include, but are not limited to, vitamins, e.g., vitamins A, B, C, D and E, alpha-hydroxy acids, moisturizers and other additives, as further described below.
  • the compositions contains more than one active agent, thus the compositions comprises at least one additional active agent, which can be either a pharmaceutical active or a therapeutic active.
  • the compositions includes a retinoid as a pharmaceutical active and alpha-hydroxy acid as a therapeutic active.
  • the invention will be discussed in relation to retinoids.
  • any active agent that can be used in a topical delivery system can be used in the compositions and methods of the present invention.
  • the active agent is a substance that has a molecular weight less than about 300,000 Daltons.
  • preferred agents include retinoids, e.g., retinoic acid and retinol (Vitamin A), 5-FU, anti-fungal agents, anti-viral agents, anti-histamines, hormones and corticosteroids.
  • topical as used herein is known in that art and includes the application of the compounds of the present invention to skin surfaces, including mucosal surfaces, such as labial, rectal and genital mucosal surfaces.
  • carrier base includes a component of the delivery system that assists in the release of the active agent that is being delivered.
  • Preferred carrier bases comprise a high viscosity chitosan having a molecular weight of at least about 100,000 Dalton, more preferably at least about 250,000 Dalton and most preferably at least about 300,000 Dalton. In other preferred embodiments the chitosan has a concentration of at least about 2 weight %.
  • the carrier bases comprises a high viscosity chitosan biopolymer having a molecular weight of at least about 300,000 Dalton and at a concentration of at least 2 weight%.
  • high viscosity chitosan refers to a chitosan biopolymer having a viscosity of at least about 100 cps.
  • the viscosity of the chitosan solution can readily be determined by one of ordinary skill in the art, e.g., by the methods described in Li et al., Rheological Properties of aqueous suspensions of chitin crystallites. J Colloid Interface Sc 183:365-373, 1996.
  • the high viscosity chitosan preferably has a viscosity greater than at least 100 pcs, and more preferably greater than at least 500 cps.
  • the term "low viscosity” chitosan refers to a chitosan solution having a viscosity of at least about 1-30 cps.
  • “Middle viscosity” refers to a chitosan having a viscosity of about 30- 100 cps.
  • Viscosity measurements reported here refer to a chitosan solution at 1% concentration in 1% acetic acid measured in a Brookfield LVT viscometer with appropriate spindle at 30 RPM, as common in the art.
  • the term "high concentration” as used herein, may refer to a concentration of greater than about 2% chitosan in the solution.
  • the term “low concentration” refers to up to about 1% chitosan.
  • middle concentration refers to between about 1 and about 2%.
  • high molecular weight chitosan refers to chitosan having a molecular weight of at least about 250,000 Dalton.
  • the term “low molecular weight” chitosan, also referred to herein as LMW refers to chitosan having a molecular weight up to about 50,000 Dalton.
  • the carrier base is a chitosan having a molecular weight of at least about 250,000 Dalton, more preferably at least about 300,000.
  • compositions and methods of the present invention rely on the discovery of the inventors that the desired viscosity of the chitosans can be achieved by manipulating the concentration, i.e., percentage, of different molecular weight chitosans. For example, as shown in Table 1 , a viscosity of greater than 100,000 cps can be obtained by using 12% of a LMW chitosan, 5% of a MMW chitosan or 3% of a HMW chitosan.
  • the methods and compositions of the present invention enable the control of the active agent by varying the concentration, molecular weight and, therefore the viscosity of the chitosan.
  • concentration molecular weight
  • viscosity of the chitosan.
  • the use of a greater concentration of a lower molecular weight chitosan will provide similar release rates as a higher molecular weight chitosan.
  • Retinoids e.g., retinoic acid
  • retinoic acid are hydrophobic and highly insoluble.
  • delivery of retinoic acid is highly dependent on the viscosity of the carrier base.
  • the higher the viscosity of the colloidal solution of chitosan the slower the release of the agent being delivered.
  • the retinoids in the present compositions are released as the polymer film on the skin surface becomes hydrated. As the film containing the drug and carrier dissolves away, new layers of the compositions containing the drug are exposed, leading to further release of the drug to the affected area of the skin.
  • the chitosan-based controlled delivery system of the present invention for delivery of retinoids enhances the transdermal delivery of retinoids where warranted, yet prevents the overload that results from traditional retinoid treatments and thus reduce skin irritation.
  • experiments using Franz diffusion cells have shown that carrier bases of the present invention slow down the release of retinoids which is delivered across the epidermal membrane, thus limiting the overload of retinoids to the dermal compartment.
  • the compositions of the present invention enable the slow, sustained release of the drugs, as desired.
  • the cumulative All-Trans-Retinoic Acid (ATRA) levels in each skin compartment of hairless mouse skin after about 200 hrs exposure to different chitosan formulations is shown in Figure 1.
  • the viscosity of the chitosan from 550 cps for the 1% High Molecular Weight (HMW) chitosan (MW ⁇ 360,000 Dalton) to an estimated 3.27 million cps for the 8% Middle Molecular Weight (MMW) chitosan (MW ⁇ 120,000 Dalton) it is possible to obtain a wide range of retinoid distributions.
  • the cumulative percutaneous penetration across the skin is inversely proportional to the amount of retinoid remaining on the skin surface. As the amount of retinoid remaining on the skin surface decreases from around 90% of the applied dose for the 8% MMW chitosan to less than 30% for the 1% HMW, the percutaneous penetration of retinoid increases from less than 10% to around 70%. Likewise, the amount of retinoids in the skin layers increases from less than 1% for the 8% MMW to around 5% for the 1% HMW.
  • Figure 2 shows the 1% HMW chitosan, containing 0.1% ATRA compared to a control gel, containing 0.1 g ATRA.
  • the 1% HMW chitosan contains 0.1% ATRA (0. 1 g ATRA, 0.04 g butylated hydroxytoluene (BHT), 1 g of Cremophor® RH40, 15 g ethanol (200 proof), 1 g of Chitosan HMW, 81.8 g water, 1 g of glacial acetic acid].
  • the control gel contained the following: 0.1 g ATRA, 0.04 g BHT, 1 g of Cremophor® RH40, 15 g of ethanol, 0.5g of Carbopol 940 NF, 76 g water and 0.7 g Triethanolamine.
  • the results show a higher percutaneous penetration was obtained with the 1%HMW compared with the standard gel.
  • a full 70% of the applied retinoid dose was delivered transcutaneously with the HMW formulation compared to around 45% with the control gel formulation.
  • a 1% HMW chitosan formulation can be used to enhance the transdermal penetration of retinoids to maximize the therapeutic power of retinoids.
  • Figure 3 shows that the 3 % HMW chitosan [containing 0. 1% ATRA (0. 1 g ATRA, 0.04 g butylated hydroxytoluene (BHT), 1 g of Cremophor® RH40, 15 g ethanol (200 proof), 3 g of Chitosan HMW TD012, 80.8 g water, 1 g of glacial acetic acid] compared to a standard control gel [containing the following: 0.1 g ATRA, 0.04 g BHT, 1 g of Cremophor® RH40, 15 g of ethanol, 0.5g of Carbopol 940 NF, 76 g water and 0.7 g Triethanolamine].
  • a standard control gel containing the following: 0.1 g ATRA, 0.04 g BHT, 1 g of Cremophor® RH40, 15 g of ethanol, 0.5g of Carbopol 940 NF, 76 g water and 0.7 g Triethanolamine.
  • a lower percutaneous penetration was obtained with the 3% HMW compared with the control gel. 32% of the applied retinoid dose was delivered percutaneously with the HMW formulation compared to 45% with the control gel formulation. A 3% HMW chitosan formulation could be used to control release the retinoids and limit the potential for irritation.
  • the topical control gel consisting of
  • Carbopol® 940 NF polymer displays a percutaneous ATRA delivery which lies somewhere in between the Topical ATRA formulations ranging from 1% to 3% HMW.
  • chitosan component as the carrier for the compositions and methods of the present invention, based upon the teachings described herein.
  • one of ordinary skill in the art can use Phillipof s equation for predicting release rates from polymer concentrations and viscosities. As aforesaid, a lower viscosity chitosan used at higher concentrations will provide similar release rates as a higher viscosity chitosan.
  • a carrier base having a high viscosity chitosan e.g., a chitosan with molecular weight of at least about 100,000 Dalton, e.g., 300,000, at a concentration of least 2 weight%.
  • This type of composition is desirable to minimize the overload of retinoids which may lead to irritation of the skin.
  • a chitosan solution having a high molecular weight, e.g., of at least about 250,000, at a lower concentration, e.g.,. from about 1% to about 2%.
  • Such compositions are useful for increasing the transdermal release of the active agent over a shorter period of time.
  • compositions of the present invention enhances the normal tissue architecture of naturally and photoaged skin while reducing skin irritation, normally seen with retinoid preparations.
  • compositions of the present invention can be formulated into gels, lotions, ointments or creams according to known methods.
  • the delivery systems can be used to form gels at concentrations greater than 2%.
  • these gels can be used as is or formed into creams by including an oil and emulsifying the mixture, by known methods.
  • Preferred oils include avocado oil, sea buckthorn oil, jojoba oil, etc.
  • Other compounds can also be added as desired to increase the effectiveness of the formulations. Examples of such additives may include, but are not limited to, vitamins such as A, B, C, D, E, K, etc., moisturizers such as alpha-hydroxy acids, etc.
  • additives may be used to improve the appearance of the formulation, e.g., odor, texture or visual appeal.
  • additives include, but are not limited to, fragrances, coloring, emoll:ents and ingredients for the enhanced percutaneous absorption of various there Guideic actives, such as glycerol, propylene glycol, oleic acid, surfactants, etc.
  • the delivery systems of the present invention can contain a large number of pharmaceutical and therapeutic actives that can be applied topically either singularly or in combination.
  • these actives include, but are not limited to compounds such as the following: Anti-fungal agents such as Imidazoles, Clotrimazole, Clotrimazole/betamethasone dipropionate, Econazole, Ketoconazole, Miconazole, Oxiconazole, Sulconazole, Allylamines, Naftifine, Terbinafine, Polyenes, Ny statin, Nystatin/triamcinolone, Ciclopirox olamine,
  • Anti-fungal agents such as Imidazoles, Clotrimazole, Clotrimazole/betamethasone dipropionate, Econazole, Ketoconazole, Miconazole, Oxiconazole, Sulconazole, Allylamines, Naftifine, Terbinafine, Polyenes, Ny statin, Nystatin/
  • Anti-inflammatory agents such as coal tar, shale tar, wood tar, non-steroidal anti-inflammatory drugs (NSAIDS) salicylic acid, salicylate esters and salts, acetylsalicylic acid, and the like.
  • Local anaesthetics such as cocaine, benzocaine, tetracaine, lidocaine, bupivacaine, their hydrochloride salts, and the like.
  • Antibiotic agents such as bacitracin, mupirocim, erythromycin, neomycin, clindamycin, doxycycline, trimethoprim- sulfamethoxazole, penicillin-V, trimthoprim-sulfamethoxazole, chloramphenicol, gentamycin, azithromycin, ciprofloxacin, ofloxacin, ceftriaxone, minocycline, amoxicillin-clavulanate, first-generation cephalosporin, ceftriaxone, and the like.
  • Sulfanilamide antibacterial agents such as sulfanilamide, sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, trimethoprim, pyrimethamine, and the like.
  • Antiviral agents such as Imiquamod, acyclovir, valacyclovir, famcyclovir, penciclovir, idoxuridine, trifluridine, foscarnet, cidofovir, interferons, IFN- ⁇ , IFN- ⁇ 2b, IFN- ⁇ n3, nucleoside analogues, protease inhibitors and the like.
  • Antiseptic agents such as acridine dyes, alcohols, bronopol, chlorhexidine, phenols, hexachlorophene, organic mercurials, organic peroxides, i.e., benzoyl peroxide, quaternary ammonium compounds, and the like.
  • Vitamin and vitamin derivatives such as Vitamin A, retinol, retinoic acid (both cis and trans) , alpha-tocopherol (Vitamin E), 7-dehydrocholesterol (Vitamin D), Vitamin K, thiamine riboflavin, niacin, pyridoxine, biotin, pantothenic acid, ascorbic acid, choline, inositol, and the like.
  • Anti- inflammatory corticosteroids such as progesterone, hydrocortisone, prednisone, fludrocortisone, triamcinolone, dexamethasone, betamethasone, fluocinolone, and the like.
  • Autacoids such as prostaglandins, prostacyclin, thromboxanes, leukotrienes, angiotensins (captopril), as well as other pharmaceutically active peptides such as serotonin, endorphins, vasopressin, oxytocin, and the like.
  • Kerolytic agents such as benzoyl peroxide, salicylic acid, trichloroacetic acid, and piroctone, and wart treatment compounds such as salicyclic acid, trichloroacetic acid and lactic acid, singularly or in combination with anti-viral agents.
  • Anti-alopecia agents such as niacin, nicotinate esters and salts, and minoxidil.
  • Sun-Protective agents such aminobenzoates, Para-aminobenzoic acid (PABA), Ethyl-4-[bis(hydroxypropyl)-aminobenzoate, Glyceyl PABA, Amyl p- dimethylaminobenzoate (padimate A), 2-ethylhexyl PABA (padimate O), Cinnamates, Dietholamine p-methoxycinnamate (Parsol MCX), Salicylates, 2- ethylhexyl salicylate, Homosalate (homomenthyl salicylate), Octyl salicylate, Triethanolamine salicylate, Trolamine salicylate, Benzophenones, Dioxybenzone, Sulisobenzone, Oxybenzone, Ethylhexyl, 2-cyano-3, 3-diphenyl- acrylate (octocrylene), Lawsone and dihydroxyacetone, 2-phenylbenzimidazole-
  • PABA Para-amin
  • Methyl anthranilate Butylmethoxydibenzoyl methane (avobenzone), zinc oxide.
  • additives can also be used, e.g., moisturizing agents such as lactic acid, pyrrolidone carboxylic acid, glycolic acid, water, glycerine, propylene glycol, sorbitol, other alphahydroxy carboxylic acids, and various salts of these esters and salts, and the like and additives for the enhanced percutaneous absorption of various pharmaceutical or therapeutic actives.
  • moisturizing agents such as lactic acid, pyrrolidone carboxylic acid, glycolic acid, water, glycerine, propylene glycol, sorbitol, other alphahydroxy carboxylic acids, and various salts of these esters and salts, and the like and additives for the enhanced percutaneous absorption of various pharmaceutical or therapeutic actives.
  • Such percutaneous enhancers include propylene glycol, glycerol, urea, diethyl sebecate, sodium lauryl sulfate, sodium laureth sulfate, sorbitan ethoxylates, nicotinate esters (such as hexyl nicotinate), oleic acid, pyrrolidone carboxylate esters, (such as dodecyl pyrrolidone carboxylate), N-methyl pyrrolidone, N,N- diethyl-mtoluamide, dimethyl sulf oxide, decyl methyl sulfoxide, alkyl methyl sulfoxides, N,N-dimethyl formamide, cis-11-octadecenoic acid, 1- dodecylazacycloheptan-2-one, and 1 ,3-dioxacyclopentane or 1 ,2- dioxacyclohexane containing at least one ali
  • the amount of active employed will be that amount necessary to deliver a pharmaceutically or therapeutically effective amount to achieve the desired result at the site of application. In practice, this will vary depending upon the particular medicament, severity of the condition as well as other factors. In general, the concentration of the actives in the delivery systems can vary from as little as 0.0001 up to 5 percent or higher, by weight of the delivery system. For retinoids, a preferred dose is between 0.01%- 1% for retinol and between 0.01% -0.1% for all-trans-retinoic acid.
  • adjuvant ingredients such as glycerin, propylene glycol, sorbitol, preservatives, stearic acid, cetyl alcohol, other high molecular weight alcohols, surfactants, menthol, eucalyptus oil, other essential oils, fragrances, penetration enhancers, and the like to give stable cremes, ointments, lotions, aerosols, solutions, may also be included.
  • solutions or mixtures of the actives with the chitosan derivatives may be prepared with or without some of the adjuvant ingredients, and these solutions or mixtures may be fabricated into films, rods, sheets, sponges or fibers for use as suppositories, medicated sutures, medicated sheets, medicated bandages, patches, and the like. It is relatively easy to process chitosan into various forms such as small particles, gel, and cotton mesh for drug delivery applications. Such methods are known in the art.
  • alpha-hydroxy acid AHA is used to completely dissolve the chitosan.
  • AHA is also referred to as glycolic acid in the methods and examples described below. The benefit of using alpha -hydroxy acid is two-fold.
  • alpha-hydroxy acid helps dissolve the chitosan.
  • chitosan which is basic, raises the pH of the composition which in turn, minimizes the peeling seen with standard alpha-hydroxy acid formulations.
  • Neutral or mildly acidic vehicles of alpha-hydroxy acids are actively being sought (Neudecker et al., 2000). It is common practice to use ammonium salts to neutralize the alpha- hydroxy acids present in most current cosmetic preparations. Ammonium salts present in most current cosmetic preparations of alpha-hydroxy acids may prevent hyaluronan (HA) enhancement (Neudecker et al., 2000).
  • HA hyaluronan
  • Chitosan through the presence of its amino groups on the polymer chain, can be used to neutralize the alpha hydroxy acids.
  • the addition of 3% HMW chitosan raises the pH of an alpha hydroxy solution from 3.5 to 5.5 , thus bringing the pH of the AHA formulation in the mildly acidic range where the action of AHA can effect the ability to stimulate HA production rather than implement their action by peeling the skin and cause diffuse wound healing.
  • AHA is thus useful as an active agent alone, or in conjunction with another pharmaceutical or therapeutic active.
  • compositions of the present invention are stable, as is necessary for topical treatments.
  • ATRA gels made from the HMW chitosan at concentrations greater than 2% are stable for at least 120 days and comparable in stability to the standard control gels made from Carbopol as shown in Figure 6.
  • Lower concentrations of chitosan may cause a reduction in the stability of the ATRA in the gel formulation.
  • creams made from the 3% HMW are highly stable, again as a result if the high viscosity of this type of chitosan when present at greater than 2% concentration. Similar results would be obtained with the MMW chitosan present at concentration than 5% w/w.
  • the difference in stability is related to the addition of the surfactant Cremophor RH40 which causes a reduction in ATRA stability compared to the HMW formulation alone.
  • a carrier base with a high- viscosity grade chitosan e.g., having a molecular weight of at least about 300,000 Dalton and at a concentration, e.g., of at least 2 weight % results in a greater stability of the retinoid preparation, over a period of months. See Figure 8 and Example 3, below.
  • a high molecular weight chitosan in delivering an active agent, such as retinoids is the ability to use a lower concentration to obtain a sufficient viscosity required for stabilization of the retinoids. Stability of formulations is often tested at 40 °C for a period of several months.
  • chitosan is used in cosmetology to make moisturizing creams.
  • the concentration in moisturizers and soaps varies from 0.3% to 1% chitosan. These concentrations have been experimentally tested by the manufacturers and are well tolerated on the skin. It is also used in hair sprays, styling gels and shampoos: its cationic nature enables a close bond to the keratin anion (Sachetto, 1986; Cleenewerck, 1994).
  • Chitosan is a biodegradable polymer which has advantages over a synthetic polymer, e.g., PP2.
  • chitosan is completely degraded in the body. It degrades without leaving residual matter which could build up in the tissues. As suture material, chitosan has been shown to be completely absorbed in one to two months so it would release the drug during the same period (Suzuki, 1995). It is unnecessary to remove chitosan from the body after the complete release of the drug because chitosan has good biodegradability and is completely dissolved by enzymes such as lysozyme.
  • the present invention provides methods for the treatment of many skin ailments. To our knowledge there is no controlled topical delivery system of retinoids for melanoma chemoprevention.
  • One aspect of the present invention is a chitosan based percutaneous delivery system for the chemoprevention of melanoma in individuals with dysplastic nevi who are at high risk of developing melanoma.
  • compositions of the present invention utilize the property of chitosan to initiate immune and reparative functions, either directly or indirectly through the stimulation of macrophages in the skin tissue.
  • cytokines such as IL- 1 leads to increased angiogenesis and skin reparative functions.
  • IL- 1 and TNF- ⁇ produced by macrophages, stimulate fibroblasts (Chang J et al.1986). Chitosan has been shown to stimulate macrophage production, resulting in activation of cytokines such as interleuken- 1 (IL- 1) and interferon gamma (IFN- ⁇ ).
  • IL- 1 interleuken- 1
  • IFN- ⁇ interferon gamma
  • the degree of deacetylation for immuno stimulatory activity is optimal around 70% and other degrees of deacetylation result in the reduction of immunostimulatory activity (Nishimura et al, 1984, 1985, 1986, 1990).
  • a 70% deacetylated chitin has been used in combination with petrolatum to immunostimulate the skin in the management of senile erythroderma. (Horuchi & Otoyama, 1996).
  • the chitin derivative is not employed in these studies as a delivery system but rather as the active ingredient in the topical petrolatum-based formulation.
  • chito-oligomers released from chitosan by the in vivo hydrolytic action of lysozyme and N-acetyl- ⁇ -D-glucosaminidase after penetration of chitosan into the skin may stimulate hyaluronan synthesis.
  • DG42 protein a chito-oligomer synthase
  • DG42 chito-oligomers
  • hyaluronan synthase preparations also contain chitin synthase activities (Varki A, 1996; Semino et al. , 1996; Bakkers et al., 1997).
  • Chitosan has the potential, directly or indirectly through the formation of hyaluronic acid, to correct this deficiency and to provide correct deposition of collagen fibers such as reduced space and fiber thinness, fiber disorganization and depth of disorganization. Therefore the administration of retinoids via a chitosan carrier base has the potential of enhancing both the quantity and quality of new collagen production in skin connective tissue.
  • the methods of the present invention take advantage of the reparatory effect of chitosan to stimulate fibroblasts in conjunction with the therapeutic effect of retinoids to obtain a synergistic effect.
  • the increase in collagen repair is useful for treating conditions that which would benefit from an immunostimulatory response, e.g., in preparations used for anti-wrinkle products as well as for products that are used to treat photodamage and other such skin conditions.
  • the compositions of the present ivention are useful for treating skin diseases. Examples of skin diseases which can be treated include, but are not limited to, acne, melanoma, premature skin aging, and photodamage.
  • the active agent comprises a pharmaceutical active, e.g., an agent that is used for the treatment of skin diseases.
  • pharmaceutical actives include, but are not limited to retinoids, such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS) , hormones, anti-fungal agents, anti-septic agents, local anaesthetics, kerolytic agents, 5-FU, etc.
  • the active agent comprises a therapeutic active, e.g., vitamins, moisturizing agents such as alpha-hydroxy acids, etc., as further described below.
  • the amount and frequency of the application of the delivery systems can readily be determined by one of ordinary skill in the art, based upon the type and severity of the ailment, as well as the amount of agent present in the system.
  • compositions of the present invention in some methods of treating certain skin diseases, it may be useful to use the compositions of the present invention in conjunction with other treatments for the disease.
  • m treating precancerous skin conditions it may be useful to use the compositions of the present invention with standard treatments that use an anti-cancer drug, e.g., 5-FU, for the treatment of actinic keratosis.
  • an anti-cancer drug e.g., 5-FU
  • the present invention is further illustrated by the following Examples.
  • the Examples are provided to aid in the understanding of the invention and are not construed as a limitation thereof. All examples are carried out using standard techniques, which are well known and routine to those of skill in the art, except where otherwise described in detail. Routine techniques of the following examples can be carried out as described in standard laboratory manuals.
  • Table 2 shows the types of chitosan used.
  • the chitosan was obtained from Primex Ingredients, Avaldnes, Norway. These formulations were then tested in in vitro assays, i.e. penetration and recovery studies using conventional and radiolabeled retinoids and long- term stability studies at 20 °C and 40 °C, as described below with a Franz diffusion cell. Human subjects are then exposed to selected formulations (in vivo) and compared to current dermal retinoid formulation to test their ability to reduce irritation.
  • Table 2 shows the types of chitosan used.
  • the chitosan was obtained from Primex Ingredients, Avaldnes, Norway.
  • the degree of deacetylation was measured by the UV-method (From Primex Ingredients, Product Literature).
  • sample TD012 is an example of a high molecular weight (HMW) chitosan
  • TM761 is an example of a middle molecular weight (MMW) chitosan
  • TM615, TM816 and TM61 1 are examples of low molecular weight (LMW) chitosans.
  • Gel Chitosan TD012 has a viscosity of 500 cP when dissolved with 1% glacial acetic acid at 1% concentration. The viscosity increases as a function of concentration of the polymer, reaching an estimated 171 , 163 cps at 3% concentration .
  • Colloidal solutions up to 3% (wt/wt) chitosan were obtained by dissolving high molecular weight chitosan (HMW (TD012); MW 360,000 Daltons) in 1% glacial acetic acid at room temperature.
  • Carrier bases up to 8% were obtained by suspending chitosan powder of middle molecular weight (MMW (TM761); MW 120,000) (8 g in 66 g of deionized water) in water at room temperature, raising the temperature to 90 °C and adding 25 g of water and 1 g of glacial acetic acid, dropwise to chitosan to form a clear, highly viscous solution after cooling at room temperature.
  • MMW middle molecular weight
  • EXAMPLE 2 In vitro skin penetration studies using radiolabeled retinoids. Fresh hairless mouse skin samples were obtained from surgery, and upon arrival to the lab they were stored in a freezer (-20 °C). Immediately prior to the permeation experiments, skin samples without subcutaneous fat were thawed by floating on water at 22 °C for about 10-20 minutes. A 1.0 cm 2 portion of the skin samples was fastened between the Franz diffusion cell's receptor chamber and chimney top by an o-ring and a spring clamp (PermeGear, Inc.) (Lehman et al., 1988.)
  • radiolabeled 3 H-Retinoic Acid 20 microcuries (NEN LifeSciences, Boston, MA) were added to 1.5 grams of a retinoic acid stock solution, comprised of 100 mg of retinoic acid in 15 grams of absolute ethanol (200 proof) and 1 g of hydrogenated castor oil (cremophor RH40, BASF Corporation) and were mixed with 8.5 grams of the chitosan colloidal solution.
  • a retinoic acid stock solution comprised of 100 mg of retinoic acid in 15 grams of absolute ethanol (200 proof) and 1 g of hydrogenated castor oil (cremophor RH40, BASF Corporation) and were mixed with 8.5 grams of the chitosan colloidal solution.
  • a retinoic acid stock solution comprised of 100 mg of retinoic acid in 15 grams of absolute ethanol (200 proof) and 1 g of hydrogenated castor oil (cremophor RH40, BASF Corporation) and were mixed with 8.5 grams of the chitosan colloidal solution
  • retinoic acid stock solution (comprised of 100 mg of retinoic acid, 10 g of avocado oil and 1 g of Cremophor RH40).
  • the solution was then mixed with 1.5 g of glycerin, 0.05 g of Vitamin E, 0.1 g of Seabuckthorn Seed Extract.
  • each formulation was applied to the sample compartment (i.e. the epidermal side) of the skin sample.
  • the dermal surface of the skin was perfused with receptor phase solution (phosphate buffered saline containing 0.5% Volpo surfactant (Croda, Inc.) .
  • receptor phase solution phosphate buffered saline containing 0.5% Volpo surfactant (Croda, Inc.) .
  • Each formulation was tested in triplicate.
  • the receptor volume was sampled every 24 hours by withdrawing 500 ⁇ L. It was then mixed with scintillation fluid for scintillation counting.
  • tissue solubilizer Solvable Tissue and Gel Solubilizer -Packard Instruments
  • scintillation fluid Ultima Gold -Packard Instruments
  • TD012 chitosan M.Wt 360,000 Dalton
  • TD012 Chitosan 2.96% because it forms a highly viscous colloidal solution at room temperature and it offers a favourable ATRA release profile.
  • Solution A was prepared by dissolving chitosan in a 1% glacial acetic acid solution as follows: 2.9% Chitosan TD012, 79.98%Water in 1% Acetic Acid.
  • Solution B was prepared by dissolving cremophor RH40 in ethanol in an amber container followed by BHT and retinoic acid. The amounts are as follows: 15% Ethanol, 1% Cremophor RH40, 0.02% BHT and 0.1% Retinoic Acid. Solution B was mixed into solution A using a 3-blade laboratory mixer.
  • Retinol 50C Solution A was prepared by adding glycolic acid to water. While stirring, NaOH (10g/ 100 ml) was added dropwise to raise the pH from 2.12 to 3.5. Then chitosan was added and allowed to dissolve completely overnight. The final pH was 5.3-5.5.
  • Solution B was prepared by combining the glycerin, cremophor RH40, vitamin E acetate, avocado oil, and sea buckthorn oil. The perfume and retinol 50C (50% w/w of retinol in Polysorbate 20 -BASF) were added sequentially to obtain an homogeneous solution. Solution B was then incorporated into Solution A using a 3-blade laboratory stirrer.
  • retinoic acid cream 100 mg retinoic acid was substituted for the 200 mg of retinol 50 C.
  • the retinoic acid was initially suspended in 10 g of avocado oil containing 1 g of cremophor RH40. The rest of procedure is similar to the retinol cream.
  • the stability of the retinoic acid gels was tested at both 20 °C and 40 °C in a water bath. Retinoid concentrations were tested by dissolving 0.2g of the gel (or cream) in 6.7g of a 1% acetic acid in ethanol solution. The solution was then stirred using a magnetic stirring bar and plate until the retinoid and chitosan had dissolved.
  • a 100 ⁇ L quantity was diluted 10-fold in 1% acetic acid/ethanol solution and the absorbance measured at 351 nm using a
  • Gel samples designated 87-1 consist of 0.1% ATRA in 2.9% TD012 as in
  • EXAMPLE 1 101-1 is 0.1 % ATRA in 0.5% Carbopol 940 NF instead of 2.9 TD012 ; 109-1 is 0.1% ATRA as in EXAMPLE 1 with 3.5% TD012 instead of
  • Cream samples 2-3-1 consist of 1% retinol in TD012 (2.9%) as in
  • Cream sample 2-5-1 is the same as 2-3- 1 without the Cremophor component.
  • the human evaluation involved three strengths of commercially available tretinoin (ATRA) cream (0.01%, 0.05% and 0. 1%) with two concentrations of chitosan ( 1% and 3%) in the formulation.
  • ATRA tretinoin
  • the data is evaluated in terms of a Mean Irritation Score by evaluating the extent of erythema, as previously described (Mills and Berger, 1998).
  • Statistical evaluation includes both frequency and severity of erythema seen at sites treated with tretinoin containing chitosan and commercially available tretinoin using analysis of variance (ANOVA) and the paired t-test.
  • the drug product (ATRA Cream) consists of a modified retinoic acid formulation.
  • the control cream was obtained from Technical bulletin ME 142e for Retinoic acid (BASF Corporation, NJ).
  • ME 142e for Retinoic acid
  • Tegiloxan® 100 (2) 0.5 g
  • Mixture II is heated to 75 °C and stir in Solution I.
  • Mixture III is heated until a completely clear solution is obtained, then added to the heated Mixture I/II and stirred until cold.
  • I ATRA (USP) 100 m;
  • Cremophor A 25 ( 1) 1 .5 g
  • Tegiloxan® 100 (2) 0.5 g
  • Cremophor® RH40 ( 1) i g
  • Mixture I is incorporated with solution II and the Mixture I/II is homogenized to a fine consistency.
  • Mixture I is incorporated with solution II and the Mixture I/II is homogenized to a fine consistency.
  • Part I involves 6 human volunteers. Each volunteer receives the 6 formulations listed below. Each formulation consists of 0.2 g of test sample, applied to the volar forearm (3 formulations on each forearm) in the form of a patch (Hill Top Research, Inc., Cincinnati, OH). Each human subject is evaluated at 24 hours for signs of irritancy (e.g. erythema).
  • Part II involves 3 additional human subjects, each subject receiving 3 patches containing 0.2 grams of test sample to the paraspinal area of the back to verify any irritation caused by the base alone without ATRA.
  • the patch application is for 24 hours with irritancy evaluation at 30 minutes after patch removal and 24 hours after patch removal.
  • Site 1 A Base Cream
  • Site 2 C HMW-Chitosan 1%)
  • Site 3 C HMW-Chitosan 3%) The location of each test sample is rotated for each individual according to latin square design.
  • Part III involves the testing of 6 additional human subjects. Each participant receives 6 patches applied to the paraspinal area on the back, including 3 patches of the control cream and 3 patches of the 3.9% HMW-chitosan cream each containing 3 strengths of ATRA. Patches are removed after 24 hours and irritancy scored 30 minutes and 24 hours.
  • Statistical evaluation includes ANOVA and paired t-test to evaluate any significant difference between treatments, sites and patients.
  • Site 6 D (3% HMW-Chitosan + 0.15% ATRA) The location of each test sample is rotated for each individual according to latin square design.
  • EXAMPLE 5 CHITOSAN GELS AS DELIVERY VEHICLES FOR RETINOIC ACID
  • the topical carrier base consisting of high viscosity chitosan with a molecular weight of at least 300,000 Dalton and at a concentration of at least 2 weight% acts as a delivery system to control the release of retinoic acid (RA) .
  • RA retinoic acid
  • [ 3 H]retinoic acid [ 3 H]retinoic acid.
  • a high molecular weight chitosan viscosity of 552 cP with 1% solutions in 1% acetic acid measured on a Brookfield LVT viscometer at 25 C, appropriate spindle at 30 rpm, MWt of 360,000 Dalton.
  • Fresh skin (female abdominal) was obtained from surgery, and upon arrival to the lab was washed and stored with 0.1 M phosphate-buffered saline (PBS) buffer (pH 7.4).
  • PBS phosphate-buffered saline
  • Subcutaneous fat was removed and the skin was rinsed in PBS, it was then dried and stored in the freezer (-20 C).
  • split skin samples Prior to skin splitting, full skin was thawed overnight in sterile PBS.
  • the split skin procedure consisted of taking a 4 x 4 cm full skin sample and immersing it in water at 60 °C for approximately 60 sec. The epidermis was then carefully removed with forceps and placed on aluminum foil and stored at -20 °C. Prior to the permeation experiment, split skin samples were thawed by floatation in water at 22 °C for ⁇ 20-40 minutes.
  • HMW-Chitosan (88.8% deacylated chitosan, 1000 cps viscosity, 800,000 MWt; Primex Ingredients SA, Avaldsnes, Norway) was dissolved in 1% acetic acid for 24 hours prior to mixing.
  • the retinoid/chitosan formulation was made up by adding concentrations of retinoids (ATRA or 9-cz ' s-RA) ranging from 0.01% to 0.1% in a colloidal formulation containing 50% ethanol, 1% vitamin E, 8% cremophore RH40, 40% water and 1.75% HMW-chitosan
  • Receptor fluid consisting of 25% ethanol and 75% PBS was placed within the receptor compartment. This concentration of ethanol in PBS prevented the formation of a two-phase system (turbidity) while maintaining the retinoid in solution.
  • a known quantity of conventional retinoid (0.01%-0.1%) was placed in the donor compartment, covered with aluminum foil to prevent evaporation.
  • Samples (200 ⁇ l) for spectrophotometric analysis were then removed from the receptor port at timely intervals up to 48 hours and stored in amberized 1ml Teflon-capped vials.
  • the same quantity of receptor fluid (at 37 °C) was then returned to the receptor compartment to ensure a constant volume. Samples from the vials were diluted five-fold and then quantitated via UV absorbance using a Shimadzu UV160U spectrophotometer.
  • Retinoid penetration through human skin was determined as follows: 5 ⁇ l of 3 H-ATRA (NET- 1 1 17) were mixed homogenously to 500 ⁇ l of HMW- Chitosan to make a 0.001 % gelling solution. consisting of 0.05 g Tretinoin, 50 ml 95% Ethanol, 3.2 g Cremophor RH-40, 1.0 g Vitamin E acetate, 50 ml 2.5% Chitosan ( high MW Primex Superior). For the ethanol solution, the chitosan was omitted in the formulation.
  • the EpiDermTM Skin Model (Epi-200, MatTek Corporation, Ashland, MA) is used to obtain in vitro skin toxicity MTT and IL- lcx measurements indicative of skin irritation as follows: Individual human equivalent cultures are transferred to six- well culture plates, each well containing 0.9 ml of culture medium and placed in a humidified incubator at 37 °C, 5% CO 2 , for 1 hour. Prior to dosing, the medium is replaced with fresh medium. 25 ⁇ L of test solution containing 0.05% ATRA with either ethanol or 1.25% IVR59 are topically applied to the apical surface of each culture in duplicate and the culture plate is returned to the incubator.. Culture plates are removed at 18 hrs, according to the protocol.
  • Deionized water is used as the negative control and 0.3% Sodium Dodecyl Sulfate (SDS) as the positive control.
  • SDS Sodium Dodecyl Sulfate
  • the cultures are assayed for residual mitochondria! dehydrogenase enzyme activity ("MTT assay") as an indicator of culture viability (Osborne and Perkins, 1994). Washed cultures are incubated for 3 hrs in a humidified chamber at 37 °C in MTT reagent (Sigma) at a concentration of 1 mg MTT dye per 1.0 ml of incubation medium (EpiDermTM Assay Medium). The remaining medium was saved for IL- l ⁇ cytokine analysis.
  • MTT assay residual mitochondria! dehydrogenase enzyme activity
  • cultures are washed again in PBS and 2 ml of 2-propanol was added to each culture plate to extract the purple formazan product of the MTT dye metabolism. Extraction is performed at room temperature for 2 hrs.
  • the absorbance of 200 ⁇ L aliquots of the formazan /alcohol extracts are measured at 570 nm.
  • IL- l ⁇ was measured on the saved culture medium using a standard ELISA and protocol from Cayman Chemical Corporation (Ann Arbour, MI). The level of absorbance in the 0 pg/ml sample is subtracted from all other standard concentration absorbencies. A linear regression formula for the standard curve was obtained providing the IL- l ⁇ concentrations.
  • Balassa LL Process for Promoting wound healing with chitin derivatives.
  • Gallo JM Hassan EE. Receptor-mediated delivery system.
  • Halpern AC et al. Effects of topical tretinoin on dysplastic nevi. J Clin Oncol, 12: 1028- 1035, 1994. Halpern AC. Retinoids and the chemoprevention of melanoma. In:
  • Muzzarelli RAA et al., histology and clinical uses of chitins and chitosans in wound healing.
  • Chitin and Chitinases Jolles P and Muzzarelli RAA (Eds), Birkhauser Verlag Publ., Basel, Switzerland, pp.251-264, 1999.
  • Muzzarelli RAA Biochemical significance of exogenous chitins and chitosans in animals and patients. Carbohydr Polym 20:7- 16, 1993. Muzzarelli RAA. Wound dressing materials. In: The polymeric materials encyclopedia. CRC Press, Boca Raton, FL, 1996.
  • Nishimura K, et al. Stimulation of cytokine production in mice using deacetylated chitin
  • Nishimura K, et al. "Adjuvant activity of chitin derivatives in mice and guinea-pig", Vaccine 3:379-384, 1985.
  • RARs retinoic acid receptors
  • RXRs retinoid X receptors
  • Suzuki K A new drug delivery system for local cancer chemotherapy using cisplatin and chitin. Anticancer Reseach; 15:423-426, 1995.
  • Talwar H et al. Reduced type I and type III procollagens in photodamaged adult human skin. J Invest Dermatol 105:285-291, 1995
  • Wada M Effect of chitin, chitosan intake on metabolism of uric acid. Gekkan Fudo Kemikaru 1 1 :25-31 , 1995.
  • Wingo PA et al. Annual report to the nation on the status of cancer, 1973- 1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst;91 :675-90, 1999. Won R, et al. Methods and Compositions for Topical Delivery of Retinoic

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Abstract

La présente invention concerne une base de transport utilisée dans l'administration par voie topique d'un agent actif comprenant un biopolymère de chitosane à viscosité élevée. L'invention concerne également une méthode permettant de commander la libération d'un agent actif d'une base de transport, comprenant comme base de transport un chitosane à viscosité élevée, consistant à générer l'agent actif, et à mélanger l'agent actif et le chitosane. De préférence, la base de transport comprend un chitosane à viscosité élevée possédant un poids moléculaire d'au moins 100 000 Dalton environ, préférablement d'au moins 250 000 Dalton environ, et plus préférablement d'au moins 300 000 Dalton environ. Dans d'autres modes de réalisation, le chitosane a une concentration d'au moins 2 % en poids environ.
PCT/US2000/035319 1999-12-23 2000-12-22 Biopolymere de chitosane utilise dans l'administration par voie topique d'agents actifs WO2001045645A1 (fr)

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US10/221,307 US20030206958A1 (en) 2000-12-22 2000-12-22 Chitosan biopolymer for the topical delivery of active agents
JP2001546386A JP2003524635A (ja) 1999-12-23 2000-12-22 活性作用物の局所デリバリー用キトサンバイオポリマー
CA002394901A CA2394901A1 (fr) 1999-12-23 2000-12-22 Biopolymere de chitosane utilise dans l'administration par voie topique d'agents actifs

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US17195999P 1999-12-23 1999-12-23
US60/171,959 1999-12-23

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US10/839,907 Continuation US20040247632A1 (en) 1999-12-23 2004-05-06 Chitosan microparticles for the topical delivery of water insoluble active agents

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WO2010109422A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale pour érythème fessier et son procédé de production
WO2010109433A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antivirale et son procédé de fabrication
WO2010109418A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antifongique et son procédé de fabrication
WO2011027247A1 (fr) * 2009-09-03 2011-03-10 Sulur Subramaniam Vanangamudi Crème antifongique contenant du chlorhydrate de terbinafine
WO2011101827A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du butyrate de clobétasone, et un antifongique - du nitrate de miconazole, et son procédé de fabrication
WO2011101822A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, et un corticostéroïde - de l'acétate de dexaméthasone, et son procédé de fabrication
WO2011101829A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du dipropionate de bétaméthasone, et un antifongique - du nitrate de miconazole, et son procédé de fabrication
WO2011101831A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du butyrate de clobétasone, et un antifongique - du chlorhydrate de terbinafine, et son procédé de fabrication
WO2012023078A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème médicinale contenant de l'acide fusidique obtenue à l'aide de fusidate de sodium, et contenant un biopolymère, de l'acétate de dexaméthasone (corticostéroïde), et du nitrate d'oxiconazole (agent antifongique), et son procédé de fabrication de cette crème
WO2012023082A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant
WO2012049545A1 (fr) * 2010-10-12 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
WO2012049539A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
WO2012049540A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
EP3397286A4 (fr) * 2015-12-28 2019-01-23 Alumend, LLC Compositions et procédés ayant un effet sur l'irritation cutanée
US11344507B2 (en) 2019-01-08 2022-05-31 Alumend, Llc Topical compositions containing low molecular weight chitosan derivatives

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JP2015211810A (ja) * 2014-05-07 2015-11-26 公立大学法人大阪市立大学 自己硬化型リン酸カルシウム組成物、該組成物を製造するためのキットおよび製造方法
KR20140113614A (ko) * 2014-05-14 2014-09-24 손미경 키토산을 이용한 ｄｉｙ 천연화장품 및 이의 제조방법
CN109125099B (zh) * 2018-08-24 2021-04-13 杭州氢源素生物科技有限公司 一种可持续释放氢气的面膜及其使用方法
KR102623698B1 (ko) * 2021-06-24 2024-01-12 아주대학교산학협력단 키토산-콜라겐 고분자 복합체 및 이의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968528A (en) * 1997-05-23 1999-10-19 The Procter & Gamble Company Skin care compositions
US6013270A (en) * 1998-04-20 2000-01-11 The Procter & Gamble Company Skin care kit
US6174533B1 (en) * 1997-05-23 2001-01-16 The Procter & Gamble Company Skin care compositions and method of improving skin appearance

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9604610D0 (sv) * 1996-12-16 1996-12-16 Noviscens Ab Medical composition
DE19719856A1 (de) * 1997-05-12 1998-11-19 Henkel Kgaa Hautpflegemittel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968528A (en) * 1997-05-23 1999-10-19 The Procter & Gamble Company Skin care compositions
US6174533B1 (en) * 1997-05-23 2001-01-16 The Procter & Gamble Company Skin care compositions and method of improving skin appearance
US6013270A (en) * 1998-04-20 2000-01-11 The Procter & Gamble Company Skin care kit

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010109422A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale pour érythème fessier et son procédé de production
WO2010109433A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antivirale et son procédé de fabrication
WO2010109418A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antifongique et son procédé de fabrication
WO2011027247A1 (fr) * 2009-09-03 2011-03-10 Sulur Subramaniam Vanangamudi Crème antifongique contenant du chlorhydrate de terbinafine
WO2011101827A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du butyrate de clobétasone, et un antifongique - du nitrate de miconazole, et son procédé de fabrication
WO2011101822A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, et un corticostéroïde - de l'acétate de dexaméthasone, et son procédé de fabrication
WO2011101829A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du dipropionate de bétaméthasone, et un antifongique - du nitrate de miconazole, et son procédé de fabrication
WO2011101831A3 (fr) * 2010-02-22 2011-12-29 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique préparée avec du fusidate de sodium et incorporant un biopolymère, un corticostéroïde - du butyrate de clobétasone, et un antifongique - du chlorhydrate de terbinafine, et son procédé de fabrication
WO2012023078A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème médicinale contenant de l'acide fusidique obtenue à l'aide de fusidate de sodium, et contenant un biopolymère, de l'acétate de dexaméthasone (corticostéroïde), et du nitrate d'oxiconazole (agent antifongique), et son procédé de fabrication de cette crème
WO2012023082A1 (fr) * 2010-08-17 2012-02-23 Sulur Subramaniam Vanangamudi Crème médicamenteuse à base d'acide fusidique préparée avec du fusidate de sodium et comprenant un biopolymère, un corticostéroïde - acétate d'hydrocortisone, et un agent antifongique - chlorhydrate de terbinafine, et procédé de préparation correspondant
WO2012049545A1 (fr) * 2010-10-12 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
WO2012049539A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
WO2012049540A1 (fr) * 2010-10-15 2012-04-19 Sulur Subramaniam Vanangamudi Crème médicinale à base d'acide fusidique réalisée au moyen de fusidate de sodium, d'un corticostéroïde et d'un agent anti-fongique, et par incorporation d'un biopolymère, procédé permettant de fabriquer une telle crème
EP3397286A4 (fr) * 2015-12-28 2019-01-23 Alumend, LLC Compositions et procédés ayant un effet sur l'irritation cutanée
US10245283B2 (en) 2015-12-28 2019-04-02 Alumend, Llc Compositions and methods to affect skin irritation
US10258643B2 (en) 2015-12-28 2019-04-16 Alumend, Llc Compositions and methods to affect skin irritation
US11123362B2 (en) 2015-12-28 2021-09-21 Alumend, Llc Compositions and methods to affect skin irritation
US11135241B2 (en) 2015-12-28 2021-10-05 Alumend, Llc Compositions and methods to affect skin irritation
US11344507B2 (en) 2019-01-08 2022-05-31 Alumend, Llc Topical compositions containing low molecular weight chitosan derivatives

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