[go: up one dir, main page]

WO2010033943A1 - Endoprothèse biodégradable - Google Patents

Endoprothèse biodégradable Download PDF

Info

Publication number
WO2010033943A1
WO2010033943A1 PCT/US2009/057731 US2009057731W WO2010033943A1 WO 2010033943 A1 WO2010033943 A1 WO 2010033943A1 US 2009057731 W US2009057731 W US 2009057731W WO 2010033943 A1 WO2010033943 A1 WO 2010033943A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
another embodiment
cgp
glycerophosphate
chitosan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/057731
Other languages
English (en)
Inventor
Bert W. O'malley
Noam A. Cohen
Benjamine Bleier
Daqing Li
David Paulson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Pennsylvania Penn
Original Assignee
University of Pennsylvania Penn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Pennsylvania Penn filed Critical University of Pennsylvania Penn
Publication of WO2010033943A1 publication Critical patent/WO2010033943A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices

Definitions

  • This invention is directed to a controlled and sustained release delivery device or composition for pathologies associated with Rhinology- associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium.
  • the invention is directed to a semi-rigid biodegradable stent, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent and the use of agent impregnated Chitosan glycerophosphate (CGP) constructs in sinonasal applications.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • Allergic rhinosinusitis is an IgE mediated immune response which affects approximately 35 million Americans resulting in direct costs of up to $4.5 billion dollars.
  • Topical steroid represent the most efficacious treatment for controlling symptoms of allergic rhinitis and are considered first line therapy for patients with more than mild intermittent symptoms. While topical steroid application allows for high therapeutic concentrations at the site of pathology with minimal systemic effects, success relies on patient compliance and optimal delivery technique which are often difficult to achieve. Even with correct technique, several studies have shown that the majority of medication is deposited in the anterior nasal vault where it is expelled without ever reaching the intended site of action. Patients who ultimately fail medical treatment may require functional endoscopic sinus surgery to achieve adequate ventilation however these patients still require topical treatments to maintain postoperative sinus patency.
  • the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • the invention provides a semi-rigid biodegradable nasal implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • the invention provides a semi-rigid biodegradable nasal implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.
  • the implant of the invention comprises a drug.
  • the implant comprises a drug and one or more agents.
  • the implant comprises one or more agents.
  • the agent is a steroid.
  • the agent is an antibacterial agent.
  • the agent is an antimicrobial agent.
  • the agent is an antibiotic agent.
  • the agent is an antifungal agent.
  • the implant comprises an agent and another drug.
  • the invention provides a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination, comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination.
  • CGP chitosan- glycerophosphate
  • the invention provides a method comprising: placing a semi-rigid biodegradable stent, within a body lumen, said stent comprises comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a the stent or implant a predetermined region in a subject.
  • the invention provides a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant thereby inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology.
  • the stents used in the methods provided herein define a lumen while, in another embodiment, the implants described herein, may or may not have alumen defined by their structure.
  • the invention provides a method of reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant, thereby reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology.
  • the stent and/or implant compositions described herein, which are used in another embodiment, in the methods provided herein are agent eluting stent or compositions.
  • the agent used in the stents or implants provided herein is a combination of agents or active pharmaceutical ingredients (API's).
  • the agent is a steroid.
  • the agent is a steroid and an antibacterial agent.
  • the agent is a steroid and an antimicrobial agent.
  • the agent is a steroid and an antibiotic agent.
  • the agent is a steroid and an antifungal agent
  • the invention provides a method of producing an agent eluting implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant.
  • CGP Chitosan glycerophosphate
  • the invention provides a method of treating, inhibiting or suppressing or ameliorating symptoms associated with rhinologic pathology in a subject, comprising inserting into a sinus pathway of the subject, an agent-eluting stent, agent eluting implant, whereby the stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent, spacer, or implant and wherein the agent is effective in treating, inhibiting or suppressing or ameliorating symptoms associated with the rhinologic pathology.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • the rhinologic pathology is acute, subacute, or chronic sinusitis.
  • the sinusitis is allergic, viral, bacterial, or fungal sinusitis or their combination.
  • the sinusitis is associated with polyps.
  • the sinusitis is not associated with polyps.
  • the rhinologic pathology is any anatomical abnormality leading to obstruction or inflammation of the sinonasal cavity.
  • the rhinologic pathology is any benign or malignant neoplasm within the sinonasal cavity or a surrounding structures.
  • the surrounding structure is the skull base, pterygopalatine fossa, infratemporal fossa or their combination.
  • the rhinologic pathology is a pathology of the upper or lower respiratory tract.
  • the pathology of the upper or lower respiratory tract is any process involving the larynx, trachea, bronchi, bronchioli, alveoli, lungs or a combination thereof.
  • the invention provides a biodegradable nasal implant comprising: an effective concentration of a chitosan-glycerophosphate (CGP) impregnated with a therapeutic agent for a prolonged delivery of said agent in a nasal region.
  • said agent is an antibitic.
  • the invention provides a method of treating a disease in a subject, the method comprising the step of implanting a composition comprising an effective concentration of a chitosan-glycerophosphate (CGP) impregnated with a therapeutic agent for a prolonged delivery of said agent in a nasal region.
  • said agent is an antibitic and said disease is a bacterial disease.
  • Figure 1 shows how CGP-Dex-Hydrogel degrades in a controlled Manner.16% of solid CGP- Dex-hydrogel remains after 4 days. The degradation of CGP-Dex-hydrogel is controlled and is tapered. The error bars represent the SEM ( ⁇ 0.002 to 0.026);
  • Figure 2 shows CGP-Dex-Hydrogel release of dexamethasone in a Controlled Manner. Release of dexamethasone occurs for 4 days. The black bars represent the daily measurement and the gray bars the accumulation over the 4 days of testing. There is an initial bolus release of dexamethasone in the first 24 hours followed by a tapering off over the next three days so that by day 4 -100% of the available dexamethasone has been released. The error bars represent the SEM (+/- 0.004 to 0.115);
  • Figure 3 shows CGP-Dex-Hydrogel locally delivery of Dexamethasone into Perilymph.
  • the release of dexamethasone into perilymph was detected for 5 days. There was a significant difference between dexamethasone levels detected in the treated ear and serum for all time points. (Day 1 and 3 p ⁇ 0.01 Day 5 p ⁇ 0.05)
  • the error bars represent the SEM (+/- 0.002 to 0.509);
  • Figure 4 shows normal hearing following CGP-Dex-Hydrogel Placement.
  • 4a The solid line represents the pre-operative baseline ABR value of the sham surgery group. There was a 5 to 2OdB increase in hearing thresholds across frequencies in the immediate post-operative period (dashed line). By post-operative day 10, the hearing thresholds returned to baseline levels (dotted line). At the conclusion of the experiment, there was no statistical difference between pre-operative ABR values and those obtained 10 days after the sham surgery, (p ⁇ 0.05) 4b) The same pattern was observed in the CGP-Dex-hydrogel group. There was a 5 to 2OdB increase in hearing thresholds across frequencies in the immediate post-operative period (dashed line).
  • Figure 5 shows histologic images (H&E, 25x) showing stent degradation over 15 days with negligible surrounding inflammation
  • Figure 8 shows antibiotic concentration in the nasal lavage over a 4 day period demonstrating first order kinetics in the CGP+Vancomycin and CGP+Gentamicin arms;
  • Figure 9 shows CFU log reduction in the S. aureus arm by treatment modality.
  • Figure 10 shows CFU log reduction in the P. aeruginosa arm by treatment modality.
  • the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • the invention provides a controlled release delivery composition for otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination.
  • a composition as provided herein delivers an agent at a controlled rate for an extended time.
  • the composition is localized by spatial placement near where it is needed.
  • the composition targets a drug action by using techniques known to a person of skill in the art.
  • targeting comprises delivery of a drug to a particular organ.
  • targeting comprises delivery of a drug to a particular tissue.
  • targeting comprises delivery of a drug to a particular cell type.
  • the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.
  • the stent of the invention is placed in the maxillary sinuses of a subject suffering from a a rhinologic pathology.
  • the stent of the invention comprises a drug.
  • the stent comprises a drug and one or more agents.
  • the stent comprises one or more agents.
  • the agent is a steroid.
  • the agent is an antibacterial agent.
  • the agent is an antimicrobial agent.
  • the agent is an antibiotic agent.
  • the agent is an antifungal agent.
  • the stent comprises an agent and another drug.
  • the invention provides a semi-rigid biodegradable implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • the invention provides a semi-rigid biodegradable implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.
  • the implant of the invention is placed in the maxillary sinuses of a subject suffering from a a rhinologic pathology.
  • the implant of the invention comprises a drug.
  • the implant comprises a drug and one or more agents.
  • the implant comprises one or more agents.
  • the agent is a steroid.
  • the agent is an antibacterial agent.
  • the agent is an antimicrobial agent.
  • the agent is an antibiotic agent.
  • the agent is an antifungal agent.
  • the implant comprises an agent and another drug.
  • the invention provides a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination, comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination.
  • CGP chitosan- glycerophosphate
  • the invention provides a method comprising: placing a semi-rigid biodegradable stent, within a body lumen, said stent comprises comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a the stent or implant a predetermined region in a subject.
  • the invention provides a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant thereby inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology.
  • the invention provides a method of reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant, thereby reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology.
  • This invention relates in one embodiment to a controlled and sustained release delivery device or composition, for pathologies associated with Rhinology-associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium.
  • the invention is directed to a semi-rigid biodegradable stent, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, and the use of agent impregnated Chitosan glycerophosphate (CGP) constructs in sinonasal applications.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • Chitosan refers to an amino-polysaccharide derived from the deacetylation of chitin which is found in crustacean shells and can be engineered to form a cationic polymer.
  • a polyol salt with a single anionic head such as glycerophosphate
  • glycerophosphate a temperature dependent hydrogel results which undergoes a phase transition from liquid to gel at body temperature.
  • These hydrogels are biodegradable, inert, and capable of reversibly binding a variety of large and small molecular weight pharmaceutical compounds.
  • a chitosan glycerophosphate hydrogel is able to continuously elute dexamethasone over a four day period in the mouse middle ear.
  • chitosan based hydrogel use in sinonasal applications mandates novel formulations which are capable of eluting steroid in certain embodiments, over a longer period of time and are engineered in another embodiment, into a semi-rigid sheet capable of acting as a biodegradable sinus stent.
  • a semi-rigid sheet capable of acting as a biodegradable stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the sheet to act as a stent, spacer, or implant.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • the term "rigidity” refers to the property of the stent, spacer, or implant of resisting displacement or deformation when load is applied thereto. This ability to hold the appropriate space is important in one embodiment, to preserve adequate sinus pathway. Accordingly, when a stent, spacer, or implant exhibiting rigidity, e.g., a compression strength of on the order of from about 10 to about 10 1 centipoise (cP), the agent eluting stent, spacer, or implant used in the methods described herein, can be advantageously employed.
  • cP centipoise
  • the term "rigidity” refers to the amount of deflection which a deacetylated Chitosan glycerophosphate (CGP) matrix displays when responding to a force.
  • rigidity is measured by holding a cylinder (or similar shape) of deacetylated Chitosan glycerophosphate (CGP) matrix in a horizontal direction. The extent to which the cylinder bends toward the earth under the force of gravity is used as a measure of the rigidity of the deacetylated Chitosan glycerophosphate (CGP) matrix.
  • CGP deacetylated Chitosan glycerophosphate
  • a composition as described herein delivers an agent at a controlled rate for an extended time.
  • the composition is localized by spatial placement near where it is needed.
  • the composition targets an agent action by using techniques known to a person of skill in the art.
  • targeting comprises delivery of an agent to a particular organ.
  • targeting comprises delivery of an agent to a particular tissue.
  • targeting comprises delivery of an agent to a particular cell type.
  • the composition is applied as a stent, implant, or spacer to any area of the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium either alone or as an agent delivery vehicle.
  • the composition controls entry to the body according to the specifications of the required agent delivery profile. In another embodiment, the composition controls the rate and duration of delivery. In another embodiment, the rate and duration of delivery are designed to achieve desired concentration.
  • the composition is a sustained release composition.
  • a sustained release composition releases an agent over extended time.
  • rate and duration are not designed to achieve a particular profile.
  • the composition of the invention reduced side effects because effective concentration of an agent is maintained.
  • the composition of the invention eliminates damage to non-target.
  • the composition is in a chitosan-glycerophosphate (CGP) hydrogel form.
  • the chitosan-glycerophosphate (CGP) hydrogel serves as an agent reservoir.
  • the agent diffuses from the chitosan- glycerophosphate (CGP) hydrogel.
  • the chitosan-glycerophosphate (CGP) hydrogel comprising an agent of the invention is placed near or at the site of treatment.
  • the agent is physically blended with the chitosan- glycerophosphate (CGP) hydrogel.
  • the agent is dissolved or dispersed within the chitosan-glycerophosphate (CGP) hydrogel.
  • the agent is uniformly dissolved or dispersed within the chitosan-glycerophosphate (CGP) hydrogel.
  • the characteristics of the chitosan-glycerophosphate (CGP) hydrogel define an agent rate-controlling mechanism.
  • the active compounds may be incorporated into sustained-release, pulsed release, controlled release or postponed release preparations and formulations.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue- specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.
  • lipophilic depots e.g. fatty acids, waxes, oils.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • the composition can be delivered in a controlled release system.
  • the agent may be administered using intranasal delivery, intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • intranasal delivery is used.
  • advantages resulting from intranasal delivery include rapid adsorption into the nasal mucosa due to the abundant presence of capillary vessels in the nose, rapid onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication, and ease of administration.
  • nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 15:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the ear nose or throat, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984).
  • Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
  • the chitosan-glycerophosphate (CGP) hydrogel comprises a microbead structure.
  • the chitosan-glycerophosphate (CGP) hydrogel comprises a microtube structure or a polymeric hollow fiber.
  • the chitosan-glycerophosphate (CGP) hydrogel serves as an osmotic pump.
  • the chitosan-glycerophosphate (CGP) hydrogel is further surrounded by a polymer film that further controls the agent release rate.
  • the chitosan-glycerophosphate (CGP) hydrogel serves as an agent reservoir implant.
  • the chitosan-glycerophosphate (CGP) hydrogel comprises a rate control mechanism of solvent activation.
  • the chitosan- glycerophosphate (CGP) hydrogel absorbs fluids.
  • the chitosan- glycerophosphate (CGP) hydrogel is swollen.
  • swelling allows agent to migrate more easily.
  • water penetrates the chitosan- glycerophosphate (CGP) hydrogel thus forming pores and releasing the agent.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered parenterally.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered by an injection.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered subcutaneously.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered intramuscularly.
  • a composition comprising chitosan- glycerophosphate (CGP) hydrogel and an agent is administered intraperitonealy.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered intravenously.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered orally.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent bypasses some routes of metabolic clearance.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent substantially improves patients' compliance.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is accessible to an organ.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is accessible to a large surface area.
  • a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent exhibits elevated absorption.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 2-4 hours.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 3-9 hours.
  • a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 5-15 hours.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 10-20 hours.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 15-30 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 25-40 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 30-45 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 45-60 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 50-70 hours.
  • a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 60-90 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 90-120 hours.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 5-7 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 6-10 days. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 10-15 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 15-20 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 20-30 days.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 30-45 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 45-90 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 90-120 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 100-200 days. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 200-370 days.
  • a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1-1.5 years. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1-2 years. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1.5-3 years. [0053] In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention comprises an agent or a bioactive agent. In another embodiment, the term agent comprises a bioactive agent.
  • a chitosan-glycerophosphate (CGP) hydrogel composition of the invention treats an Otorhinolaryngology-associated pathology.
  • the CGP comprising compositions described herein, treats Head and Neck associated pathology.
  • a chitosan-glycerophosphate (CGP) hydrogel composition of the invention prevents an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination.
  • a chitosan-glycerophosphate (CGP) hydrogel composition of the invention inhibits an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination.
  • a chitosan-glycerophosphate (CGP) hydrogel composition of the invention improves the condition of a patient affected with an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination.
  • Pathologies associated with the aerodigestive tract are unique in that they may be directly treated with topical medication without having to violate healthy tissue.
  • Topical therapies are preferable to their systemic counterparts as they allow for increased agent concentrations at the site of treatment while minimizing systemic absorption with its attendant toxicity.
  • Important concepts include adequate delivery, optimal dosing, degree of mucosal absorption, duration of action at local site, and side effect profile including systemic absorption.
  • Topical treatments in the aerodigestive tract including but not limited to steroids, antibiotics, antifungals, antivirals, fibroblast inhibitors, antibiofilm agents, antiinflammatories, and immunologically active compounds have been explored in a variety of applications and have found to be of clinical benefit at all sites lined by respiratory epithelium.
  • the agent loading is between about 0.1 and 1%
  • the agent loading is between about 1 and 5%.
  • the agent loading is between about 5 and 10%.
  • the agent loading is between about 10 and 20%.
  • the agent loading is between about 20 and 20%.
  • the agent loading is between about 20 and 30%.
  • the agent loading is between about 30 and 40%.
  • the agent loading is between about 40 and 50% .
  • a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination.
  • CGP chitosan- glycerophosphate
  • the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio- materials and their combination in a predetermined region in a subject.
  • CGP chitosan-glycerophosphate
  • a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent , bio- materials and their combination in a predetermined region in a subject.
  • CGP chitosan-glycerophosphate
  • a method of reducing symptoms associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent , bio- materials and their combination in a predetermined region in a subject.
  • CGP chitosan-glycerophosphate
  • a method of producing a semi-rigid stent, spacer, or implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant.
  • CGP Chitosan glycerophosphate
  • Chitosan refers to a copolymer of glucosamine and N-acetyl glucosamine linked by ⁇ 1-4 glucosidic bonds obtained by N-deacetylation of chitin.
  • the molecular weight and degree of deacetylation can be modified during its preparation to obtain tailor-made properties.
  • chitosan has free amine as well as hydroxyl groups, which can be modified to obtain different chitosan derivatives.
  • chemical cross -linking is carried out by interacting the Chitosan glycerophosphate (CGP) matrix with negatively charged species such as TPP to prepare cross-linked chitosan matrix.
  • CGP Chitosan glycerophosphate
  • the interaction of chitosan with TPP leads to formation of biocompatible cross-linked chitosan sheet, which can be efficiently employed for creating a semi-rigid stent, spacer, or implant.
  • the agent loading, the degree of deacetylation and the degree of cross-linking are optimized for the application desired. Accordingly and in one embodiment, the agent load, degree of acetylation and cross linking for making a nasal stent for the treatment of allergic rhinosinusitis, is different than the agent load, degree of acetylation and cross linking for making a spacer for COPD associated disorder.
  • the term “stent” encompasses any prosthetic device for implantation or insertion in a body passageway (e.g. a lumen).
  • the term “spacer” refers to a spacing device for use in fenestrations of the paranasal sinus, consisting in yet another embodiment of a sheath which forms a hollow body, surrounding an internal cavity.
  • a method of treating, inhibiting or suppressing or ameliorating symptoms associated with rhinologic pathology in a subject comprising inserting into a sinus pathway of the subject, an agent-eluting stent, spacer, or implant, whereby the stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the sheet to act as a stent, spacer, or implant and wherein the agent is effective in treating, inhibiting or suppressing or ameliorating symptoms associated with the rhinologic pathology.
  • CGP deacetylated Chitosan glycerophosphate
  • CGP Chitosan glycerophosphate
  • Rhinologic applications within the sinonasal cavity depend in one embodiment on a complex interplay of efficiency of delivery, patient performance and compliance, and the efficacy of the agent being used.
  • the operative status of the patient of critical importance as well, as certain areas of the sinus can not be accessed with intact native sinus parititions.
  • persistent inflammation and iatrogenic mucosal injuries at sinus outflow tracts can lead to neoosteogenesis and circumferential stenosis leading to further disease and blocking access of topical medication. In the majority of medication is lost in the anterior nasal cavity and nasal vestibule where they are swept out of the nasal cavity without reaching their intended site of action.
  • rhinologic associated pathology is acute, subacute, or chronic sinusitis which can be characterized as allergic, viral, bacterial, or fungal, and may or may not be associated with polyps.
  • rhinologic associated pathology is any anatomical abnormality leading to obstruction or inflammation of the sinonasal cavity.
  • rhinologic associated pathology is any benign or malignant neoplasm within the sinonasal cavity or surrounding structures including but not limited to the skull base, pterygopalatine fossa, or infratemporal fossa.
  • pathology of the upper or lower respiratory tract is any process involving the larynx, trachea, bronchi, bronchioli, alveoli, or lungs.
  • CGP hydrogel chitosan-glycerophosphate hydrogel and an agent comprising an agent delivery vehicle with these characteristics.
  • CGP hydrogel are engineered by the techniques which is formed into a semi-rigid sheet which is capable of acting as an inert sinus stent in one embodiment, or a spacer, or a sinonasal implant which can be applied endoscopically and elutes an agent and spontaneously degrade over a predictable time period.
  • the provided structures apply to the entire aerodigestive tract in one embodiment, as well as the upper and lower respiratory tract in another embodiment for diseases such as asthma in one embodiment, or bronchitis, or COPD in other discrete embodiments for controlled or sustained delivery of agents such as corticosteroids in one embodiment, or beta2- agonists (long and short acting), leukotriene inhibitors, antibiotics, anticholinergics, and immunotherapy in other discrete embodiments of the agent eluted by the stents described herein.
  • diseases such as asthma in one embodiment, or bronchitis, or COPD in other discrete embodiments for controlled or sustained delivery of agents such as corticosteroids in one embodiment, or beta2- agonists (long and short acting), leukotriene inhibitors, antibiotics, anticholinergics, and immunotherapy in other discrete embodiments of the agent eluted by the stents described herein.
  • the Otorhinolaryngology-associated pathology is hearing loss. In another embodiment, the Otorhinolaryngology-associated pathology is vertigo. In another embodiment, the Otorhinolaryngology-associated pathology is a vestibular Disorder. In another embodiment, the Otorhinolaryngology-associated pathology is an ear infection. In another embodiment, the Otorhinolaryngology-associated pathology is Otitis Media. In another embodiment, the Otorhinolaryngology-associated pathology is a sinus infections or a sinus disease. In another embodiment, the Otorhinolaryngology-associated pathology is scaring or stenosis of openings within the ear and sinuses.
  • the Otorhinolaryngology-associated pathology is a cancer associted with the head and neck.
  • the Otorhinolaryngology-associated pathology comprises an abscess or an infections of the ear, nose, throat, head, neck, or a combination thereof.
  • the Otorhinolaryngology-associated pathology comprises otology pathology.
  • the Otorhinolaryngology-associated pathology comprises neurotology pathology.
  • the Otorhinolaryngology-associated pathology comprises rhinology pathology.
  • the Otorhinolaryngology- associated pathology comprises an allergy.
  • the Otorhinolaryngology-associated pathology comprises laryngology pathology. In another embodiment, the Otorhinolaryngology- associated pathology comprises bronchoesophagology pathology.
  • Head and Neck associated pathology is Branchial Cleft Cyst. Or in another embodiment, the Head and Neck associated pathology is a salivary-gland associated pathology, a thyroid- associated pathology, Verrucal Keratosis of the larynx or their combination in certain other embodiment.
  • Head and Neck- associated pathology refers to any pathology associated with the head, neck or organs or tissue comprised in the head and neck, each of which, is a discrete embodiment to be treated with the methods and compositions described herein.
  • the terms active pharmaceutical ingredient, agent, and agent are used interchangeably.
  • the agent is a steroid.
  • the agent is an antibiotic agent.
  • the agent is an antiviral agent.
  • the agent is a fungicidal.
  • the agent is a neurological agent.
  • the agent is non-steroidal anti-inflammatory agent.
  • the agent is dexamethasone.
  • the agent is acetic acid.
  • the agent is acetic acid-aluminum acetate.
  • the agent is hydrocortisone.
  • the agent is hydrocortisone-acetic acid.
  • the agent is benzocaine. In another embodiment, the agent is benzotic. In another embodiment, the agent is floxin. In another embodiment, the agent is ciprodex. In another embodiment, the agent is cipro. In another embodiment, the agent is flunisolide. In another embodiment, the agent is fluticasone. In another embodiment, the agent is mometasone. In another embodiment, the agent is ipratropium. In another embodiment, the agent is beconase. In another embodiment, the agent is triamcinolone. In another embodiment, the agent is chlorhexidine gluconate. In another embodiment, the agent is doxycycline. In another embodiment, the agent is pilocarpine. In another embodiment, the agent is levocabastine.
  • the agent is sodium cromoglycate. In another embodiment, the agent is bacitracin zinc. In another embodiment, the agent is polymyxin B-sulfate. In another embodiment, the agent is chloramphenicol. In another embodiment, the agent is erythromycin. In another embodiment, the agent is a mixture of the above agents. In another embodiment, the agent is a therapeutically effective mixture of the above agents. [0071] In another embodiment, the agent is levocabastine HCl. In another embodiment, the agent is ciprofloxacin HCl. In another embodiment, the agent is ciprofloxacin HCl/hydrocortisone. In another embodiment, the agent is erythromycin.
  • the agent is framycetin sulfate. In another embodiment, the agent is gramicidin. In another embodiment, the agent is gentamicin sulfate. In another embodiment, the agent is gramicidin. In another embodiment, the agent is neomycin sulfate. In another embodiment, the agent is ofloxacin. In another embodiment, the agent is trimethoprim sulfate. In another embodiment, the agent is sulfacetamide sodium. In another embodiment, the agent is tobramycin trifluridine. In another embodiment, the agent is beclomethasone dipropionate. In another embodiment, the agent is betamethasone sodium phosphate. In another embodiment, the agent is budesonide.
  • the agent is clioquinol. In another embodiment, the agent is fluorometholone. In another embodiment, the agent is fluorometholone acetate. In another embodiment, the agent is prednisolone acetate. In another embodiment, the agent is triamcinolone acetonide. In another embodiment, the agent is diclofenac sodium. In another embodiment, the agent is flurbiprofen sodium In another embodiment, the agent is atropine sulfate. In another embodiment, the agent is cyclopentolate HCl. In another embodiment, the agent is dipivefrin HCl. In another embodiment, the agent is homatropine Hbr.
  • the agent is benzydamine HCl In another embodiment, the agent is antazoline phosphate. In another embodiment, the agent is naphazoline HCl. In another embodiment, the agent is phenylephrine HCl. In another embodiment, the agent is brimonidine tartrate. In another embodiment, the agent is timolol maleate. In another embodiment, the agent is betaxolol HCl. In another embodiment, the agent is dipivefrin HCl. In another embodiment, the agent is levobunolol HCl. In another embodiment, the agent is acetazolamide brinzolamide. In another embodiment, the agent is dorzolamide HCl In another embodiment, the agent is carbachol.
  • the agent is pilocarpine HCl. In another embodiment, the agent is bimatoprost. In another embodiment, the agent is latanoprost . In another embodiment, the agent is travoprost. In another embodiment, the agent is apraclonidine HCl. [0072] In another embodiment, the agent is an adrenocorticoids such as but not limited to betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, paramethasone, prednisolone, prednisone, and triamcinolone.
  • Exemplary analgesics include acetaminophen, aspirin, buprenorphine, butalbital, butorphanol, codeine, dezocine, diflunisal, dihydrocodeine, etodolac, fenoprefen, fentanyl, floctafenine, hydrocodone, hydromorphone, ibuprofen, ketoprofen, ketorolac, levorphanol, magnesium salicylate, meclofenamate, mefenamic acid, meperidine, meprobamate, methadone, methotrimeprazine, morphine, nalbuphine, naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital, propoxyphene, salsalate, and sodium salicylate.
  • analgesic adjunct is caffeine.
  • exemplary anesthetics include articane-epinephrine, bupivacaine, chloroprocaine, etidocaine, ketamine, lidocaine, mepivacaine, methohexital, prilocaine, propofol, propoxycaine, tetracaine, and thiopental.
  • One exemplary analgesic-anesthetic is antipyrine-benzocaine.
  • the agent is an antibiotic such as but not limited to anti- bacterials, and anti-infectives include sulfonamides (e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, para-aminobenzoic acid, or sulfacetamide), trimethoprim- sulfamethoxazole, quinolones (e.g., ciprofloxacin, ofloxacin, or nalidixic acid), .beta.
  • sulfonamides e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, para-aminobenzoic acid, or sulfacetamide
  • trimethoprim- sulfamethoxazole quinolones (e.g., ciprofloxaci
  • -lactam antibiotics such as penicillins or cephalosporins, aminoglycosides (e.g., kanamycin, tobramycin, gentamycin C, amikacin, neomycin, netilmicin, streptomycin, or vancomycin), tetracyclines, chloramphenicol, and macrolides (e.g., erythromycin, clarithromycin, or azithromycin).
  • suitable penicillins include penicillin G, penicillin V, methicillin, oxacillin, nafeillin, ampicillin, and amoxicillin.
  • cephalosporins include cephalothin, cefdinir, cefozolin, cephalexin, cefadraxal, cefamandole, cefoxitin, cefaclor, cefonicid, cefoletan, cefotaxime, ceftizoxime, cefrtriaxone, cefditoren, and cefepine.
  • antibiotics useful for treating OM include penicillins such as amoxicillin and amoxicillin-clavulanate (Augmentin.RTM.); sulfa-based combinations such as erythromycin-sulfisoxazole (Pediazole), trimethoprim- sulfamethoxazole (Bactrim, Septra.
  • penicillins such as amoxicillin and amoxicillin-clavulanate (Augmentin.RTM.
  • sulfa-based combinations such as erythromycin-sulfisoxazole (Pediazole), trimethoprim- sulfamethoxazole (Bactrim, Septra.
  • RTM. macrolides/azalides such as azithromycin (Zithromax.RTM.) or clarithromycin (Biaxin.RTM.); second-generation cephalosporins such as cefaclor (Ceclor.RTM.), cefprozil (Cefzil.RTM.), cefuroxime axetil (Ceftin.RTM.), or loracarbef (Lorabid.RTM.); and third generation cephalosporins such as cefdinir (Omnicef.RTM.), cefixime (Suprax.RTM.), cefpodoxime proxetil (Vantin.RTM.), ceftibuten (Cedax.RTM.), cefditoren (Spectracef,.RTM.), and ceftriaxone (Rocephin.RTM.).
  • the agent is an anti-emetic such as but not limited to buclizine, chlorpromazine, cyclizine, dimenhydrinate, diphenhydramine, diphenidol, domperidone, dronabinol, haloperidol, hydroxyzine, meclizine, metoclopramine, nabilone, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, thiethylperazine, triflupromazine, and trimethobenzamine.
  • an anti-emetic such as but not limited to buclizine, chlorpromazine, cyclizine, dimenhydrinate, diphenhydramine, diphenidol, domperidone, dronabinol, haloperidol, hydroxyzine, meclizine, metoclopramine, nabilone, ondansetron, perphenazine, prochlorperazine, promethazine,
  • Exemplary antifungals include amphotericin B, clioquinol, clotrimazole, fluconazole, flucytosine, griseofulvin, ketoconazole, miconazole, and potassium iodide.
  • Exemplary anti-inflammatory agents include aluminum acetate, aspirin, betamethasone, bufexamac, celecoxib, dexamethasone, diclofenac, etodolac, flurbiprofen, hydrocortisone, indomethacin, magnesium salicylate, naproxen, prednisolone, rofecoxib, salsalate, sulindac, and triamcinolone.
  • Exemplary anti-vertigo agents suitable for the invention include belladonna, dimenhydrinate, diphenhydramine, diphenidol, meclizine, promethazine, and scopolamine.
  • Exemplary anti-viral agents suitable for the invention include acyclovir, amantadine, delavirdine, didanosine, efavirenz, foscamet, ganciclovir, indinavir, nelfinavir, ribavirin, ritonavir, zalcitabine, and zidovudine.
  • Exemplary biological response modifiers include aldesleukin, interferon .alpha. -2a, interferon .alpha. -2b, interferon . alpha.
  • cytotoxic agents include podofilox and podophyllum.
  • immunizing agents include influenza virus vaccine, pneumococcal vaccine polyvalent, and immune globulin.
  • An exemplary immunomodulator invention is interferon .gamma.
  • Other pharmacologic agents suitable for the invention include betahistine (e.g., for treating the nausea, dizziness, and ringing in the ears that occur in Meniere's disease), prochlorperazine, and hyoscine.
  • the agent is chlorhexidine gluconate.
  • the composition comprises 0.5-40% (w/w) chitosan. In another embodiment, the composition comprises 1-5% (w/w) chitosan. In another embodiment, the composition comprises 2-8% (w/w) chitosan. In another embodiment, the composition comprises 5-10% (w/w) chitosan. In another embodiment, the composition comprises 8-12% (w/w) chitosan. In another embodiment, the composition comprises 12- 20% (w/w) chitosan. In another embodiment, the composition comprises 15-25% (w/w) chitosan. In another embodiment, the composition comprises 20-30% (w/w) chitosan. In another embodiment, the composition comprises 25-35% (w/w) chitosan.
  • the composition comprises 30-40% (w/w) chitosan. [0077] In another embodiment, the composition comprises 1-60% (w/w) glycerophosphate. In another embodiment, the composition comprises 1-5% (w/w) glycerophosphate. In another embodiment, the composition comprises 5-15% (w/w) glycerophosphate. In another embodiment, the composition comprises 10-20% (w/w) glycerophosphate. In another embodiment, the composition comprises 15-25% (w/w) glycerophosphate. In another embodiment, the composition comprises 20-30% (w/w) glycerophosphate. In another embodiment, the composition comprises 25-35% (w/w) glycerophosphate.
  • the composition comprises 35-45% (w/w) glycerophosphate. In another embodiment, the composition comprises 40-50% (w/w) glycerophosphate. In another embodiment, the composition comprises 50-60% (w/w) glycerophosphate. [0078] In another embodiment, the composition is in a solid form. In another embodiment, the composition is in a liquid form. In another embodiment, the composition is in a gel form. In another embodiment, the composition is in a semi-gel form. In another embodiment, the composition's form is determined by factors comprising the ratio of glycerophosphate to chitosan.
  • the composition's the agent release profile is determined by factors comprising the ratio of glycerophosphate to chitosan.
  • the higher the ratio of chitosan to glycerophosphate when the agent is hydrophilic the longer is the agent release following the initial release.
  • the lower the ratio of chitosan to glycerophosphate when the agent is hydrophobic the longer is the agent release following the initial release.
  • the physical properties can be adjusted to fit various release strategies.
  • these properties comprise the diameter of pores in the matrix, the strength of the matrix and the rate of matrix degradation.
  • the initial volume of agent released is controlled as a bolus early in the treatment course.
  • the mechanical strength of the CGP-hydrogel is fortified by adjusting the proportions of the hydrogel components permitting the design of hydrogels with reduced susceptibility to degradation, thereby prolonging the release of agent.
  • susceptibility of CGP-hydrogel to degradation by lysozyme is also adjustable which further enables us to fine tune the agent release properties of this system for the specific requirements of a given clinical scenario.
  • the composition comprises at least two different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises two different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises three different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises four different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises five different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises six different chitosan to glycerophosphate ratio.
  • the invention provides a method of treating an Otorhinolaryngology-associated pathology in a subject, comprising the step of administering a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio- materials and their combination in a predetermined region in a subject.
  • the method comprises topical administration.
  • the method comprises trans-tympanic administration.
  • the method comprises intra-tympanic administration.
  • the method comprises intraperitoneal administration.
  • the method comprises intravenous administration.
  • the method comprises intramascular administration.
  • the method comprises intra-ear administration.
  • the method comprises administration into the Round Window Niche (RWN).
  • RWN Round Window Niche
  • the method comprises administering the composition of the invention in a solid state.
  • the method comprises adminstering the composition of the invention in a liquid state.
  • the method comprises adminstering the composition of the invention in a gel form.
  • the invention provides that the composition's states of aggregation changes from a liquid to a semi-solid gel when maintained in a temperature of 36°C to 38°C.
  • the method comprises adminstering the composition in a semi-solid gel form.
  • the method provides that a semi-solid gel form is preserved in a subject's body temperature.
  • the method comprises topically administering the composition of the invention onto an affected area. In another embodiment, the method comprises locally injecting the composition of the invention under the integument of an affected area.
  • hydrogels of the invention are suitable for use in the subject methods because they are biocompatible, by which is meant that they are suitable for contact with a human tissue.
  • the hydrogel further comprises macromolecular or polymeric materials into which water and small molecules can easily diffuse and include hydrogels prepared through the cross linking.
  • crosslinking may be either through covalent, ionic or hydrophobic bonds introduced through use of either chemical cross-linking agents or electromagnetic radiation, such as ultraviolet light, of both natural and synthetic hydrophilic polymers, including homo and co-polymers.
  • additional hydrogels of interest include those prepared through the cross- linking of: polyethers, e.g.
  • polyakyleneoxides such as poly(ethylene glycol), poly(ethylene oxide), poly(ethylene oxide) -co- (poly (propyleneoxide) block copolymers; poly (vinyl alcohol); poly(vinyl pyrrolidone); polysaccharides, e.g. hyaluronic acid, dextran, chondroitin sulfate, heparin, heparin sulfate or alginate; proteins, e.g. gelatin, collagen, albumin, ovalbumin or polyamino acids; and the like.
  • the physical characteristics such as size, shape and surface area can affect the absorption and release characteristics of the hydrogel composition.
  • the hydrogel composition that is employed may be in a variety of configurations, including particles, beads, rods, sheets, irregular shapes and the like.
  • the hydrogel shape comprises greater surface area to total mass ratios.
  • the porosity of the hydrogel affects the absorption and release characteristics of the hydrogel.
  • a composition can include any type of pharmacologic agent, including, e.g., an adrenocorticoid (corticosteroid, steroid), analgesic, analgesic adjunct, analgesic-anesthetic, anesthetic, antibiotic, antibacterial, anti- infective, antibiotic therapy adjunct, antidote, anti-emetic, anti-fungal, antiinflammatory, anti-vertigo, anti-viral, biological response modifier, cytotoxic, diagnostic aid, immunizing agent, immunomodulator, proteins, peptides, and other agents that may useful in treating ear disorders.
  • an adrenocorticoid corticosteroid, steroid
  • analgesic analgesic adjunct
  • analgesic-anesthetic anesthetic
  • antibiotic antibacterial, anti- infective, antibiotic therapy adjunct, antidote, anti-emetic, anti-fungal, antiinflammatory, anti-vertigo, anti-viral, biological response modifier, cyto
  • a composition of the invention can include a plurality of pharmacologic agents, including two or more agents within the same class (e.g., two different antibiotics) or two or more agents of various types, depending on the effect desired.
  • pharmacologic agents including two or more agents within the same class (e.g., two different antibiotics) or two or more agents of various types, depending on the effect desired.
  • a composition can contain an antibacterial, an anti-inflammatory, and an anesthetic or analgesic.
  • those skilled in the art can identify pharmacologic agents and combine them as needed to achieve a desired effect.
  • the hydrogel can be modified to provide for specific binding of one or more of the agents to the surface of the hydrogel.
  • the hydrogel comprises agents that act as water absorbents and/or precipitants, where such agents include ethanol, PEG 400, phosphate buffer and the like.
  • Chitosan glycerophosphate is used to create a semi-rigid silastic like sheet which is malleable, inert, and capable of eluting steroid in one embodiment, for a period of over 15 days in another embodiment, when implanted intranasally.
  • this material is used to create a pharmacologically active sinus stent which spontaneously degrades over time.
  • creation of the semi-rigid stent involves a chitosan cross-linking reaction with subsequent vacuum dehydration for the purposes of creating a semi-rigid stent, spacer, or implant.
  • a semi-rigid sheet capable of acting as a biodegradable stent spacer, or implant, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate
  • CGP deacetylated Chitosan glycerophosphate
  • a method of producing a semi-rigid stent, spacer, or implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant.
  • CGP Chitosan glycerophosphate
  • hydrogel compositions employed in the subject methods can be prepared by methods known to those skilled in the art.
  • subject refers in one embodiment to a mammal including a human in need of therapy for, or susceptible to, a condition or its sequelae.
  • the subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, rabbits and mice and humans.
  • subject does not exclude an individual that is normal in all respects.
  • Biodegradable Hydrogel Preparation [0097] The parameters for formulating the CGP-hydrogel loaded with dexamethasone were selected creating a model formulation for further testing (CGP-Dex-hydrogel).
  • the CGP- Dex-hydrogel was moderately viscous, injectable, and underwent phase transition to a semisolid gel in about 15 minutes at 37°C. Preparations were made on the day in which they were to be used.
  • Ninety-eight percent deacetylated chitosan (Biosyntech, Quebec) was dissolved in 0.2M acetic acid yielding a 3.4% (w/w) chitosan solution.
  • mice in the CGP-Dex-hydrogel placement group were used for quantification of dexamethasone.
  • the remaining 5 mice from this group and the 5 mice from the sham surgery group were used to evaluate the impact of the surgical procedure and of CGP-Dex- hydrogel upon the auditory system.
  • CGP-Dex-hydrogel was injected directly onto the RWM filling the RWN.
  • the injection was accomplished with the use of a custom-made flame-pulled glass syringe needle using a microcapillary tube flame-puller.
  • the skin incisions were closed with 4-0 silk, and the animals were returned to the animal facility after they fully recovered from the anesthetic agent.
  • mice Fifteen of the animals which underwent surgical placement of CGP-Dex-Hydrogel were separated into three groups of 5 animals each for sample harvesting on post-operative days 1, 3 and 5. At the time of sample collection, mice were deeply anesthetized. A cardiac puncture was performed to obtain blood for serum agent concentration analysis. The skin overlying the skull was removed and the external auditory canals were transected. Using a pick and fine forceps the tympanic membrane of the left ear was gently removed. The stapes and oval window were exposed after removing the malleus and incus. Perilymph was collected in previously prepared microcapillary tubes which had tips drawn to approximately 20 ⁇ m.
  • the tip of the glass microcapillary tube was used to gently displace the footplate of the stapes laterally.
  • the tip of the microcapillary tube was then advanced a few micrometers through the annular ligament and into the scala vestibule.
  • Via capillary action within a few seconds a target volume of 0.2 to 0.3 ⁇ l of perilymph was collected into the capillary tube.
  • each animal was euthanized by cervical dislocation.
  • Perilymph was transferred to microcentrifuge tubes and weighed to within O.Olmg. One mg of perilymph corresponded to 1 ⁇ l of perilymph. Samples were stored at -80 0 C until they were analyzed.
  • LC separations were conducted with a Zorbax 300Extend-C18 column (125 A, 3.5 ⁇ , 150 x 2.1 mm Ld., Agilent Santa Clara, CA) using a linear gradient of 5 mM ammonium acetate in water-methanol with a flow rate of 250 ⁇ l/min.
  • Perilymph and serum samples were added with flumethasone (F9507 Sigma St. Louis, MO) as an internal standard.
  • flumethasone F9507 Sigma St. Louis, MO
  • LC-MS/MS analyses were conducted using positive electrospray ionization in the monitoring MRM mode using following ion transitions: mJz 393.2 ⁇ 373.1 (dexamethasone), m/z 411.2 ⁇ 391.1 (flumethasone).
  • ABR auditory brainstem response
  • mice were anesthetized and electrodes were placed at the vertex (active), in the neighborhood of the left postauricular bulla (reference), and in the flank (ground).
  • the acoustic stimulus, generated by the TDT SigGen system consisted of 10msec tone pips at 16.OkHz, 24.OkHz, 32.OkHz, and 40.OkHz presented at a rate of 20/sec Responses were averaged over 500 stimuli and intensity increments were set at 5dB. Threshold was determined to be halfway between the intensity at which an observable response could be detected and the next lower intensity at which no response was visible. Absolute stimulus intensities were calibrated to obtain the sound pressure level in dB relative to 20 ⁇ Pa.
  • Chitosan glycerophosphate (CGP) sheets were produced with varying degrees of deacetylation (70-100%) and analyzed for structural integrity.
  • Dexamethasone release from CGP-Dex -hydrogel Sustained release of dexamethasone was observed over 4 days in vitro. In the first 24-hour period there was an initial bolus release of dexamethasone followed by a tapering of agent release until 100% of the agent was released by day 4. The experiment was repeated and the average results were plotted (Fig.2). The initial bolus release of dexamethasone is likely due to the release of dexamethasone from the voids formed in the hydrogel matrix while the gel was solidifying. The dexamethasone released over the next 3 days represents agent that was interacting more tightly with the matrix through non-covalent molecular interactions. Results were consistent between experiments with 11.4% ⁇ SEM > +/- 0.04%.
  • CGP-Dex-Hydrogel Placement Procedure Twenty five animals successfully underwent the procedure; 20 received CGP-Dex-hydrogel and 5 received no hydrogel injection (sham surgery). There were no surgical complications, the animals recovered normally and there were no infections. Following recovery and for the duration of the experiments, no animals exhibited signs of distress nor were there were no observable pathologic changes in behavior, such as log rolling or circling, indicating that both vestibular and auditory functions were preserved.
  • Perilymph and Serum Harvesting Procedures The mean volume of perilymph harvested was 0.22 ⁇ l +/- 0.07 ⁇ l. There were no statistical differences between groups or between the averages of all samples (p > 0.05).
  • Dexamethasone Concentration in Perilymph and Serum Dexamethasone was detected in the perilymph of treated ears. The average dexamethasone concentration within the perilymph peaked at 24 hours at 3.2ng/ ⁇ l and declined in a linear fashion over the 5 days of the experiment to 1.3ng/ ⁇ l. These values remained elevated compared to serum (Fig.3).
  • a chitosan based hydrogel is capable of acting as an agent delivery vehicle, its use in sinonasal applications mandate novel formulations which are capable of eluting steroid over a longer period of time and can be engineered into a semirigid sheet capable of acting as a biodegradable sinus stent.
  • Topical antibiotic treatments for sinusitis have gained popularity in recent years however their clinical efficacy has yet to be fully elucidated. Given the limited access of irrigations to obstructed or anatomically intact sinuses, an alternative method of topical antibiotic distribution would be beneficial. Topical sinonasal antibiotic treatments offer the potential for delivery of high concentrations of drug to the site of disease while minimizing systemic exposure and absorption.
  • the purpose of this study is to utilize a rabbit model of acute bacterial gram positive and gram negative sinusitis to study the elution kinetics and efficacy of CGP loaded with one of two classes of antibiotics as compared to topical saline and antibiotic irrigations alone.
  • Study Design This was a prospective study of the treatment of acute bacterial sinusitis in a rabbit model using an antibiotic eluting implant. There were two arms to this study consisting of a S. aureus infection treated with Vancomycin and a P. aeruginosa infection treated with Gentamicin. Within each arm, 6 rabbits with bilateral infections were utilized for a total of 12 experimental sinuses. Each arm was comprised of 3 treatment groups performed in duplicate including saline irrigation alone, an 80 ⁇ g/mL antibiotic solution, or a lcm 2 antibiotic loaded CGP implant. Daily bacterial colony forming units (CFU' s) were measured in the nasal lavage for each sinus over a four day period. The log reductions between each treatment group were then compared to one another using a Student's t-test.
  • CFU' s Daily bacterial colony forming units
  • the New Zealand white rabbit is a widely accepted animal model of sinusitis. Twelve Pasteurella-free, female, New Zealand white rabbits (2-4kg) were used after a 1 week acclimatization period. Each rabbit was caged independently and had free access to standard pelleted food and water. The protocol was approved by the University of Pennsylvania Institutional Animal Care and Use Commmittee (Protocol# 801513).
  • Surgical Technique The surgical technique proceeded as previously described 4 . Briefly, following standard anesthesia, prepping, and draping, a 3cm midline sagittal incision was made over the nasal dorsum down to the level of the periosteum. Medial based periosteal flaps were raised bilaterally exposing the dorsal maxillary bone. A 4mm diamond otologic drill was used to expose the maxillary sinus mucosa which was then incised using a no. 15 blade.
  • a 0.5cm x 0.2cm cotton pledget with a lcm string attached was used to obstruct the natural ostium and a small amount of Vet Bond (3M, St Paul, MN, USA) was used to reinforce the pledget.
  • 0.2mL containing 4.0 x 10 8 CFU of wild type P. aeruginosa or S. aureus was instilled into the sinus.
  • the periosteal flaps were replaced and the skin was closed with a running 4-0 nylon suture.
  • Treatment groups The three groups within each arm consisted of daily treatments of 3mL of irrigation. The first group received saline alone. The second group received an 80 ⁇ g/mL solution of either Gentamicin(Fluka, St Louis, MO) or Vancomycin (Sigma- Aldrich, St Louis, MO). The third group received saline in addition to a lcm 2 implant composed of chitosan glycerophosphate (BioSyntech, Quebec, Canada) which was loaded with 25mg of either Gentamicin or Vancomycin.
  • Antibiotic levels in the nasal lavage and peripheral blood were measured using a Synchron LX 20 system (Beckman Coulter, Fullerton, CA) with a lower limit of detection of 3.5 ⁇ g/mL for Vancomycin, and 0.5 ⁇ g/mL for Gentamicin.
  • the nasal lavage was immediately diluted 1 :50, pelleted via centrifugation at 3500 rpm for 10 minutes, and resuspended in the original volume of saline to prevent any bactericidal effect from the residual antibiotic within the lavage. The suspension was then plated and colony forming units/mL were then calculated from serially diluted samples using a standard plate count method.
  • Antibiotic elution In both the S. aureus and P. aeruginosa group, the implant exhibited first order elution kinetics over the four day period( Figure 1).
  • the CGP+ Vancomycin lavage concentrations were as follows: Day 1 : 232.0+/-37.9 ⁇ g/mL; Day 4: 34.7+/-8.4 ⁇ g/mL.
  • the Vancomycin irrigation lavage concentrations were as follows: Day 1: 67.1+/-l l.l ⁇ g/mL; Day 4: 74.2+/-4.2 ⁇ g/mL.
  • the CGP+Gentamicin lavage concentrations were as follows: Day 1: 390.8+/-99.0 ⁇ g/mL; Day 4: 4.1+/-1.3 ⁇ g/mL.
  • the Gentamicin irrigation lavage concentrations were as follows: Day 1 : 76.6+/-1.7 ⁇ g/mL; Day 4 88.6+/- 8.9 ⁇ g/mL.
  • the serum concentrations were below the limits of detection in all experimental conditions throughout the entire duration of the treatment period.
  • the inventors of the instant application have investigated the role of antibiotic eluting hydrogels in the treatment of acute bacterial sinusitis. Given the potential advantages of site specific, continuous local delivery of drug at levels well above the minimum inhibitory concentration(MIC), this represents an exciting area of investigation with important clinical applications. This study was also designed to compare both mechanical debridement alone and the more traditional topical antibiotic irrigations with the novel implantable chitosan hydrogel. The choice of antibiotic concentrations in the irrigant was based on the most commonly described solutions. The finding that approximately sixty percent of each irrigation volume was immediately lost in the nasal lavage echoes the clinical scenerio in which only a fraction of the irrigant actually reaches the site of disease.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition ou un dispositif d'administration à libération contrôlée et prolongée destiné à des pathologies associées à des affections rhinologiques, ainsi qu'à toute pathologie impliquant le tube digestif ou les voies aériennes supérieures ou inférieures, dont tous les sites recouverts d'un épithélium respiratoire ou digestif. L'invention concerne, plus précisément, une endoprothèse biodégradable semi-rigide comprenant une matrice en glycérophosphate de chitosane (CGP) désacétylé, ainsi qu'un agent dans la matrice en glycérophosphate de chitosane (CGP), le degré de désacétylation assurant une rigidité suffisante à l'endoprothèse. L'invention concerne également et plus précisément l'utilisation de structures en glycérophosphate de chitosane (CGP) imprégnées d'un agent dans des applications sino-nasales.
PCT/US2009/057731 2008-09-19 2009-09-21 Endoprothèse biodégradable Ceased WO2010033943A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9838708P 2008-09-19 2008-09-19
US61/098,387 2008-09-19

Publications (1)

Publication Number Publication Date
WO2010033943A1 true WO2010033943A1 (fr) 2010-03-25

Family

ID=42039911

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/057731 Ceased WO2010033943A1 (fr) 2008-09-19 2009-09-21 Endoprothèse biodégradable

Country Status (1)

Country Link
WO (1) WO2010033943A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103371963A (zh) * 2012-04-19 2013-10-30 贵阳医学院 注射用右旋酮洛芬氨丁三醇温敏水凝胶及其制备工艺
WO2015061606A1 (fr) * 2013-10-24 2015-04-30 Medtronic Xomed, Inc. Pâte d'occlusion au chitosane
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste
US9999754B2 (en) 2014-12-09 2018-06-19 Gyrus Acmi, Inc. Delivery method for biodegradable stents
US10596330B2 (en) 2015-08-26 2020-03-24 Medtronic Xomed, Inc. Resorbable, drug-eluting submucosal turbinate implant device and method
EP3831349A1 (fr) * 2012-06-13 2021-06-09 Matheny Enterprises, LLC Support structural d'élution d'ingrédient actif biodégradable

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030134810A1 (en) * 2001-10-09 2003-07-17 Chris Springate Methods and compositions comprising biocompatible materials useful for the administration of therapeutic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030134810A1 (en) * 2001-10-09 2003-07-17 Chris Springate Methods and compositions comprising biocompatible materials useful for the administration of therapeutic agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAROLL, B.: "Hydrogels for Tissue Engineering and Delivery of Tissue-Inducing Substances", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 3, no. 9, September 2007 (2007-09-01), pages 2197 - 2223 *
GRASSI ET AL.: "Temperature-Sensitive Hydrogels: Potential Therapeutic Applications", AM J DRUG DELIV, vol. 3, no. 4, 2005, pages 239 - 251 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103371963A (zh) * 2012-04-19 2013-10-30 贵阳医学院 注射用右旋酮洛芬氨丁三醇温敏水凝胶及其制备工艺
EP3831349A1 (fr) * 2012-06-13 2021-06-09 Matheny Enterprises, LLC Support structural d'élution d'ingrédient actif biodégradable
WO2015061606A1 (fr) * 2013-10-24 2015-04-30 Medtronic Xomed, Inc. Pâte d'occlusion au chitosane
US9192574B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan paste wound dressing
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste
JP2016534050A (ja) * 2013-10-24 2016-11-04 メドトロニック・ゾーメド・インコーポレーテッド キトサンステント材ペースト
AU2014340006B2 (en) * 2013-10-24 2018-06-28 Medtronic Xomed, Inc. Chitosan stenting paste
US9999754B2 (en) 2014-12-09 2018-06-19 Gyrus Acmi, Inc. Delivery method for biodegradable stents
US10596330B2 (en) 2015-08-26 2020-03-24 Medtronic Xomed, Inc. Resorbable, drug-eluting submucosal turbinate implant device and method
US11654250B2 (en) 2015-08-26 2023-05-23 Medtronic Xomed, Inc. Resorbable, drug-eluting submucosal turbinate implant device and method

Similar Documents

Publication Publication Date Title
CA2620374C (fr) Compositions pharmaceutiques pour le traitement de pathologies de l'oreille interne
Paulson et al. A novel controlled local drug delivery system for inner ear disease
RU2334525C2 (ru) Оторинологическое доставляющее устройство
AU2018229478B2 (en) Biodegradable, active ingredient-eluting structural support
JP7026507B2 (ja) 眼において薬物徐放を達成する方法及び生体適合性組成物
KR20130108269A (ko) 약물의 지속 전달을 위한 콜라겐계 이식물
WO2010033943A1 (fr) Endoprothèse biodégradable
US20220168465A1 (en) Biodegradable nasal splint
KR20160047490A (ko) 소아 귀 질환의 치료
AU2011204275B2 (en) Methods and compositions for applying moxifloxacin to the ear
US8945625B2 (en) Regulated delivery systems for inner ear drug application and uses thereof
US10245274B2 (en) Chitosan-based matrices and uses thereof
WO2021252507A1 (fr) Administration à base de microparticules à libération prolongée par thermogel à une cavité paranasale et/ou nasale
Schilling Engineering a temperature-responsive, local and sustained release system for the paranasal sinuses
Saber Round window membrane and delivery of biologically active agents into the cochlea
HK1235660B (en) Methods and biocompatible compositions to achieve sustained drug release in the eye

Legal Events

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

Ref document number: 09815351

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09815351

Country of ref document: EP

Kind code of ref document: A1