EP1494633A1 - Dispositifs d'administration de medicament n,o-carboxymethylchitosane adhesif pour tissus humide et leurs procedes d'utilisation - Google Patents

Dispositifs d'administration de medicament n,o-carboxymethylchitosane adhesif pour tissus humide et leurs procedes d'utilisation

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Publication number
EP1494633A1
EP1494633A1 EP02721645A EP02721645A EP1494633A1 EP 1494633 A1 EP1494633 A1 EP 1494633A1 EP 02721645 A EP02721645 A EP 02721645A EP 02721645 A EP02721645 A EP 02721645A EP 1494633 A1 EP1494633 A1 EP 1494633A1
Authority
EP
European Patent Office
Prior art keywords
tissue
nocc
moist
adherent
drug
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.)
Withdrawn
Application number
EP02721645A
Other languages
German (de)
English (en)
Other versions
EP1494633A4 (fr
Inventor
Clive Elson
Agis Kydonieus
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.)
Kytogenics Pharmaceuticals Ltd
Original Assignee
Chitogenics Inc
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 Chitogenics Inc filed Critical Chitogenics Inc
Publication of EP1494633A1 publication Critical patent/EP1494633A1/fr
Publication of EP1494633A4 publication Critical patent/EP1494633A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • 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
    • A61L31/16—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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • a variety of drug delivery devices are known in the art. These include implants, various polymers, microcapsules, liposomes, stents and many hybrids devices. While these drug delivery devices work well in certain body locations, such as skin or muscle tissue, they often fail to work in moist tissue locations. In moist tissue, such as mucosal membranes or tissue in the serous cavities, there is a problem keeping the drug delivery device in place for a sufficiently long time to provide the requisite delivery of the drug at the proper site. While physical methods of keeping the drug delivery device at the proper site, such as the use of sutures have been tried, there may still be problems with controlling the delivery rate or biocompatibility. Accordingly, it has been theorized that an adherent drug delivery device might provide certain benefits.
  • the bioadhesives described in the Robinson patent actually show cohesive failure rather than adhesive failure (see Example 1 above).
  • NOCC as the bioadhesive in the drug delivery device allows one to tailor the device such that failure of breakaway from tissue can be controlled to be either adhesive or cohesive as desired.
  • biocompatibility is improved where desired.
  • These devices can also be tailored to provide sustained release of drugs in a controlled manner.
  • Robinson's polymers are not bioresorbable.
  • Another object of the invention is to provide adherent drug delivery devices for use with moist tissue that can be tailored in terms of delivery time and compatibility through the use of additional structural materials.
  • a further object of the invention is to provide an adherent drug delivery device and methods of their use for buccal, eye, vaginal, gastrointestinal, or intra-serous cavity drug delivery.
  • a still further object of the invention is to provide an adherent coating that helps prevent the formation of surgical adhesions.
  • An additional object of the invention is to provide an adherent coating that helps seal tissue.
  • the present invention features a method of utilizing an adherent form of N,O- carboxymethylchitosan ("NOCC") to deliver a series of materials to tissue.
  • NOCC N,O- carboxymethylchitosan
  • the invention is based, in part, on the discovery of adherent coatings of NOCC may be applied to various substrates, such as mammalian tissue, so as to allow delivery of materials such as drugs or hormones to the specific site.
  • the present invention provides a series of compositions that is adherent to a variety of synthetic materials and mammalian tissues. These compositions can be used as a device for vaginal delivery of hormones, as buccal implants, as eye implants or drug delivery devices and the like for localized or systemic delivery of a variety of materials when adhered to the delivery site.
  • the invention provides a composition and method of delivering drugs, proteins, and other therapeutic agents from an adhesive device or composition that is adherent to soft (mucosal or non-mucosal) tissue or hard tissue.
  • the adherent delivery device can be used as a buccal, oral, vaginal, inhalant, or the like delivery system.
  • the device can be in a variety of forms including solutions, creams, pellets, particles, beads, gels, and pastes.
  • the NOCC is supplemented with a structural support material selected from the group consisting of rubber, plastic, resin, natural and synthetic polymers, and mixtures thereof. The method is useful for providing sustained release of a drug to moist tissue.
  • the method uses the steps of applying to said moist tissue a drug delivery device which is adherent to said moist tissue and includes a level of N,O-carboxymethylchitosan as a component thereof to provide said adherence.
  • the drug delivery device further containing a sufficient quantity of the drug to be delivered to provide sustained release of said drug and permeation into said moist tissue.
  • the preferred moist tissues are mucosal tissue and tissue within serous cavities.
  • Preferred mucosal tissue is tissue of the oral cavity such as buccal tissue, vaginal tissue, ocular tissue, and gastrointestinal tissue.
  • Preferred tissues within a serous cavity are tissues within the pleural, pericardial or peritoneal cavities.
  • the method is useful for delivering a number of drugs such as chlorhexidine, tetracycline and mixtures thereof for treatment of buccal problems like mouth sores and periodontal disease or drugs such as melatonin and chlorpheniramine through the buccal mucosa for systemic therapy.
  • the method can also be used to deliver drugs to the vaginal tissue like progestins, estrogens, antifungal agents, antibacterial agents, antiviral agents, proteins and peptides, particularly levonorgestrel.
  • the method can be used to deliver drugs to ocular tissue such as beta blockers and glaucoma treating drugs.
  • the method of the invention may also provide for adherence or sealing of tissue and prevention of post-surgical adhesions.
  • This method utilizes a medical device that includes NOCC and optionally, a tissue sealant such as a fibrin sealant or a cyanoacrylate.
  • a tissue sealant such as a fibrin sealant or a cyanoacrylate.
  • the preferred moist tissue is at the site of a surgical incision.
  • the primary tissues to be sealed are lung tissues, heart tissues and intestinal tissue.
  • FIG. 1 is a schematic of the apparatus used in Example 1.
  • FIG. 2 is a bar graph showing the results of Example 1.
  • FIG. 3 is a schematic of the procedure used in Example 2.
  • FIG. 4 is graph showing the total volume of 125I_N()CC adhered to rat femur, as calculated using Equation 1.
  • FIG. 5 is graph showing the total volume of 125J_NQCC adhered to rat femur, as calculated using Equation 3.
  • FIG. 6 is a graph showing the in vitro permeation of levonorgestrel from a vaginal cream in a diffusion test chamber.
  • FIG. 7 is a graph showing the in vitro permeation of melatonin from a buccal device in a diffusion test chamber.
  • FIG. 8 is a graph showing the permeation of chlorpheniramine maleate from a buccal device in a diffusion test chamber.
  • FIG. 9 is a graph showing the permeation of chlorhexidine diacetate from a buccal device in a diffusion test chamber.
  • FIG. 10 is a graph showing the permeation of timolol maleate from an eye delivery device using a diffusion test chamber.
  • the present invention relates to the delivery of a variety of drugs, hormones and the like through the use of a site adherent delivery device.
  • the method of the invention uses an adherent coating of N,O-carboxymethylchitosan (“NOCC”) that provides unexpected benefit.
  • NOCC N,O-carboxymethylchitosan
  • NOCC is a derivative of chitin, which is found in the shells of crustaceans and many insects. Chitin and its derivatives are normally biocompatible, naturally resorbed by the body, and have previously been suggested for use for sustained drug release, bone induction and hemostasis (Chandy and Sharma, Biomat. Art. Cells & Immob. Biotech. 79:745-760 (1991); Klokkevold, P. et al, J. Oral Maxillofac. Sur. 50:41-45 (1992)). Due to its prevalence, chitin may be obtained relatively cheaply, largely from waste products. One of the most useful of the chitin derivatives is NOCC. As disclosed in U.S. Pat. No.
  • NOCC has carboxymethyl substituents on some of both the amino and primary hydroxyl sites of the glucosamine units of the chitosan structure.
  • NOCC may be used in an uncrosslinked form as a solution or may be cross-linked or complexed into a stable gel. Because of its advantageous physical properties, and its relative low cost, NOCC presents advantageous properties for use in site localized delivery systems.
  • adherent coating of NOCC mean a coating or composition of NOCC that exhibits an adhesion between freshly excised tissues of at least about 100 dynes/cm 2 , using the procedure described in Example 1.
  • medical device means any device which is implanted in the body for medical reasons or which has a portion of the device extending into the body (like a catheter) as well as devices which provide a medical benefit when attached to, or are in contact with, the body .
  • medical devices include, without limitation, hemostats, tissue sealants, and adhesion prevention barriers.
  • delivery device means any type of device that can be used to deliver the contained material at the localized site.
  • the delivery device may be as simple as an adherent paste applied to the site or may be shaped or constructed for the particular application.
  • drug means any product which causes an effect in a cell or organism including, but not limited to classic drugs, peptides, proteins, antibodies and the like.
  • Moist tissue means a tissue that in its normal activity is kept moist. Moist tissue includes mucosal tissue and tissue in the serous cavities.
  • adherent NOCC used in the present invention may take many forms.
  • adherent NOCC may be used in a solution, a hydrogel, a paste, a rehydratable film, cream, foam, or a sponge. These forms are prepared by methods well known to those of ordinary skill in the art.
  • the delivery device may have other structural materials as well as NOCC. Some of these include chitosan, carboxymethylcellulose, resins, alginate, rubbers and the like.
  • the adherent NOCC used in the present invention may be the parent compound or may be cross-linked. Cross-linked adherent NOCC may be either covalently cross- linked or ionically cross-linked. Various methods of cross-linking NOCC are known in the art and are within the scope of this invention.
  • the degree to which the adherent NOCC is cross-linked may be optimized for specific applications by one of ordinary skill without undue experimentation. It has been found that the degree of cross- linking is roughly inversely proportional to the adhesiveness of the coating. That is, the greater the degree of cross-linking of the adherent NOCC, the lesser degree of adherence. In preferred embodiments, the degree of cross-linking is less than 1 :5 (moles cross-linking agent to moles, NOCC monomer), more preferably between 1 : 100 and 1 : 1000 on a molar basis.
  • the bioadhesive strength of several adherent NOCCs was compared to that of polycarbophil, a cross-linked acrylic acid polymer available from B.F. Goodrich. As more fully described in Example 1 , solutions of low and high viscosity NOCC were prepared, as well as hydrogels of high viscosity NOCC. The bioadhesive was applied to stomach and cecal tissue samples and the bioadhesive strength was measured according to a modified version of the procedure disclosed in U.S. Pat. No. 4,615,697, the disclosure of which is hereby incorporated by reference. The transfer of polymer to both tissue surfaces indicated that the adhesive force of the polymer exceeded the cohesive force. A summary of results appears in Tables 1 and 2, and Figure 2.
  • the bioadhesive strength of adhesive NOCC coatings of the invention is desirably greater than at least about 1000 dynes/cm 2 , more preferably greater than at least about 2000 dynes/cm 2 , and most preferably greater than at least about 3000 dynes/cm 2 .
  • Example 1 the bioadhesive strength of several adherent NOCC coating compositions is compared to that of polycarbophil.
  • Polycarbophil B.F. Goodrich, Akron, Ohio
  • LV Low viscosity
  • HV High viscosity
  • P78NOCC1 was prepared as 2.5% w/v solution in citrate buffer (pH 5.6).
  • High viscosity NOCC was prepared as 1% and 2.5 % in citrate buffer (pH 5.6-5.7), autoclaved and cross-linked (1 :500). HV NOCC was also prepared as 2.5% solution in phosphate buffered saline (PBS). Gels were formed from 1% HV NOCC by cross- linking (1:100) in PBS and by cross-linking (1 :250) in saline following autoclaving.
  • PBS phosphate buffered saline
  • Both stomach and cecal tissues from Sprague-Dawley rats were harvested immediately prior to testing and were kept moist in saline solution.
  • Tissue samples were mounted on circular plastic disks with the inner surfaces of stomach tissues and the outer surfaces of cecal tissues exposed. Tissue samples were held in place with a suture around the end of the plastic disks.
  • the plastic disks were obtained from the plungers of 3 and 5 ml syringes; the diameters of the disks were 7.0 (surface area of 38.5 mm 2 ) and 9.5 mm (surface area of 70.9 mm 2 ), respectively.
  • the tissue holders were attached to a cantilever load cell and to the actuator of an MTS servohydraulic material testing machine (see Figure 1).
  • the temperature compensated load cell was wired into a Daytronic 3720 Strain Gauge Conditioning Unit in a half bridge configuration. Data collection was performed using a Macintosh Centris 650 computer equipped with labVIEW software and a 12-bit NB-MIO-16 data acquisition board. The cantilever load cell was calibrated over the working range of 0-3 grams using a series of proving masses (0.1, 0.23, 0.5, 1 to 3.0 g) verified on a Mettler PJ 360 balance. A least squares calibration curve was determined to convert the resulting output from volts to grams force.
  • the smaller diameter tissue of the pair of fresh tissue samples received 30 ⁇ l of test material.
  • the software was designed to take a zero reading after attaching the tissue samples and applying a coating of the bioadhesive.
  • the testing system actuator was then manually advanced using the displacement potentiometers to bring mating faces into compression while visually monitoring the resulting load level on the computer monitor. The mating faces were allowed to remain compressed at a nominal load of 0.9 g for one minute.
  • the computer then displaced the actuator at a constant rate of 12.0 mm/min, monitoring the distraction force with time. After failure the computer determined the peak distraction load and saved the loading curves to a spreadsheet file.
  • the tissues were scraped with the side of a syringe needle, rinsed with citrate buffer or water as appropriate and a new aliquot of the same polymer was applied. Fresh tissues were used for each different polymer sample; all samples in citrate buffer were tested on stomach tissue and all samples at neutral pH were tested on cecal tissue. All testing was performed in air.
  • polycarbophil measured under the present conditions exhibited twice the adhesive force as reported in U.S. Pat. No. 4,615,697. This is presumably due to testing in air rather than in solution.
  • adherent NOCC solutions were either comparable to or exceeded the performance of polycarbophil: the force required to achieve failure was equal to or larger than that of polycarbophil and failure was due to cohesion not adhesion.
  • NOCC hydrogels on both types of tissue were adhesive; however, they were significantly less adhesive than materials that were not cross-linked. They demonstrated an adhesive failure rather than cohesive; also it was observed that increasing the extent of cross-linking decreased the adhesive force.
  • Table 2 Bioadhesion of NOCC Formulations to Cecal Tissue.
  • This example illustrates the adherent property of an adherent NOCC coating of the present invention.
  • Six female rats were anaesthetized using sodium pentobarbital (60 mg/kg) and subsequently sacrificed by cervical dislocation. Twelve femurs were harvested and stripped of connective tissue by sha ⁇ dissection. Excess connective tissue was removed from the rat femur by immersing the rat femurs in boiling water for thirty minutes. The femurs were then rinsed and air dried.
  • Each femur was immersed in 1 ml of 125 I labeled NOCC such that half the surface area of the femur was in direct contact with the l25 I NOCC solution ( Figure 3). The other half of the femur was used to manipulate the femur. Subsequently, the femur was either placed directly into a scintillation vial and then placed in a ⁇ - counter rack, or the femur was subjected to a uniform "wash" before being placed into a scintillation vial and the ⁇ - counter rack.
  • a wash consisted of the uniform agitation of the femur in approximately 150 ml of PBS for five seconds.
  • Two washes consisted of a wash, removing the femur from PBS for one second, and then repeating a wash.
  • three washes consisted of a wash, removal of the femur, a wash, removal of the femur, and one last wash.
  • the PBS solution was replaced for each group of femurs.
  • the activity of 125 I NOCC was evaluated by a Beckman ⁇ -counter.
  • the amount of 125 I NOCC adhered to a rat femur was calculated using Equation 1, which uses the activity of 1 ml of 125 I NOCC (7.2 xlO 7 CPM) and the activity of the 125 I NOCC on the femur, (detected by the ⁇ - counter). The results appear in Figure 4.
  • Equation 2 The surface area that was in direct contact with the 125 I NOCC solution was calculated for one representative rat femur. Equation 2:
  • Table 3 outlines the number of washes each femur was subjected to, the activity of 125 I NOCC, amount of 125 I NOCC adhered to femur, and the amount of 125 I NOCC per unit area of femur.
  • Example 3 In this example, a vaginal cream containing levonorgestrel, a steroid, was prepared. This cream is useful as an intravaginal delivery device.
  • the NOCC-based cream was prepared with the following composition:
  • SPAN 60 sorbitan monostearate, Atkemix, Inc.
  • the cream was prepared by dissolving solid NOCC in hot citrate buffer and adjusting the pH to 5 with citric acid. Separately, SPAN 60 was warmed and combined with mineral oil, the levonorgestrel was added, and finally the glycerol. The warm
  • NOCC solution was then combined with the levonorgestrel mixture to form the cream.
  • the resulting cream was homogeneous, easily smeared, and adherent to tissue.
  • the cream contained 3 mg levonorgestrel per gram.
  • Example 4 a spermicidal and anti-microbial cream containing Nonoxynol-
  • spermicide 9 a well known spermicide, was prepared. This cream is adherent to mucousal tissue such as vaginal tissue.
  • a NOCC-based cream was prepared with the following composition:
  • N,O-Carboxymethylchitosan (NOCC) 2.5%o hydroxypropylmethyl cellulose (HPMC) 5%
  • NOCC N,O-Carboxymethylchitosan
  • HPMC hydroxypropylmethyl cellulose
  • the Antifoam A and the Nonoxynol-9 were added to hot citrate buffer.
  • the NOCC and the HPMC were combined in equal weights and then added to the warm citrate buffer mixture and blended. Finally, the solid SDS was combined to form a creamy paste.
  • the resulting cream was homogeneous, easily smeared, and adherent to tissue.
  • a buccal device containing NOCC and other polymers was prepared. This device is useful as a buccal drug delivery device.
  • a PVC resin composition was made by diluting a high viscosity (polyvinyl chloride'TVC”) resin (available from Plast-o-Meric, Inc) with dioctylphthalate in the ratio of two thirds resin to one third dioctylphthalate.
  • An alginate paste was prepared having the following composition:
  • a NOCC paste was also prepared having the following composition:
  • the buccal device was prepared by compressing 60 mg of the alginate paste in a hand-held potassium bromide pellet press (Barnes Analytical, Pellet Holder for Handi- Press) to form a pellet. Two mg of the NOCC paste was placed on top of the pellet and the combination was compressed again in the pellet holder. The portion of the pellet coated with the NOCC paste and the sides of the pellet were coated with the PVC resin. The pellet was then cured at 150C° for several minutes.
  • the resulting pellet was 7 mm in diameter and 2-3 mm thick and durable with some flexibility.
  • the device contained 1% NOCC, and was adherent to moist tissue.
  • Example 6 The formulation described in Example 5 was modified by incorporating melatonin into the alginate paste component prior to pellet formation.
  • the alginate paste was made 3.3% (w/w) melatonin, with the remaining ingredients having the same proportions.
  • a pellet was then prepared as described in Example 5.
  • the resulting pellet contained 2 mg of melatonin and was of the same dimensions and physical properties as the device of Example 5.
  • the formulation was adhesive to moist tissue. Using the same approach, pellets containing 4 mg of melatonin were also prepared.
  • Example 5 The formulation described in Example 5 was modified by incorporating chlorpheniramine maleate into the alginate paste component.
  • the alginate paste was made 16.7% (w/w) chlorpheniramine maleate, with the remaining ingredients having the same proportions.
  • a pellet was then prepared as described in Example 5.
  • the resulting pellet contained 10 mg of chlorpheniramine maleate and was of the same dimensions and physical properties as the device of Example 5.
  • the formulation was adhesive to moist tissue. Using the same approach, pellets containing 5 mg of chlorpheniramine maleate were also prepared.
  • Example 5 a buccal device similar to that shown in Example 5 was prepared with an increased concentration of NOCC.
  • the general methods and materials are similar to those shown in Example 5.
  • An alginate paste was prepared having the following composition:
  • a NOCC paste was also prepared having the following composition:
  • the buccal device was prepared by compressing 70 mg of the alginate paste in a hand-held potassium bromide pellet press (Barnes Analytical, Pellet Holder for Handi- Press). Ten mg of the NOCC paste was placed on top of the pellet and the combination was compressed again in the pellet holder. The portion of the pellet coated with the NOCC paste and the sides of the pellet were coated with the PVC resin composition. The pellet was then cured at 150C° for several minutes.
  • the resulting pellet was 7 mm in diameter and 3-3.5 mm thick and durable with some flexibility.
  • the device contained 6% NOCC.
  • the formulation was adhesive to moist tissue.
  • a paste was prepared having the following composition:
  • the buccal device was prepared by compressing 100 mg of the paste in a hand- held potassium bromide pellet press (Barnes Analytical, Pellet Holder for Handi-Press). The end and sides of the pellet were coated with the PVC resin composition. The pellet was then cured at 150C° for several minutes.
  • the resulting pellet was 7 mm in diameter and 3-4 mm thick and durable with some flexibility.
  • the device contained 4% NOCC throughout and was adhesive to moist tissue.
  • a buccal device containing a liquid silicone rubber, rather than a heat-curable plastic was manufactured.
  • a paste was prepared with the following composition:
  • the buccal device was prepared by compressing 60 mg of the paste in a hand- held potassium bromide pellet press (Barnes Analytical, Pellet Holder for Handi-Press). A second 60 mg of the paste was placed on top of the pellet and the combination was compressed again in the pellet holder. The entire pellet was then coated with a diluted mixture of liquid silicone rubber (30% Silastic® Q7-4840 plus 70% hexanes). The pellet was then cured at 150C° for 20 minutes. The pellet was cleaved at the union between the portions of paste to yield two devices with one non-coated surface each.
  • the device was 7 mm in diameter and 2-3 mm thick; it was durable and somewhat flexible.
  • the device contained 10% NOCC and was adhesive to moist tissue.
  • adhesive buccal devices incorporating NOCC can be prepared with different thermoplastics and thermoset rubbers.
  • the attachment times can be altered by changing the composition or the method of preparation of the device.
  • Vaginal creams based on NOCC released very limited amounts (i.e. less than 0.5%) of levonorgestrel through normal tissue over a 48 hr period. This finding implies that such creams would maintain low levels of systemic hormones in vivo and would allow for the attachment of LN to steroid receptors on the surface of mucosal tissue
  • NOCC-based vaginal creams appear to be suitable candidates for vaginal delivery devices.
  • This example tested the release of melatonin from one of the described buccal devices.
  • the buccal devices containing 2 mg of melatonin described in Example 6 were placed directly onto pieces of previously harvested rabbit large bowel that were mounted in Franz Diffusion Cells as described in Example 12.
  • the permeation studies were conducted as described in Example 12 except that the HPLC analysis was modified; a Spectra Physics, Model SP8800, fitted with Alltima phenyl, 5 micron, 15cm X 4.6 mm column, and a UV detector set at 223 nm was used with an acetonitrile (40%)- 0.1% phosphoric acid mobile phase.
  • the in vitro permeation profile is shown in Figure 7. The flux can be calculated from this graph by determining its slope.
  • the average permeation rate (flux) was 19.5 ⁇ g/cm 2 /hr.
  • the flux was approximately the same as for the 2 mg pellet, indicating that even at 2 mg, the pellet is saturated with melatonin.
  • the flux of 19.5 ⁇ g/cm 2 /hr is adequate to produce a systemic therapeutic level of melatonin.
  • Example 7 the buccal devices of Example 7 were tested for permeation of chlorpheniramine maleate through mucosal membranes in vitro.
  • Several buccal devices, containing chlorpheniramine maleate described in Example 7 were placed directly onto pieces of previously harvested rabbit large bowel that were mounted in Franz Diffusion Cells as described in Example 12.
  • the permeation studies were conducted as described in Example 12 except that the HPLC analysis was modified: a Spectra Physics, Model SP8800, fitted with Alltima C8, 5 micron, 15cm X 4.6 mm column, and a UV detector set at 261 nm with an acetonitrile (30%)- 0.05% potassium dihydrogen phosphate plus lml of phosphoric acid, pH 2.5 (70%) mobile phase.
  • the in vitro permeation profile is shown in Figure 8.
  • the flux can be calculated from this graph by determining its slope.
  • the average permeation rate through the mucosal tissue was 182 ⁇ g/cm 2 /hr.
  • the average permeation rate through the mucosal tissue was 97.3 ⁇ g/cm 2 /hr. This value is approximately half of that for the pellet containing 10 mg of chlorpheniramine maleate, indicating that these buccal devices (pellets) are not saturated with the drug.
  • the flux of 182 ⁇ g/cm 2 /hr is adequate to produce systemic therapeutic levels since the oral daily dosage for chlorpheniramine maleate is 2 mg.
  • a dental device containing chlorhexidine diacetate was made.
  • Silastic® liquid silicone rubber: 7-6860
  • a paste was prepared with the following composition: 42% sodium alginate 16% chitosan 10% NOCC 32% Silastic® 7-6860
  • chlorhexidine diacetate (Sigma Aldrich) was added to 410 mg of this paste with mixing. Chlorhexidine diacetate is a broad-spectrum anti-bacterial used for control of periodontal disease. Buccal-adhering devices were prepared as described in Example 10 using 60 mg portions of the mixture.
  • the device was 7 mm in diameter and 2-3 mm thick; it was durable and somewhat flexible.
  • the device contained 9.15% NOCC and 5.08 mg of chlorhexidine diacetate and was adhesive to moist tissue.
  • Timolol maleate is a beta-blocker used to reduce pressure in the eye.
  • a paste was prepared with the following composition:
  • timolol maleate (Sigma Aldrich) was added to 243 mg of the paste (Sigma Aldrich) with mixing. Thin wafers were prepared using the press and techniques described in Example 10 but with 20 mg portions of the paste-drug mixture.
  • the device was 7 mm in diameter and less than 1mm thick; it was durable and somewhat flexible.
  • the device contained 9.25% NOCC and 1.50 mg of timolol maleate and was adhesive to moist tissue.
  • This example tested the permeation from the buccal device of Example 15.
  • the buccal-adhering devices, containing 5 mg of chlorhexidine diacetate, described in Example 15 were placed directly onto pieces of previously harvested rabbit large bowel that were mounted in Franz Diffusion Cells as described in Example 12.
  • the permeation studies were conducted as described in Example 12 except that the analysis of the receptor solution was performed using a UV -Visible Spectrophotometer (Pharmacia Biotech Ultraspec 2000, set at a wavelength of 230 nm) and 3.0ml aliquots were withdrawn at 0.5, 1, 2, 3, 4, 6, 18, and 24 hours.
  • the flux can be calculated from this graph by determining its slope.
  • the average permeation rate through the mucosal tissue was 160.8 ⁇ g/cm 2 /hr.
  • Example 18 This example shows the permeation from the eye drug delivery device made in
  • the wafers, containing 1.50 mg of timolol maleate, described in Example 16 were placed directly onto pieces of previously harvested rabbit large bowel that were mounted in Franz Diffusion Cells as described in Example 12.
  • the permeation studies were conducted as described in Example 12 except that the analysis of the receptor solution was performed using a UV- Visible Spectrophotometer (Pharmacia Biotech Ultraspec 2000, set at a wavelength of 295 nm) and 3.0ml aliquots were withdrawn at 0.5, 1, 2, 3, 4, 6, 18, and 24 hours.
  • the flux can be calculated from this graph by determining its slope.
  • the average permeation rate through the mucosal tissue was 103.8 ⁇ g/cm 2 /hr.
  • the flux of 103.8 ⁇ g/cm 2 /hr is adequate to produce a therapeutic effect to treat glaucoma when the wafer is inserted between the eye and eye lid.
  • these devices are suitable for the delivery of drugs (such as beta blockers) to the eye.
  • an adherent formulation containing a fibrin sealant for prevention of surgical adhesions was prepared.
  • a commercial 2-component fibrin sealant kit (Tisseel® Kit, Baxter Hyland Immuno) was used following the manufacturer's directions with one exception.
  • the vial of protein concentrate (containing fibrinogen) was divided into portions that were reconstituted with either saline or NOCC solution (1.25% w/v).
  • Thrombin was used at a level of 4 IU/ml for "slow solidification" according to the manufacturer's directions.
  • the fibrin sealant with and without NOCC was applied to pieces of rabbit large bowel tissue. The tissues with sealant were cured for several minutes at 35-37C 0 and inspected.
  • the NOCC-containing sealant provides an improved adhesion barrier that remains at the site of application and forms a more flexible layer.
  • an adherent formulation containing a fibrin sealant for sealing or attaching tissues was prepared.
  • a two component commercial fibrin sealant kit (Tisseel® Kit, Baxter Hyland Immuno) was used to test for an adherent formulation with NOCC.
  • the vial of protein concentrate (containing fibrinogen) was divided into portions that were reconstituted at 35C° with either saline or NOCC solution (1.25% w/v).
  • Freeze-dried thrombin was reconstituted with saline to yield a solution containing 13.9 IU/ml.
  • Two ml of the thrombin solution was mixed with 2 ml of 10 mg/ml calcium chloride solution.
  • Fibrin sealant with and without NOCC was applied to rabbit large bowel tissue using the mixing dispenser supplied by the manufacturer.
  • the tissues were approximately 1 inch square and the sealant was applied to half of the tissue.
  • the tissue was folded onto itself and pressed together lightly for 10-20 seconds.
  • the tissues were kept warm (35-37C°) for 30 minutes and then evaluated.

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Abstract

L'invention concerne des dispositifs d'administration de médicaments pour tissus humides, en particulier le tissu des muqueuses ou celui des cavités séreuses, ainsi qu'un procédé d'utilisation associé. Lesdits dispositifs, qui renferment NOCC, collent au tissu des muqueuses, facilitent une administration de médicament localisée et sont particulièrement utiles dans des dispositifs vaginaux, buccaux et oculaires.
EP02721645A 2002-03-28 2002-03-28 Dispositifs d'administration de medicament n,o-carboxymethylchitosane adhesif pour tissus humide et leurs procedes d'utilisation Withdrawn EP1494633A4 (fr)

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PCT/US2002/010149 WO2003082163A1 (fr) 2002-03-28 2002-03-28 Dispositifs d'administration de medicament n,o-carboxymethylchitosane adhesif pour tissus humide et leurs procedes d'utilisation

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ES2209649B1 (es) * 2002-12-09 2005-03-16 Carlos Arana Molina (Titular Al 25%) Utilizacion de la melatonina para la higiene bucodental para uso humano y veterinario como producto activo.
EP2200674A2 (fr) 2007-09-10 2010-06-30 Boston Scientific Scimed, Inc. Dispositifs médicaux avec matériau bioadhésif susceptible d'être activé
CN110731377B (zh) * 2019-10-25 2022-08-30 浙江大学 一种羧甲基壳聚糖基褪黑素双层自组装膜及其应用方法

Citations (3)

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Publication number Priority date Publication date Assignee Title
US5948401A (en) * 1995-12-22 1999-09-07 Union Carbide Chemicals & Plastics Technology Corporation Cationic therapeutic systems
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
WO2001098206A1 (fr) * 2000-06-22 2001-12-27 Rxkinetix, Inc. Composition de vecteur d'administration et procede pour l'administration d'antigenes et d'autres medicaments

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Publication number Priority date Publication date Assignee Title
US5888988A (en) * 1995-05-08 1999-03-30 Chitogenics, Inc. Covalently linked N,O-carboxymethylchitosan and uses thereof
US6030635A (en) * 1998-02-27 2000-02-29 Musculoskeletal Transplant Foundation Malleable paste for filling bone defects

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948401A (en) * 1995-12-22 1999-09-07 Union Carbide Chemicals & Plastics Technology Corporation Cationic therapeutic systems
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
WO2001098206A1 (fr) * 2000-06-22 2001-12-27 Rxkinetix, Inc. Composition de vecteur d'administration et procede pour l'administration d'antigenes et d'autres medicaments

Non-Patent Citations (3)

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Title
LUBBEN VAN DER I M ET AL: "CHITOSAN AND ITS DERIVATIVES IN MUCOSAL DRUG AND VACCINE DELIVERY" EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 14, no. 3, 2001, pages 201-207, XP001115063 ISSN: 0928-0987 *
RAVI KUMAR M N V: "A review of chitin and chitosan applications" REACTIVE & FUNCTIONAL POLYMERS, ELSEVIER SCIENCE PUBLISHERS BV, NL, vol. 46, no. 1, November 2000 (2000-11), pages 1-27, XP004224437 ISSN: 1381-5148 *
See also references of WO03082163A1 *

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CA2481227A1 (fr) 2003-10-09
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AU2002252565A1 (en) 2003-10-13
WO2003082163A1 (fr) 2003-10-09

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