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WO1999032151A1 - Methodes et compositions pour l'apport d'agents pharmaceutiques et/ou la prevention d'adherences - Google Patents

Methodes et compositions pour l'apport d'agents pharmaceutiques et/ou la prevention d'adherences

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Publication number
WO1999032151A1
WO1999032151A1 PCT/US1997/023865 US9723865W WO9932151A1 WO 1999032151 A1 WO1999032151 A1 WO 1999032151A1 US 9723865 W US9723865 W US 9723865W WO 9932151 A1 WO9932151 A1 WO 9932151A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
polymer
polyoxyalkylene
weight
copolymer
Prior art date
Application number
PCT/US1997/023865
Other languages
English (en)
Inventor
Stephen G. Flore
Luis A. Dellamary
Lorraine E. Reeve
Jeffry G. Weers
Original Assignee
Alliance Pharmaceutical Corporation
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 Alliance Pharmaceutical Corporation filed Critical Alliance Pharmaceutical Corporation
Priority to PCT/US1997/023865 priority Critical patent/WO1999032151A1/fr
Priority to AU55335/98A priority patent/AU753206B2/en
Priority to US09/582,508 priority patent/US6280745B1/en
Priority to EP97951781A priority patent/EP1039932A1/fr
Priority to JP2000525141A priority patent/JP2001526246A/ja
Priority to CA002316248A priority patent/CA2316248A1/fr
Priority to PCT/US1998/027410 priority patent/WO1999032152A2/fr
Priority to AU19438/99A priority patent/AU1943899A/en
Publication of WO1999032151A1 publication Critical patent/WO1999032151A1/fr

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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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention generally relates to pharmaceutical preparations and methods of their use. More particularly, the present invention relates to preparations suitable for the reduction of adhesion formation in mammals or the delivery of pharmaceutically active compounds.
  • Aqueous liquids which can be applied at room temperature in a free flowing state but which forms a semi- solid gel when warmed to body temperature have been used in such capacities for some time.
  • Such systems combine ease of application with greater retention at the site of application than the use of exclusively free flowing vehicles.
  • Pluronic ® polyols are used in aqueous compositions to provide thermally gelling aqueous systems. Adjusting the concentration provides the desired sol-gel transition temperature. More particularly, the lower the concentration of the incorporated polymer the higher the sol-gel transition temperature.
  • Adhesions are thought to form following a trauma or injury to the peritoneum. This results in increased vascular permeability, which produces an inflammatory exudate and results in the formation of a fibrin matrix.
  • the fibrin matrix is removed by fibrinolysis, and subsequent fibroblast proliferation results in remesothelialization.
  • the fibrinolytic process is suppressed and the fibrin matrix may persist. If it persists until about day three, significant collagen deposition within the fibrin matrix, can lead to adhesion formation.
  • dextran 70 in preventing post-operative adhesions was shown to be limited to the more dependent regions of the pelvis.
  • TC-7 Johnson and Johnson Products, Inc., New Brunswick, N.J.
  • Other solid sheet devices include polytetrafluoroethylene (Gore-Tex®, W. L. Gore) and crosslinked hyaluronic acid (Seprafilm ⁇ Genzyme Corp.).
  • Chondroitin sulfate and sodium carboxymethyl cellulose have also been used to prevent the formation of postoperative adhesions in the rabbit uterus (Oelsner et al., J Reprod. Med. 32:812-814 (1987)). Chondroitin sulfate solutions have also been proposed for intraperitoneal use in the prevention of adhesions in rabbits
  • aqueous gel compositions comprising polyalkylene polymers have been shown to successfully reduce adhesions (U.S. Pat. No. 5,366,735, incorporated herein by reference). These compositions can be applied below room temperature as a liquid and form semi-solid gels when warmed to body temperature.
  • precise control of the sol-gel transition temperature and dissolution rate of the gel within the physiological environment still present problems in many cases. Accordingly, despite these previous efforts, a need exists for improved means to treating and/or preventing post-surgical adhesions. As such, it is an object of the present invention to provide polymeric gel compositions which allow for precise control of the sol-gel transition temperature and/or dissolution rate of the gel once formed.
  • the present invention accomplishes these and other objectives by providing polymeric compositions that exhibit well defined sol-gel transition temperatures (or defined ranges of temperatures) and/or established dissolution rates.
  • the disclosed compositions generally comprise at least one constitutive polymer and at least one modifier polymer that may be used to modify or control the dissolution rate of gel once it has been formed.
  • the compositions of the present invention comprise at least one constitutive polymer and at least one hydrophilic co-surfactant whereby the gelation temperature (or sol-gel transition temperature) of the composition may be controlled or modified.
  • compositions may comprise at least one constitutive polymer in combination with both at least one modifier polymer and at least one hydrophilic co-surfactant to provide preparations having both selected gelation temperatures and superior dissolution times.
  • compositions may comprise at least one constitutive polymer in combination with both at least one modifier polymer and at least one hydrophilic co-surfactant to provide preparations having both selected gelation temperatures and superior dissolution times.
  • preferred embodiments of the invention will comprise the aforementioned preparations and at least one bioactive agent.
  • the polyphase preparations of the present invention may be used to retard or prevent the formation of scar tissue or adhesions in a mammal, for the prolonged delivery of a bioactive agent or both.
  • the present invention comprises methods for the reduction of adhesion or scar tissue formation comprising the administration of the disclosed preparations to a mammal in need thereof.
  • compositions of the present invention comprise methods of delivering a bioactive agent to a mammal comprising administering the disclosed polyphase compositions incorporating a pharmaceutically effective amount of at least one bioactive agent to a mammal in need thereof.
  • the compositions of the present invention will be administered as a relatively free flowing liquid that gels upon contact with the mammalian tissue to provide a viscoelastic semi-solid barrier or mask that may remain in place for an extended period.
  • the constitutive polymer will be a polyoxyalkylene copolymer. More particularly, in selected embodiments the constitutive polymer will be selected from the group consisting of polyoxyalkylene block copolymers, polyoxyalkylene polyethers and combinations thereof. In especially preferred embodiments of the invention, the constitutive polymer will comprise Poloxamer 407.
  • the constitutive polymer or polymers may be present at any concentration that provides the desired gel viscosity and/or viscoelastic properties. Preferably, the constitutive polymers are present in a concentration which, when combined with the other components of the preparation, allows for the administration of the composition as a relatively free flowing liquid which gels upon contact with mammalian tissue.
  • modifier polymers compatible with the present invention comprise any polymeric entity capable of slowing or retarding the dissolution rate of the constitutive polymer once it has gelled. That is, the modifier polymers of the present invention comprise any polymer that, when added to the constitutive polymer(s), provides for a slower dissolving or diffusing gel when compared with a gel formed from pure constitutive polymer(s) under equivalent conditions.
  • Preferred modifier polymers typically have a relatively high average molecular weight on the order of tens or hundreds of thousands.
  • modifier polymers While a large number of polymeric compounds are suitable for use as modifier polymers, particularly preferred compounds comprise cellulose ethers (carboxymethyl cellulose) and Carbopols (e.g. Carbopol 940-NF).
  • the absolute incorporated concentration of the modifier polymers in the compositions of the present invention is not critical and may be adjusted to provide the desired dissolution rates and/or retention times.
  • compositions disclosed herein may further comprise one or more hydrophilic co-surfactants which may be used to modify the gelation temperature (sol-gel transition temperature) of the resulting preparation. More particularly, selected hydrophilic co-surfactant(s) may be added to compositions comprising a constitutive copolymer(s) or compositions comprising constitutive copolymer(s) and modifier polymer(s) to alter or modify the gelation temperature of the resulting composition when compared to similar compositions not comprising the hydrophilic co-surfactant.
  • the hydrophilic may be added at an effective concentration to lower the gelation temperature of the composition so as to provide for more rapid and complete gelation upon contact with the relatively high temperature mammalian tissue.
  • hydrophilic co-surfactants include fatty acid soaps such as sodium laureate, sodium caprate or sodium caprylate.
  • combinations of hydrophilic co- surfactants may be incorporated in the compositions of the present invention to provide the desired transition temperature or transition temperature range.
  • bioactive agents compatible with the present invention include, but are not limited to, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, -mtihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases, gastrointestinal agents and combinations thereof.
  • compositions may comprise one or more humectants, bactericides, bacteriostatic agents, fibrinolytic agents or agents effective in preventing leukocyte migration into the area of surgical injury.
  • Pharmaceutically effective amounts of the selected bioactive agents may be determined using techniques well known in the art. It will further be appreciated that the bioactive agents may be incorporated in the form of relatively insoluble solid particulates or associated with insoluble polymeric particulates.
  • the preparations of the present invention may be administered to a patient using a route of administration selected from the group consisting of topical, subcutaneous, pulmonary, synovial, intramuscular, intraperitoneal, nasal, vaginal, rectal, aural, oral and ocular routes.
  • the administered composition preferably gels upon contact with the relatively warm mammalian tissue and may act as a depot for the prolonged delivery of one or more incorporated bioactive agents.
  • the gelled compositions may act as a barrier or film which prevents or retards the formation of adhesion or scar tissue.
  • the present invention provides particularly effective methods for the prevention of post-surgical and other adhesion formation, administration of pharmaceutically effective amounts to the peritoneal, pelvic or pleural cavity is especially preferred.
  • adhesions are often associated with injury to mammalian organs, those skilled in the art will appreciate that the compositions are particularly useful when applied to the selected area during or immediately following surgery.
  • compositions of the present invention may further comprise pharmaceutically acceptable stabilizers, preservatives and buffers, preferably in an amount sufficient to maintain the pH of the composition at about pH 7.4 ⁇ 0.2.
  • Figure 1 is a graphical representation of an exemplary phase diagram for a prior art composition comprising a constitutive polymer
  • Figure 2 illustrates an equilibrium phase diagram of 20% w/w poloxamer 407 (407F) in tromethamine/maleate buffer with added sodium caprate with arrows indicating that the cloud point temperature is greater than the highest temperature measured, i.e. 140 °C;
  • Figure 3 is a graphical representation of a gelation profile of 1%, 3% and 5% (w/w) sodium caprylate in 20% w/w poloxamer 407 (407F) in hypotonic tromethamine/maleic acid buffer
  • Figure 4 is a graphical representation illustrating the effect of fatty acid soap concentration on the lower gelation temperature (LGT) of 20% w/w poloxamer 407F solutions for soaps of varying alkyl chain lengths and degrees of saturation.
  • LGT lower gelation temperature
  • compositions and methods are disclosed herein for delivering bioactive agents and/or reducing post-surgical adhesion formation reformation in mammals following injury to the organs or tissues, particularly those of the peritoneal, pelvic or pleural cavity.
  • the compositions of the invention are also useful in reducing adhesion formation/reformation in other body spaces such as the subdural, extraocular, intraocular, otic, synovial, tendon sheath, or those body spaces created either surgically or accidentally.
  • the concentration of the constitutive polymer in the disclosed compositions may be adjusted to take advantage of the gelation properties of certain polyoxyalkylene polymers.
  • compositions may be formed in accordance with the teachings herein that do not gel or thicken following application to the selected area or tissue.
  • the osmolality and pH of the compositions are adjusted to match the pH and osmotic pressure of mammalian bodily fluids, i.e. approximately pH 7.4.
  • the constitutive polymer i.e., a polyoxyalkylene block copolymer
  • compositions may also be used as a distending medium during diagnostic or operative endoscopic procedures, such as, for example, for intrauterine procedures.
  • diagnostic or operative endoscopic procedures such as, for example, for intrauterine procedures.
  • certain aqueous concentrations of the preferred polyoxyalkylene block copolymers form a clear gel, their use is well suited for visualization of interior cavities.
  • the disclosed formulations provide a barrier between tissues for hours or days. Because they are applied as liquids, they are easier to use, particularly for laparoscopic surgical procedures. That is, the compositions of the instant invention may be administered though a relatively small incision using a cannula or catheter assembly.
  • the disclosed compositions of the present invention are preferably aqueous based preparations.
  • the compositions typically comprise water in an amount of from about 60% to about 90%, by weight, preferably, about 70% to about 85%, by weight, and most preferably, about 75% to about 82% by weight, based upon the total weight of the composition.
  • the terms "peritoneal” and “abdominal” cavity are used as synonyms, as are the terms “pleural” and "thoracic” cavity.
  • polyalkylene block polymers include those polymers which form clear gels at mammalian body temperatures but are liquids at ambient temperatures or below.
  • gel is defined as a solid or semisolid colloid containing a certain quantity of water. The colloidal solution with water is often called a "hydrosol”.
  • the constitutive polymer will be a polyoxyalkylene polymer. More particularly, in selected embodiments the constitutive polymer will be selected from the group consisting of polyoxyalkylene block copolymers, polyoxyalkylene polyethers and combinations thereof. In especially preferred embodiments of the invention, the constitutive polymer will comprise poloxamer 407.
  • the constitutive polymer or polymers may be present at any concentration that provides the desired gel viscosity and/or viscoelastic properties. Preferably, the constitutive polymers are present in a concentration which, when combined with the other components of the preparation, allows for the administration of the composition as a relatively free flowing liquid which gels upon contact with mammalian tissue.
  • compositions comprise one or more polyoxyalkylene block copolymers of the formula
  • A is a polyoxyalkylene moiety; x is at least 2; Y is derived from water or an organic compound containing x reactive hydrogen atoms;
  • E is a polyoxyethylene moiety; n has a value such that the average molecular weight of A is at least about 500; and the total average molecular weight of the copolymer is at least about 5000.
  • the polyoxyalkylene moiety A has an oxygen/carbon atom ratio of less than 0.5.
  • A is derived from an alkylene oxide selected from the group consisting of butylene oxide, propylene oxide or a mixture thereof.
  • A is a polyoxypropylene moiety, and preferably has an average molecular weight of from about 3,000 to about 4,000 g mol "1 .
  • the polyoxyethylene moiety E preferably constitutes from about 60 to about 85% by weight of the copolymer, more preferably at least about 70%.
  • Y is derived from a water soluble organic compound having 1 to about 6 carbon atoms. In another embodiment, Y is derived from an organic compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol trimethylolpropane, ethylenediamine and mixtures thereof.
  • the copolymer has the formula: HO(C 2 H 4 O)£(C 4 H 8 O) fl (C 2 H 4 O) 6 H (H)
  • a and b are integers such that (C 4 H 8 O) ⁇ has a molecular weight of at least about 500.
  • Useful polyoxyalkylene block copolymers which will form gels in aqueous solutions can be prepared using a hydrophobe base (such as A in Formulas (I) and (II)) derived from propylene oxide, butylene oxide or mixtures thereof. These block copolymers and representative methods of preparation are further generally described in U.S. Pat. Nos. 2,677,700; 2,674,619; and U.S. Pat. No. 2,979,528, inco ⁇ orated herein by reference.
  • the polyoxybutylene-based block copolymers useful in the compositions of the invention are prepared by first condensing 1,2 butylene oxide with a water soluble organic compound initiator containing 1 to about 6 carbon atoms such as 1,4 butylene glycol or propylene glycol and at least 2 reactive hydrogen atoms to prepare a polyoxyalkylene polymer hydrophobe of at least about 500, preferably at least about 1000, most preferably at least about 1500 average molecular weight. Subsequently, the hydrophobe is capped with an ethylene oxide residue. Specific methods for preparing these compounds are described in U.S. Pat. No. 2,828,345 and British Patent No. 722,746, both of which are herein incorporated by reference.
  • compositions comprise polyoxyethylene- polyoxypropylene block copolymers of the formula (III):
  • compositions comprise a polyxyethylene-polyoxyproplyene block copolymer of formula (III), having a polyoxyproplyene hydrophobe base average molecular weight of about 4000, a total average molecular weight of about 12,000 and containing oxyethylene groups in the amount of about 70% by weight of the total weight of the copolymer.
  • poloxamer 407 is a tri-block copolymer containing two polyoxyethylene blocks flanking a central polyoxypropylene block.
  • the USP material has an average molecular formula of (EO) 101 -(PO) 56 -(EO) 101 , and average molecular weight of ca. 12,000 g mol "1 .
  • poloxamer 407 self-assembles so as to remove contact between the polyoxypropylene groups and water (i.e.
  • the self-assembly is driven by the hydrophobic effect).
  • the self-assembled units are termed micelles.
  • the structure of the micelles and the interactions between them is strongly dependent on temperature.
  • a large increase in solution viscosity i.e. gel-phase formation
  • Gel phase formation occurs as a result of organization of the micelles into a three- dimensional cubic array.
  • the copolymer has the formula:
  • R is H(OC 2 H 4 ) b (OC 3 H 6 ) a -; and a and b are integers such that the hydrophobe base represented by (C 3 H 6 O) a has a sum average molecular weight of at least about 2000, about 3 to about 5%.
  • the hydrophobe base is prepared by adding propylene oxide for reaction at the site of the four reactive hydrogen atoms on the amine groups of ethylenediamine. An ethylene oxide residue is used to cap the hydrophobe base.
  • the polyoxyethylene chain constitute from about 60 to about 85% by weight of the colpolymer, preferably at least about 10%. It is further preferred that the copolymer have a total average molecular weight of at least about 5000, preferably from about 9,000 to about 15,000 as specified in the USP).
  • aqueous solutions which form gels of the polyoxyalkylene block copolymers is well known.
  • Either a hot or cold process for forming the solutions can be used.
  • a cold technique involves the steps of dissolving the polyoxyalkylene block copolymer at a temperature of about 5° to about 10° C in water. When solution is complete the system is brought to room temperature whereupon it forms a gel. If the hot process of forming the gel is used the polymer is added to water heated to a temperature of about 75 °C to about 85 °C, with slow stirring until a clear homogeneous solution is obtained. Upon cooling, a clear gel is formed.
  • Block copolymer gels containing polyoxybutylene hydrophobes must be prepared by the above hot process, since these will not liquefy at low temperatures.
  • the organic compound initiator which is utilized in the preparation of the polyoxyalkylene block copolymers generally is water or an organic compound, and can contain a plurality of reactive hydrogen atoms.
  • Y in formulas (I) and (II) above is defined as derived from a water soluble organic compound having 1 to about 6 carbon atoms and containing x reactive hydrogen atoms where x has a value generally, of at least 1, preferably, a value of at least 2.
  • Y is derived from water soluble organic compounds having at least two reactive hydrogen atoms
  • water soluble organic compounds such as propylene glycol, glycerin, pentaerythritol, trimethylolpropane, ethylenediamine, and mixtures thereof and the like.
  • the oxypropylene chains can optionally contain small amounts of at least one of oxy ethylene or oxy butylene groups.
  • Oxy ethylene chains can optionally contain small amounts of at least one of oxypropylene or oxybutylene groups.
  • Oxy butylene chains can optionally contain small amounts of at least one of oxy ethylene or oxypropylene groups.
  • the physical form of the polyoxyalkylene block copolymers can be a viscous liquid, a paste or a solid granular material depending upon the molecular weight of the polymer.
  • the present compositions may comprise other polyoxyalkylene polymers which form gels at low concentrations in water.
  • polymers are described in U.S. Pat. No. 4,810,503, incorporated herein by reference. These polymers are prepared by capping conventional polyoxyalkylene polyether polyols with an alphaolefin epoxide having an average of about 20 to about 45 carbon atoms, or mixtures thereof. Aqueous solutions of these polymers gel in combination with surfactants, which can be ionic or nonionic. The combination of the capped polyether polymers and the surfactants provide aqueous gels at low concentrations of the capped polymer and surfactant which generally do not exceed 10% by weight total.
  • copolymer polyether polyols are prepared by preparing block or heteric intermediate polymers of ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms as intermediates. These are then capped with the alpha-olefin epoxide. Ethylene oxide homopolymers capped with the alpha-olefin oxides are also useful as intermediates.
  • the heteric copolymer intermediate is prepared by mixing ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with a low molecular weight active hydrogen-containing compound initiator having at least two active hydrogens and preferably,
  • 2 to 6 active hydrogen atoms such as a polyhydric alcohol, containing from 2 to 10 carbon atoms and from 2 to 6 hydroxyl groups, heating said mixture to a temperature in the range of about 50° C to 150° C, preferably, from 80° C to 130°, under an inert gas pressure, preferably, from about 30 psig to 90 psig.
  • a block copolymer intermediate is prepared by reacting either the ethylene oxide or the alkylene oxide having 3 to 4 carbon atoms with the active hydrogen-containing compound followed by reaction with the other alkylene oxide.
  • the ethylene oxide and the alkylene oxides having from 3 to 4 carbon atoms are used in the intermediates in amounts so that the resulting polyether product will contain at least 10 percent by weight, preferably about 70 percent to about 90 percent by weight, ethylene oxide residue.
  • the ethylene oxide homopolymer intermediate is prepared by reacting ethylene oxide with the active hydrogen-containing compound.
  • the reaction conditions for preparing the block copolymer and ethylene oxide homopolymer intermediates are similar to those for the heteric copolymer intermediate.
  • the temperature and pressure are maintained in the above ranges for a period of about one hour to ten hours, preferably one to three hours.
  • the alpha-olefin oxides which are utilized to modify the conventional polyether intermediates are those oxides, and commercially available mixtures thereof, generally containing an average of about 20 to 45, preferably about 20 to 30, carbon atoms.
  • the amount of alpha-olefin required to obtain the more efficient capped polyethers is generally about 0.3 to 10 percent, preferably about 4 to 8 percent, of the total weight of the polyethers. Further description regarding the preparation of heteric and block copolymers of alkylene oxides and ethylene oxide homopolymers is described in the art (U.S. Pat. Nos.
  • One major advantage of the present invention is that the desired gelation temperatures and viscosity of the resulting gels may be adjusted through the addition of modifier polymers and hydrophilic co-surfactants. This allows the use of lower concentrations of constitutive polymer without markedly reducing the ultimate gel characteristics of the composition.
  • exemplary concentrations of constitutive polymer may range from approximately 2% w/w to 50% w/w and more preferably from 4% to 30% w/w and even more preferably from 16% to 28% w/w.
  • any biocompatible polymeric entity that modifies the dissolution time of the gel resulting from the administration of the compositions of the present invention may be used in accordance with the teachings herein.
  • preferred modifier polymers to alter the dissolution time should preferably have the following characteristics: (a) high molecular weight; (b) effective swelling in water but poor dissolution: (c) compatibility with the constitutive polymer and, in particular, poloxamers; and (d) stability to extremes in heat and pH.
  • alter the dissolution time is held to mean the alteration of the gel dissolution time in vitro or in vivo with respect to a gel comprising constitutive polymer without the modifier polymer under similar conditions.
  • the alteration of dissolution times or release rates of the constitutive polymer from the gel matrix may be used to optimize formulations for antiadhesion applications as well as for other applications including controlled drug delivery.
  • release is a function of several physicochemical characteristics within the gel, and can be modified by the addition of high molecular weight polymers such as sodium carboxymethyl cellulose, polyacrylates (i.e. Carbopols) or other polyester based polymers. It appears that the dissolution rate is modified by the formation of a strong polymeric matrix (i.e. the modifier polymeric matrix) that controls the release of the constitutive polymer via diffusion through the formed modifier polymer interstices. One possible reason for this effect may be that the constitutive polymer has to diffuse around the long linear molecules of the incorporated modifier polymer.
  • the selected modifier polymer(s) have a molecular weight greater than or equal to approximately 500,000 although modifier polymers of much lower molecular weight (i.e. on the order of 50,000).
  • the selected modifier polymers will combine a relatively high molecular weight with a biodegradable moiety in their structure to speed excretion.
  • High molecular weight polylactic-glycolide copolymers which are broken down by hydrolytic decomposition are one example of such a polymer. It should be emphasized that these modifier polymers may also be used to slow the dissolution (and hence prolong delivery time) of any incorporated bioactive agent.
  • exemplary polymers compatible with the teachings herein include, but are not limited to: poly(acrylic acid), poly(styrene sulfonate), carboxymethylcellulose, poly(vinyl alcohol), poly(ethylene oxide), poly(vinylpyrrolidone), shellac, cellulose acetate phthalate, cellulose acetate succinate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate, poly(methacrylic acid-co- methylmethacrylate), poly(methyl acrylate), poly(methyl methacrylate), poly(glutamic acid), poly(lactic acid), poly(lactic-glycolide), poly(glycolic acid), poly( ⁇ -caprolactone), poly( ⁇ - hydroxybutyric acid), poly( ⁇ -hydroxy valeric acid), polydioxanone, poly(ethylene terephthalate), poly (malic acid), poly(tartronic acid), poly
  • any pharmaceutically acceptable salt of the foregoing compounds may be used in the disclosed compositions with compromising the effectiveness thereof.
  • the modifier polymers of the present invention may be used in suprisingly low concentrations to provide extended dissolution times or release times.
  • the selected modifier polymers are preferably inco ⁇ orated in a range between about 0.05% and about 25% by weight and more preferably in a range of from approximately 0.5% to approximately 5% by weight.
  • the absolute amount of modifier polymer included in the composition will depend on factors such as the constitutive polymer selected, the molecular weight of the modifier polymer and the physiochemical properties of the various composition components. These determinations are well within the purview of the skilled artisan and may easily be determined without undue experimentation.
  • hydrophilic Co-Surfactants Yet another aspect of the present invention comprises the addition of a hydrophilic co- surfactant to the disclosed compositions (i.e. constitutive polymer preparations and constitutive polymer + modifier polymer preparations) to alter the physiochemical properties thereof. That is, the inco ⁇ oration of a hydrophilic co-surfactant in accordance with the teachings herein may provide several advantages over prior art formulations. These advantages are most easily understood in conjunction with a graphical representation of a polyphase system of the instant invention and examples set forth below.
  • Fig. 1 a phase diagram for a constitutive polymer solution (poloxamer 407) is shown.
  • the lower gelation temperature (LGT) refers to the temperature at which the poloxamer micelles (sol phase) self-assemble into the cubic array (i.e. the gel phase).
  • UGT upper gelation temperature
  • the micelles change their shape from spheres to prolates, thereby negating their ability to assemble in a cubic packing. This leads to the reformation of the low viscosity sol phase.
  • Above another critical temperature, termed the cloud point (CP) the micelles separate into their own coacervate phase in excess water. The solution clouds due to mixing of the two insoluble phases.
  • the lower gelation temperature (LGT) of the constitutive polymer solutions in water is largely dependent upon the total constitutive polymer concentration, such that increases in concentration lead to decreases in the LGT.
  • Fractionation of the constitutive polymer fractionated using organic phase separation or other means known in the art, such as described, for example, in Textbook of Polymer Science. F. Billmeyer, Wiley-Interscience, pp. 45-56 (1971)
  • CMC carboxymethylcellulose
  • FloGel 28 (28% w/w poloxamer 407) has an LGT of 13 °C, and is currently applied surgically at a temperature of 0°C. Therefore, application of the product will have to be done in a timely fashion to avoid gelation in the application catheter. Additionally, it has been hypothesized that increases in the LGT to a temperature close to or above room temperature may be advantageous.
  • hydrophilic co-surfactants comprising fatty acid soaps are particularly compatible with the present invention.
  • long chain, saturated soaps appear to be particularly efficient at altering the phase behavior to provide the desired composition characteristics.
  • the rheological properties of the gelled compositions of the present invention are unaltered by the presence of the fatty acid soaps, indicating that, as long as the critical packing volume of the cubic phase is exceeded, the rheology will remain virtually unchanged.
  • the addition of hydrophilic co-surfactants to the disclosed polyphase systems provides an efficient method for modifying the gelation temperature and cloud point temperature. These changes in phase behavior are particularly advantageous for a drug delivery vehicle or antiadhesion product as they allow for storage and application at temperatures near room temperature. Moreover, these characteristics reduce the potential for significant syneresis during terminal sterilization.
  • preferred embodiments of the present invention may comprise effective amounts of at least one hydrophilic co-surfactant.
  • the inco ⁇ orated hydrophilic co-surfactant will comprise a fatty acid soap.
  • fatty acid soaps are GRAS (generally regarded as safe) materials, present naturally in the human body, and included in many pharmaceutical products including large volume parenterals (e.g. Fluosol ® ). Their toxicological profile is well understood and, at the concentrations compatible with the present invention, they pose no toxicological risk. While several compounds comprising fatty acids are useful in the present invention, especially compatible fatty acid soaps comprise sodium oleate, sodium laurate, sodium caprate, sodium caprylate and combinations thereof.
  • the hydrophilic co-surfactants of the present invention may be inco ⁇ orated in relatively low concentrations to provide the desired gelation properties. It will be appreciated that the selected hydrophilic co-surfactant or surfactants may comprise any concentration that provides for the preferred gelation temperatures. However, exemplary concentrations of hydrophilic co-surfactants compatible with the instant invention are typically in a range between about 0.05% and about 25% by weight and more preferably in a range of from approximately 0.5% to approximately 5% by weight.
  • the preparations also provide for the efficient delivery of bioactive agents.
  • bioactive agents may increase the solubilization and bioavailability of inco ⁇ orated pharmaceutical compounds.
  • the micelle core of the gelled compositions of the present invention may serve as a reservoir for solubilizing nonpolar solutes such as hydrophobic drugs.
  • the micelles may also self-assemble to form stiff gels above a critical temperature. As previously discussed, gel formation appears to occur when the micelles behave as hard spheres in a close-packed simple cubic array.
  • poloxamer gels may also be an ideal drug delivery vehicle, owing to their low toxicity and ability to impede drug diffusion.
  • compositions disclosed herein may further optionally comprise one or more pharmaceutically acceptable adjuvants such as a humectant, a bactericide, a bacteriostatic agent, an antihistamine, or a decongestant, an agent to prevent leucocyte migration into the area of surgical injury, or a fibrinolytic agent.
  • humectants include, but are not limited to, glycerin, propylene glycol and sorbitol.
  • Useful bactericides include, by way of example, antibacterial substances such as ⁇ -lactam antibiotics, such as cefoxitin, n- formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides; aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin; nalidixic acids and analogs such as norfloxacin and the antimicrobial combination of fluoroalanine/pentizidone; nitrofurazones, and the like.
  • antibacterial substances such as ⁇ -lactam antibiotics, such as cefoxitin, n- formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, s
  • Antihistamines and decongestants such as pyrilamine, chlo ⁇ heniramine, tetrahydrozoline, antazoline, and the like, can also be used in admixtures as well as anti-inflammatories such as cortisone, hydrocortisone, beta-methasone, dexamethasone, fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac, its salts and its corresponding sulfide, and the like. Both steroidal and nonsteroidal compounds are particularly compatible with the compositions and methods of the present invention. With regard to the latter, ketoprofen, indomethacin and tolmetin sodium are particularly preferred.
  • Nitric oxide donors such as nononates and nitrosylated compounds may also be inco ⁇ orated.
  • Useful leucocyte migration preventing agents which can be used in admixtures include but are not limited to silver sulfadiazine, acetylsalicylic acid, indomethacin and Nafazatrom.
  • Useful fibrinolytic agents include urokinase, streptokinase, tissue plasminogen activator (TPA) and acylated plasmin.
  • compatible bioactive agents comprise both hydrophilic and lipophilic compounds including antibiotics, antivirals, mydriatics, antiglaucomas, anti- inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents including anti- glaucomics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases, gastrointestinal agents and combinations thereof.
  • hydrophilic and lipophilic compounds including antibiotics, antivirals, mydriatics, antiglaucomas, anti- inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents including anti- glaucomics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases, gastrointestinal agents and combinations thereof.
  • the preparations of the present invention are uniquely suited for various administrative techniques such as ocular, oral, pulmonary, rectal, synovial, subcutaneous, intramuscular, intraperitoneal, nasal, vaginal, or aural administration of medicaments or diagnostic compounds, they are compatible for use with a wide variety of bioactive agents.
  • bioactive agents for example, ophthalmic applications involving topical administration of the disclosed preparations are particularly preferred.
  • the foregoing list of compounds is exemplary only and not intended to be limiting. It will also be appreciated by those skilled in the art that the proper amount of bioactive agent and the timing of the dosages may be determined for the formulations in accordance with already-existing information and without undue experimentation.
  • the compositions are applied to surgically injured tissue as an aqueous solution which upon contact with living mammalian tissue forms a firm, adherent gel.
  • the composition is a viscous liquid or paste
  • these compositions can be applied without dilution to areas of surgical injury in the abdominal or thoracic cavities.
  • the formulations adhere to the site of tissue injury and reduce or prevent the formation of postsurgical adhesions during the healing process.
  • the preparations of the invention may also be used to deliver therapeutic and diagnostic agents to the gastrointestinal tract by, for example, the oral or direct routes of administration.
  • a contemplated example would be the delivery of antibiotics to the lining of the gastrointestinal tract in the treatment of Heliobacter pylori infections.
  • H. pylori has been implicated in the cause of gastric ulcers and stomach cancer.
  • Antibiotics effective in the treatment of H pylori infections could be administered in the form of a free flowing liquid that gels and adheres to the sites of infection.
  • compositions of the present invention may further contain preservatives, cosolvents, suspending agents, viscosity enhancing agents, ionic- strength and osmolality adjustors and other excipients in addition to buffering agents.
  • Suitable water soluble preservatives which may be employed are sodium bisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorabutanol, thimerosal, phenylmercuric borate, parabens, benzylalcohol phenylethanol and others. These agents may be present, generally, in amounts of about 0.001% to about 5% by weight and, preferably, in the amount of about 0.01 to about 2% by weight.
  • Suitable buffering agents or salts useful in maintaining p ⁇ include alkali or alkaline earth metal carbonates, chlorides, sulfates, phosphates, bicarbonates, citrates, borates, acetates and succinates such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and tromethamine (TRIS).
  • these agents are present in amounts sufficient to maintain the p ⁇ of the system at 7.4+ 0.2 and preferably, 7.4.
  • the buffering agent can be as much as 5% by weight.
  • preparations of the present invention may be sterilized, for example, by heat, irradiation, ultrafiltration or combinations of any of these or equivalent techniques.
  • preparations of the invention may be sterilized, for example, by autoclaving at 121 °C for 15 minutes or by filtration through a 0.22 mm filter.
  • the high bioavailability bioactive preparations of the present invention may advantageously be supplied to the physician in a sterile prepackaged form. More particularly, the formulations may be supplied as stable, preformed preparations, ready for administration or as separate, ready to mix components. When supplied as components the final preparation of the polyphase material could easily be performed in the pharmacy just prior to administration.
  • compositions comprising a constitutive polymer (poloxamer 407) and a modifier polymer (sodium carboxymethylcellulose) were prepared by dissolving the poloxamer in distilled water (4°C) to give a concentration of 28% by weight in accordance with the cold process described above for forming aqueous solutions.
  • Example 1 The following test procedure was utilized to determine the effect of the formulations of Example 1 on surgically injured rats.
  • Female Sprague-Dawley rats having a 300-400 gram body weight were anesthetized with pentobarbital sodium (30 milligrams per kilogram of body weight) by application intrapertoneally through the left lumbar region of the ventral abdominal wall.
  • Surgical defects (2) were created in directly opposed proximity by excising the peritoneal membrane and thereby exposing sidewall muscle tissue (2x1 cm).
  • the outer membrane of the cecum was removed by surgical peeling, thus exposing blood vessel loops (2xlcm). Both exposed defects were abraded to cause petechial bleeding, and then exposed to direct radiant heat source for 15 minutes to accelerate desiccation.
  • One ml of the compositions of Example 1 application temperature of 0 °C was applied to one injured site. The other injured site was left untreated.
  • the following example is directed to the determination of dissolution rates for various formulations prepared in accordance with the teachings herein.
  • Several of the formulations inco ⁇ orate at least one modifier polymer.
  • Poloxamer 407 (BASF. Mount Olive, NJ) Fractionated Poloxamer 407 (APC Lot #9630201)
  • Carbopol 940 NF (BF-Goodrich. Cleveland, OH) Hydroxypropylmethylcellulose K100M, HPMC-K100M, (Dow Chemical Company, Midland, MI)
  • Carboxymethylcellulose high viscosity, CMC (Spectrum Chemical Co., Gardena, CA)
  • Carboxymethylcellulose medium viscosity CMC-MV Purcosity
  • Polymer solutions were prepared by first dispersing the modifier polymer (i.e., CMC, hydropropylmethylcellulose (HPMC) or Carbopol) in the Tris/maleate buffer solution (0.1515 g of tris(hydroxymethyl)-aminomethane and 0.1726 g of sodium maleate were dissolved and brought up to 100 g with DI water) until fully hydrated.
  • the modifier polymer i.e., CMC, hydropropylmethylcellulose (HPMC) or Carbopol
  • Tris/maleate buffer solution 0.1515 g of tris(hydroxymethyl)-aminomethane and 0.1726 g of sodium maleate were dissolved and brought up to 100 g with DI water
  • In-vitro dissolution rate of poloxamer gels were determined using a modified USP dissolution apparatus (Hanson Research model SR6,) equipped with enhancer cells. Each of the dissolution vessels were filled with 25 mL of 0.1 M phosphate buffer (pH 7.4) (26.78 g of sodium phosphate dibasic (Na 2 HPO 4 »7H 2 0) was brought to a volume of 1L with DI water) and left to equilibrate for about 20 minutes to 36.8°C.
  • Membranes 1.2 ⁇ m cellulose ester membranes, 25 mm diameter, type RAWP
  • the determination of poloxamer concentration in the aqueous phase was carried out using the potassium picrate spectrophotometric method. This method is based on the extraction of picrate ion from water into an organic solvent in association with potassium ion complexes of polyoxyethylene chains.
  • the procedure consists of mixing 250 ⁇ L of potassium picrate solution (0.23g of picric acid (wet-based) dissolved in 10 mL of potassium hydroxide solution and brought to a volume of 50 mL with DI water) with 1 mL of 2.5 M potassium nitrate solution (50.55g of potassium nitrate was brought up to a volume of 200 mL with DI water; the pH was then adjusted to 12 with 0.1 N KOH) and 0.1 mL of the sample containing the poloxamer solution in a 16x250 mm test tube. The mixture is then vortexed and extracted with 3 mL of CH 2 C1 2 . The absorbance of the organic phase was measured at 378 run vs.
  • a reagent blank with the concentration determined from a calibration curve (Table 1) prepared by adding aliquots of surfactant standard solution (1024 ug/mL).
  • a Beckman UN/Vis spectrophotometer model DU-65 was used to measure poloxamer concentration. The pH was adjusted to 7.4 with IN HCl using a Sentron pH meter.
  • FloGel 25 refers to a 25% w/w formulation of poloxamer 407 in the Tris/maleate buffer system. Should the letter F follow the number, the poloxamer 407 has been fractionated to remove low molecular weight impurities. For the pu ⁇ oses of this example, poloxamer 407 is the constitutive polymer. Should the formulation contain a modifier polymer, it follows after a slash. Thus, FloGel 20F/0.5C, contains 20% w/w fractionated poloxamer 407 and 0.5% w/w high viscosity grade CMC. The acronyms for the modifier polymers are denoted in Table II immediately below.
  • a modifier polymer especially one of high molecular weight
  • a modifier polymer can have profound effects on poloxamer dissolution.
  • Cellulose ethers e.g. CMC and HPMC
  • the solution characteristics appear to depend on the average chain length as well as the degree of substitution. As molecular weight increases, the viscosity will increase rapidly.
  • Fractionated poloxamer 407 i.e. poloxamer 407F
  • Pluronic F-127 BASF Co ⁇ oration, Mount Olive, NJ
  • Hydrophilic co-surfactants in the form of fatty acid soaps i.e. sodium oleate, sodium laurate, sodium caprate, and sodium caprylate
  • Nu-Chek Prep. Elysian, MN
  • the buffer materials tromethamine (EM Sciences Inc., Gibbstown, NJ) and maleic acid (Sigma Chemical Co., St. Louis, MO), were used as received, and a hypoosmotic buffer containing 0.1515% w/w tromethamine and 0.1451% w/w maleic acid was prepared.
  • Final formulations contained a constant 20% w/w percentage of poloxamer 407F, and varying levels of fatty acid soaps. For phase behavior studies, samples were loaded into 5 ml Wheaton vacuoles (Fisher
  • FIG. 2 a typical phase diagram obtained for poloxamer 407F/fatty acid soap mixtures is shown in Figure 2. This diagram illustrates the effect of increasing sodium caprate concentrations on the phase behavior of 20% w/w poloxamer 407F solutions in the hypo-osmotic tromethamine/maleate buffer system.
  • the LGT is observed to increase systematically from 19 °C to 87 °C.
  • concentrations between ca. 1.5 and 2.0% caprate the LGT is in the temperature range between room and body temperature. Having a LGT in this temperature range might have some importance for the formulation of antiadhesion products, possibly improving the ease of use by obviating the need to maintain product temperature near 0 °C, and allowing the surgeon greater time to apply compositions in accordance with the methods herein.
  • the gel phase is completely suppressed.
  • the cloud point temperature is above typical steam sterilization temperatures. Being able to maintain a single phase above terminal sterilization temperatures may play a role in reducing post-sterilization syneresis.
  • the addition of fatty acid soaps represents a very efficient way of altering the LGT and cloud point of constitutive polymer gels without varying the rheological characteristics of the gel. This is, of course, in contrast to changing the LGT by varying poloxamer concentration, or the nature of the poloxamer (e.g. poloxamer 338).
  • the chainlength and degree of unsaturation of the hydrophilic co-surfactant may also be used to selectively alter the characteristics of the constitutive polymer gels. These effects are graphically illustrated in Figure 4 where the LGT is plotted as a function of soap concentration for different fatty acid soaps. The value next to the curve refers to the fatty acid portion of the soap. Thus, 8:0 represents an eight carbon fatty acid soap with no double bonds in the alkyl chain. 18:1, on the other hand, represents an alkyl chain containing eighteen carbons and a single double bond. It is apparent from Figure 4 that longer chainlength saturated soaps provide more substantial alterations of the gel characteristics than shorter chainlength analogues which appear to be less efficient at disrupting gel phase formation.
  • Ketoprofen (Sigma Chemical Co., St. Louis, MO)
  • Poloxamer 407 (BASF, Mount Olive, NJ)
  • Drug Concentration Determinations The samples were diluted to a suitable concentration with ethanol (for water insoluble drugs) or DI water. Drug concentrations were measured at the appropriate wavelength for each drug (see Table I) using a UV/Vis spectrophotometer (Beckman model DU-65). Concentrations were determined using Beer's law from the appropriate calibration curve (Table II). Gentamicin sulfate determination was performed by the UCSD Medical Center laboratory.
  • In-vitro release rate of drugs in poloxamer gels were determined using a modified USP dissolution apparatus (Hanson Research model SR6) equipped with enhancer cells. Each of the dissolution vessels was filled with 25 mL of .01 M phosphate buffer (pH 7.4) 1 and left to equilibrate for about 20 minutes to 36.8°C.
  • Membranes 1.2 ⁇ m cellulose ester membranes, 25 mm diameter, type
  • Ketoprofen Conc mg /L 22.9(Abs)-0.2 0.9996
  • Hydrocortisone Conc mg / 27.8(Abs)-0.1 0.9956 solubilization was, for most of the cases, enhanced in the gel state. Solubilization for hydrocortisone was higher in the liquid state. Two reasons could be responsible for the observed reduction in solubilization: 1) hydrocortisone has a relatively higher water solubility than the rest of the hydrophobic drugs tested: 2) samples below the gel transition temperature were equilibrated at room temperature, instead of the lower temperature used for the gels.
  • S and S 0 are the concentration of solubilized drug in the presence and absence of poloxamer, respectively.
  • C is the concentration of poloxamer (weight fraction).
  • Table V shows the apparent distribution coefficients. The higher the value of K, the greater the amount of drug that can be inco ⁇ orated into the system.
  • the modifier polymer is preferably of sufficient molecular weight that it too alters the diffusion path of the solute.
  • the fact that the size of the drug molecules did not seem to affect release rate also supports this hypothesis.

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Abstract

La présente invention concerne une composition renfermant un ou plusieurs polymères constitutifs et polymères modificateurs et/ou co-tensioactifs hydrophiles utiles pour réduire les adhérences ou assurer l'apport d'agents bioactifs. L'invention concerne également des méthodes pour prévenir et/ou réduire les adhérences post-opératoires ou bien assurer l'apport d'agents bioactifs.
PCT/US1997/023865 1997-12-23 1997-12-23 Methodes et compositions pour l'apport d'agents pharmaceutiques et/ou la prevention d'adherences WO1999032151A1 (fr)

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AU55335/98A AU753206B2 (en) 1997-12-23 1997-12-23 Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions
US09/582,508 US6280745B1 (en) 1997-12-23 1997-12-23 Methods and compositions for the delivery of pharmaceutical agents and/or the prevention of adhesions
EP97951781A EP1039932A1 (fr) 1997-12-23 1997-12-23 Methodes et compositions pour l'apport d'agents pharmaceutiques et/ou la prevention d'adherences
JP2000525141A JP2001526246A (ja) 1997-12-23 1997-12-23 薬剤送達及び／又は癒着防止のための方法及び組成物
CA002316248A CA2316248A1 (fr) 1997-12-23 1997-12-23 Methodes et compositions pour l'apport d'agents pharmaceutiques et/ou la prevention d'adherences
PCT/US1998/027410 WO1999032152A2 (fr) 1997-12-23 1998-12-23 Procedes d'administration d'agents pharmaceutiques a des muqueuses
AU19438/99A AU1943899A (en) 1997-12-23 1998-12-23 Methods for delivering pharmaceutical agents to mucosal surfaces

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JP6143286B2 (ja) * 2013-05-13 2017-06-07 学校法人 関西大学 癒着防止材及びその製造方法
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AU1943899A (en) 1999-07-12
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WO1999032152A2 (fr) 1999-07-01
WO1999032152A3 (fr) 1999-12-09
CA2316248A1 (fr) 1999-07-01

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