WO2007008206A1 - Compositions viscoelastiques resistantes a la dilution - Google Patents

Compositions viscoelastiques resistantes a la dilution Download PDF

Info

Publication number
WO2007008206A1
WO2007008206A1 PCT/US2005/024723 US2005024723W WO2007008206A1 WO 2007008206 A1 WO2007008206 A1 WO 2007008206A1 US 2005024723 W US2005024723 W US 2005024723W WO 2007008206 A1 WO2007008206 A1 WO 2007008206A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
concentration
polymer
viscoelastic
chondroitin sulfate
Prior art date
Application number
PCT/US2005/024723
Other languages
English (en)
Inventor
Mandar V. Shah
Alan L. Weiner
Original Assignee
Alcon, 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 Alcon, Inc. filed Critical Alcon, Inc.
Priority to PCT/US2005/024723 priority Critical patent/WO2007008206A1/fr
Publication of WO2007008206A1 publication Critical patent/WO2007008206A1/fr

Links

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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • 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
    • 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
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • the present invention relates to novel viscoelastic compositions and their use in the field of surgery utilizing viscous and/or viscoelastic materials, also known as viscosurgery.
  • the invention involves the combination of polymeric materials in aqueous solutions to enhance the performance of the viscosurgical materials, especially in certain environments.
  • the invention also relates to methods of using such enhanced viscoelastic materials for all conventional purposes, and particularly those in which retention of the viscoelastic material is desirable, such as in intra-articular use and in certain ophthalmic surgical procedures.
  • Viscous or viscoelastic agents used in surgery may perform a number of different functions, including, without limitation, maintenance and support of soft tissue, tissue manipulation, lubrication, tissue protection, and adhesion prevention. It is recognized that the differing rheological properties of these agents necessarily impact their ability to perform these functions, and, as a result, their suitability for certain surgical procedures. See, for example, U.S. Patent No. 5,273,056, the contents of which are by this reference incorporated herein.
  • agents viscous or viscoelastic agents
  • viscoat ® Alcon Laboratories
  • Healon ® , Healon ® GV, and Healon ® 5 (Pharmacia Corporation), Amvisc ® and Amvisc ® Plus (Bausch & Lomb, Inc.), and Vitrax ® (Allergan Inc.) all of which contain sodium hyaluronate; and Cellugel ® (Alcon) which contains hydiOxypropylmethylcellulose (HPMC).
  • AU of the foregoing examples of viscoelastics may be used in cataract surgery. They are used by the skilled ophthalmic surgeon for several purposes, including maintenance of the anterior chamber of the eye and protection of ophthalmic tissues during surgery, particularly corneal endothelial cells, and as an aid in manipulating ophthalmic tissues.
  • Viscoelastics that are dispersive tend to offer better coating and protection of delicate tissues, such as the endothelial lining of the cornea.
  • Cohesive viscoelastics tend to be "stiffer", offering an advantage in soft tissue manipulation, e.g., capsulorhexis, but do not coat as well and are prone to accidental or premature aspiration. See, Miyauchi et al., "The Optimal Molecular Weight of Dispersive Type Sodium Hyaluronate for the Reduction of Corneal Endothelial Damage Induced by Sonication, Irrigation, and Aspiration," Jpn J.
  • IOP intraocular pressure
  • the pressure increase has been attributed to the agent's interference with the normal outflow of aqueous humor through the trabecular meshwork and Schlemm's canal. (See, Berson et al., Obstruction of Aqueous Outflow) by Sodium Hyaluronate in Enucleated Human Eyes, Am. J.
  • IOP spikes depending on their magnitude and duration, can cause significant and/or irreversible damage to susceptible ocular tissues, including, without limitation, the optic nerve.
  • viscoelastics are typically removed from the eye just prior to the close of surgery.
  • the ease with which an agent can be removed from the surgical site, typically by aspiration, has traditionally been considered an important characteristic in the overall assessment of the agent's usefulness in cataract surgery. By removing the agent before the close of surgery, the surgeon hopes to minimize or avoid any significant IOP spike.
  • removal of agents which are relatively dispersive (as opposed to cohesive) or which adhere to the ocular tissue is often difficult and may cause additional trauma to the eye.
  • that invention involves supplementing the irrigating solution used in such surgeries with relatively low molecular weight polymers that, when mixed with a cohesive hyaluronate-based viscoelastic, have the effect of modifying the rheological properties at the interface with the irrigating solution, and particularly the cohesiveness of such viscoelastic, to improve its performance in surgery.
  • Irrigating solutions for use in surgery and particularly ophthalmic surgery are well known. See, e.g. commonly assigned U.S. Patent No. 4,443,432. It has also been suggested that viscous or viscoelastomeric substances may be added to irrigating solutions to reduce cell loss. See commonly assigned U.S. Patent No. 5,409,904, the contents of which are by this reference incorporated herein.
  • Viscoelastic joint therapy involves the intra- articular application of commercially available sodium hyaluronate viscoelastic materials such as HYLAN G-F 20, SYNVISC, HYALGAN, ARTZ, etc.
  • the sodium hyaluronate substance is thought to affect the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain in patients suffering from chondromalacia and/or arthritis, and particularly osteoarthritis.
  • Chondroitin sulfate is also known to be useful in the treatment of diseased or traumatized joints. See U.S. Patent No. 5,498,606.
  • Viscoelastic materials such as sodium hyaluronate have also been used in cosmetic and reconstructive surgery to treat wrinkles and add fullness. Further, viscoelastic agents, for example sodium hyaluronate and chondroitin sulfate, have been used as a packing material for use in middle ear surgery, as described in commonly assigned U.S. Patent No. 6,632,423, the contents of which are incorporated herein.
  • the embodiments of the dilution resistant viscoelastic compositions of this invention substantially meet these needs and others.
  • the present invention is directed to improved viscoelastic compositions for performing surgery, especially ophthalmic surgery, and for performing therapies, especially viscoelastic joint therapy, that require an increased resistance to dilution and loss of viscosity and/or varying rheological properties.
  • Embodiments of this invention comprise viscous or viscoelastic agents in combination with an irrigating solution comprising a relatively low molecular weight polymer.
  • inventive methods of the embodiments of the present invention comprise transitioning the rheological properties (specifically viscosity and cohesiveness) of hyaluronate-based viscoelastic agents while also increasing their resistance to dilution and viscosity loss, by exposing such viscoelastic agents to irrigating solutions containing low levels of relatively low molecular weight biocompatible polymers, such as chondroitin sulfate ("CS"), and cellulosic polymers, especially methylcellulose (“MC”) and hydroxypropylmethylcellulose (“HPMC”).
  • CS chondroitin sulfate
  • MC methylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the decreased cohesiveness and increased viscosity of the surface hyaluronate interfacing the irrigating solution in situ renders it less susceptible to unintentional aspiration during a surgical procedure, such as cataract surgery.
  • the hyaluronate material that is further removed from such surface i.e. deeper within the bolus of material retains its original lower viscosity and higher cohesiveness, and may therefore be readily aspirated at the conclusion of the surgery.
  • the skilled surgeon will be able to enjoy the positive aspects of different rheological profiles using the same hyaluronate-based material by modifying its properties with the polymer-containing irrigating solution to suit the particular phase of a surgery, i.e., capsulorhexis, phacoemulsification or aspiration of the viscoelastic.
  • a further aspect of the embodiments of this invention is especially applicable to therapies, such as viscoelastic joint therapy, that benefit from the ability of a viscoelastic composition to provide prolonged relief.
  • This ability is directly related to the viscoelastic composition's dilution characteristics.
  • FIGURE 1 shows the viscosity profile of various compositions of this invention plotted against the viscosity profiles of test solutions
  • FIGURE 2 illustrates zero shear viscosity at different HPMC concentrations and mixing ratios according to the teachings of this invention.
  • the methods and compositions of the present invention may be utilized in any viscosurgical procedure with a hyaluronate-based viscoelastic, and especially those in which there is concern over unintentional or premature removal of the viscoelastic material from the surgical site.
  • cataract surgery the anterior chamber of the eye, i.e., the space between the iris and the corneal endothelium is filled with viscoelastic.
  • the viscoelastic serves two purposes: (1) maintaining the corneal dome to give the surgeon an unobstructed view of the interior surgical site, and (2) protecting the delicate endothelial cells of the cornea by coating them.
  • the viscoelastic compositions of the present invention are also well-suited for joint therapy through intra- articular injection.
  • the effect of conventional hyaluronate is temporary because the material remains within the articular chamber for only about 72 hours before it is absorbed and/or metabolized.
  • the benefit of the longer retention times afforded by the compositions of the present invention is readily apparent, as the therapeutic effects of intra-articular viscotherapy with the compositions of the present invention should outlast those obtained with conventional viscoelastics.
  • the compositions of the present invention for use in joint therapy will contain chondroitin sulfate, which is known to be particularly beneficial for human and animal joints.
  • hyaluronate-based viscoelastic as used herein means any aqueous solution of hyaluronic acid or physiologically acceptable salts thereof, which is free of any significant amount of any low molecular weight, non-HA polymer.
  • hyaluronate-based viscoelastics As used herein, a "cohesive" hyaluronate-based viscoelastic would include any hyaluronate-based viscoelastic containing a hyaluronate component with a molecular weight of approximately 1,000,000 Daltons or more.
  • Lens removal surgery such as cataract surgery, or the less common clear lensectomy, involves several different steps or phases. As previously discussed, differing rheological profiles may be preferred for the viscoelastic used in each of those steps or phases. For example, during capsulorhexis (opening of the capsular bag to expose the clear or cataractous lens), it is desirable to have a cohesive viscoelastic for space maintenance; during phacoemulsification (ultrasonic fragmentation of the lens) it is desirable to have a dispersive viscoelastic for better coating and maneuverability; finally, during artificial lens insertion and completion of the surgery, it is desirable to have a cohesive viscoelastic both for space maintenance and ease of removal.
  • One embodiment of the present invention comprises the following steps.
  • a cohesive viscoelastic like PROVISC ® (Alcon Laboratories, Inc., Fort Worth, Texas), HEALON ® , or HEALON GV ® (Pharmacia & Upjohn, Peapack, New Jersey), or
  • AMVISC ® PLLTS (Bausch & Lomb Surgical, Claremont, California) is used before and during the capsulorhexis step.
  • a small amount of polymer-containing irrigating solution is permitted to flow, without aspiration into the space separating the viscoelastic from the anterior surface of the exposed, typically cataractous lens.
  • the phaco emulsification device is then engaged, without irrigation/aspiration, and the tip of the phaco emulsification handpiece is introduced into the surgical site and placed in the irrigating solution above the exposed lens.
  • the ultrasonic waves from the tip of the phaco emulsification handpiece will promote the mixture of the irrigating solution and the viscoelastic agent at the interface of those two substances. This will change the cohesive property of the hyaluronate-based viscoelastic in the immediate vicinity of the lens rendering the viscoelastic more dispersive. After one to twenty seconds of mixing, the phacoemulsification of the lens, with irrigation/aspiration, is completed in the ordinary manner.
  • the irrigation aspiration tip may be inserted into the bolus of viscoelastic material in the anterior chamber, i.e., beyond the more dispersive surface material at the interface and into the material not effected, or less effected, by admixture with the polymer-containing irrigating solution.
  • the viscoelastic material in this region remains more cohesive and is therefore easily aspirated out with minimal effort and minimal trauma to the delicate endothelial cells.
  • the cohesive, hyaluronate viscoelastics suitable for use in the methods of the present invention include those commercial products identified above, which may generally be characterized as containing sodium hyaluronate (of course other physiologically acceptable hyaluronate salts could also be used) having average molecular weights greater than 500,000 Daltons, preferably from about 1,000,000 to about 5,000,000 Daltons, and concentrations from about 1.0 to about 3.0% by weight.
  • Irrigating solutions that may be used in the methods of the present invention include any sterile, aqueous irrigating solution suitable for surgery.
  • Preferred are balanced salt solutions such as BSS ® or BSS PLUS ® (Alcon Laboratories, Inc., Fort Worth, Texas).
  • BSS ® or BSS PLUS ® Alcon Laboratories, Inc., Fort Worth, Texas.
  • the addition of polymers to the irrigating solution may be effected in the manner described in U.S. Patent No. 5,409,904, previously incorporated by reference.
  • Preferred polymeric components for the irrigating solution include CS, MS and HPMC.
  • the relatively low weight CS suitable for purposes of the present invention would include material having an average molecular weight of less than about 100,000 Daltons, preferably from about 20,000 to about 80,000 Daltons, and most preferably from about 30,000 to about 50,000.
  • HPMC or MC used as the polymeric component of the irrigating solution in the present methods will have an average molecular weight below about 400,000 Daltons and, preferably from about 50,000 to about 200,000 Daltons, and most preferably from about 70,000 to about 100,000 Daltons. Concentration ranges for the polymeric components will vary depending upon the molecular weight of the polymeric component chosen, but should be maintained at levels low enough to retain the flow properties desired for an irrigating solution.
  • the concentration in the irrigating solution may be from 0.1 to 10% by weight, preferably from 0.5 to about 7%, and most preferably from about 2% to about 5% by weight.
  • the concentration in the irrigating solution may be from 0.05 to 5%, preferably from about 0.1 to about 0.5%, and most preferably from about 0.2 to about 0.3%.
  • Combinations of different low molecular weight polymers may also be used.
  • the viscoelastic compositions of the present invention are mixed without an irrigation solution.
  • the low molecular weight polymers are mixed with a hyaluronate-based viscoelastic, as discussed below, to achieve the properties described herein.
  • a 0.4 mL aliquost of PROVISC or VISCOAT, as the case may be is placed in a 5 mL reaction vial (conical interior, covered with a flat bottom).
  • 5 microliters of Na fluorescein solution (25%w/v) is added for visualization of the viscoelastic.
  • 0.6 mL of appropriate irrigating solution is then added to the above vial, using a micropipette.
  • the irrigating solution in contact with the viscoelastic is then agitated to promote partial mixing by engaging the ultrasound on the phacoemulsification handpiece tip, and placing such tip in the irrigating solution, (expression of additional irrigating solution should be avoided by lowering the irrigating solution bottle to a height below the level of the reaction vial).
  • the ultrasound mixing is continued for 20 seconds, while moving the phaco tip, to mix the solution with the viscoelastic, along with the dye.
  • the height of the irrigating solution bottle is raised and irrigation/aspiration of the colored viscoelastic is commenced with ultrasound on. The time taken to frilly aspirate the viscoelastic, working as efficiently and as quickly as possible, is recorded.
  • the irrigating solution was mixed here with the help of ultrasound for 20 seconds, which was likely excessive.
  • the mixing is only required at the interface of the irrigating solution and the viscoelastic, so the actual time needed may be 1 second or less, as the viscosity and cohesiveness of the viscoelastic changes almost instantly upon mixing.
  • the formulation described in Table 2 above may be prepared as follows: First, the water for Injection is brought close to boiling or at boiling. The HPMC is then slowly added to the water under continuous stirring to thoroughly disperse it in the water. Then the mixture is slowly allowed to cool, stirring continuously. Once at room temperature, the mixture should start clearing up. The mixture is then stored overnight at 4 ° to 8 ° C in an appropriate container to fully hydrate the HPMC. The following day, the remaining ingredients are added to the HPMC solution, pH of the solution is adjusted and additional water for injection is added if needed to bring the solution to final volume. The final solution is filtered, packaged in bottles and autoclaved.
  • the formulation described in Table 3 above may be prepared as follows: First, the water for Injection is brought close to boiling or at boiling. The MC is then slowly added to the water under continuous stirring to thoroughly disperse it in the water. Then the mixture is slowly allowed to cool, stirring continuously. Once at room temperature, the mixture should start clearing up. The mixture is then stored overnight at 4 ° to 8 ° C in an appropriate container to fully hydrate the MC. The following day, the remaining ingredients are added to the MC solution, pH of the solution is adjusted and additional water for injection is added if needed to bring the solution to final volume. The final solution is filtered, packaged in bottles and autoclaved.
  • the formulation described in Table 4 above may be prepared as follows: First, the water for injection is allowed to cool to room temperature. The appropriate quantity of CS is slowly added to the water under continuous sti ⁇ ing to thoroughly disperse it in the water. Stirring continues until all CS is in solution. The remaining ingredients are then added sequentially to the CS solution, making sure that each such ingredient is dissolved before adding the next one. PH and volume of the solution are then adjusted. The final solution is sterile filtered and packaged in bottles. The solution may even be terminally sterilized by autoclaving.
  • HPMC, MC and CS have a strong polymeric interaction with HA.
  • the polymers have some basic difference in their interaction, resulting in different physical properties.
  • HPMC and MC interact with HA, there is a large impact on viscosity.
  • CS appears to have less of an impact on the resultant viscosity.
  • HPMC and MC both make the mixture more dispersive than the control (BSS PLUS ® ).
  • HPMC and MC are surface active polymers, which means they reduce the surface tension of the mixture, thus making the mixture more dispersive.
  • the interaction of MC with HA is much stronger than that of HPMC with HA.
  • the interaction of MC and HA is so strong that the resultant increase in viscosity overcomes the dilution effect.
  • An important aspect of the interaction of MC and HPMC with HA is that the resultant viscosity in both the cases is resistant to dilution. This property has applications beyond use of these polymers in an irrigating solution, such as for intra-articular therapy.
  • irrigating solution is infused, which continuously dilutes the viscoelastic.
  • irrigation solution comprising various ratios of the cellulosic polymers discussed herein were studied and the resultant viscosity was determined. The methodology used and results obtained are summarized below.
  • the actual amount of PROVISC and test solution varied, depending on the intended ratio of the two materials. For viscosity determination, 4 g of total material was needed.
  • the test solutions were BSS PLUS ® (control); BSS PLUS ® with varying concentrations of HPMC; BSS PLUS ® containing 2% chondroitin sulfate (CS); BSS PLUS ® containing 1% sodium carboxymethylcellulose (NaCMC); and (BSS PLUS ® with 0.22% methylcellulose (MC).
  • the weight of PROVISC to that of the test solution was adjusted such that it was in a 1:1, 1 :2, 1 :3, 1:4, 1:5 or 1:10 ratio for viscosity determination.
  • the concentrations of MC, CS and NaCMC were chosen such that they would provide a viscosity of 4.0 cps at 25°C.
  • the rheological profile was determined by using a Bohlin CS Rheometer. A 4° cone and 40 mm diameter plate (CP 4/40) at a gap width of 0.15 mm was used. Viscosity was determined at 25°C. Shear stresses applied were from 0.06 to 139 Pa. The corresponding shear rate and viscosity was calculated by the Bohlin software after 200 seconds of integration or whenever the system approved steady state was reached.
  • Viscosity Results Based on the applied shear stress, the Bohlin CS Rheometer calculates the shear rate and apparent viscosity at that shear rate.
  • the logarithm of viscosity in Pascal seconds (Pas) is plotted on the Y-axis against the corresponding shear rate in reciprocal seconds (1/s) on the X-axis.
  • the extent of the plateau varies with different viscoelastics.
  • the intercept of the plateau on the Y-axis is considered as zero shear viscosity.
  • proportional weight of PROVISC was always kept at 1, while that of the irrigating solution was increased upto 10.
  • the various additives listed in the column of Product Name were added to BSS PLUS ® part I.
  • Various mixtures listed here were prepared by the methods discussed above.
  • the viscosity drop upon dilution was much less than observed with the BSS PLUS ® control.
  • the resultant viscosity was 12 times higher than control; at 1 :2 dilution it was 40 times higher than control; and at 1:3 dilution, it was 130 times higher than control. This behavior is indicative of the HA interaction with HPMC.
  • the resultant composition is resistant to dilution, as illustrated graphically in FIGURE 1.
  • HPMC concentration above a critical value of 0.18% causes a substantial jump in the viscosity of the mixture. In the range of 0.21 to 0.27% HPMC, viscosity leveled off.
  • MC was tested only at a concentration of 0.22% and NaCMC was tested only at 1%.
  • MC showed strong interaction with HA to the point that it overcame the effect of dilution, with the resultant viscosity even higher than that of PROVISC (Table 4).
  • NaCMC showed little interaction with HA, being only slightly higher than the control and substantially less than HPMC or MC, based on the viscosity data.
  • HPMC, NaCMC and MC have different substituents on anhydroglucose units of natural cellulose at the same site on the molecule.
  • MC has a methyl group
  • HPMC has hydroxypropyl group
  • NaCMC has a sodium carboxymethyl group.
  • MC and HPMC have one additional methyl group on the opposite side, which is absent for NaCMC. Additionally, NaCMC is an ionic polymer, unlike HPMC and MC. As can be seen from the above, HPMC, MC and CS appear to have a strong interaction with HA while NaCMC appears to have a weak interaction with HA, if any. There appears to be some basic difference in the interaction to the different polymers, resulting in different physical properties of the different compositions. When HPMC and MC interact with HA, there is a large impact on viscosity. HPMC and MC are both surface active polymers, so they reduce surface tension of the mixture and thus make the mixture more dispersive. Surface tension of various solutions are listed in Table 6 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé destiné à mettre en oeuvre de la viscochirurgie et une thérapie intra-articulaire ainsi qu'une composition viscoélastique résistante à la dilution. L'un des modes de réalisation de la composition résistante à la dilution comprend un agent viscoélastique à base de hyaluronate et une solution contenant du polymère à faible viscosité. L'agent viscoélastique à base de hyaluronate peut consister en du hyaluronate de sodium à solution aqueuse possédant un poids moléculaire moyen supérieur à 750 000 daltons et une concentration en poids comprise entre 0,5 et 10 %. La solution contenant du polymère peut contenir un polymère sélectionné dans le groupe constitué de sulfate de chondroitine et de méthylcellulose. L'un des modes de réalisation peut contenir une solution contenant du polymère comportant de la méthylcellulose en concentration en poids comprise entre 0,05 % et environ 5 % et du sulfate de chondroitine dans une concentration en poids comprise entre environ 0,1 et 10 %.
PCT/US2005/024723 2005-07-11 2005-07-11 Compositions viscoelastiques resistantes a la dilution WO2007008206A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2005/024723 WO2007008206A1 (fr) 2005-07-11 2005-07-11 Compositions viscoelastiques resistantes a la dilution

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2005/024723 WO2007008206A1 (fr) 2005-07-11 2005-07-11 Compositions viscoelastiques resistantes a la dilution

Publications (1)

Publication Number Publication Date
WO2007008206A1 true WO2007008206A1 (fr) 2007-01-18

Family

ID=35958077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/024723 WO2007008206A1 (fr) 2005-07-11 2005-07-11 Compositions viscoelastiques resistantes a la dilution

Country Status (1)

Country Link
WO (1) WO2007008206A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2617576A (en) * 2022-04-12 2023-10-18 Hyaltech Ltd Ophthalmological viscoelastic composition

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136782A2 (fr) * 1983-08-09 1985-04-10 Nestle S.A. Compositions de sulfate de chondroitine/hyaluronate de sodium
WO2003057187A1 (fr) * 2001-12-21 2003-07-17 Alcon, Inc. Combinaisons de produits viscoelastiques a l'usage de la chirurgie
WO2003059391A2 (fr) * 2001-12-21 2003-07-24 Alcon, Inc. Produits viscoelastiques pour chirurgie oculaire
US20040082540A1 (en) * 2001-11-13 2004-04-29 Hermida Ochoa Elias Humberto Use of a mixture of sodium hyaluronate and chondroitin sulfate for the treatment of osteoarthritis
US20040241155A1 (en) * 2001-12-21 2004-12-02 Shah Mandar V. Dilution resistant viscoelastic compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136782A2 (fr) * 1983-08-09 1985-04-10 Nestle S.A. Compositions de sulfate de chondroitine/hyaluronate de sodium
US20040082540A1 (en) * 2001-11-13 2004-04-29 Hermida Ochoa Elias Humberto Use of a mixture of sodium hyaluronate and chondroitin sulfate for the treatment of osteoarthritis
WO2003057187A1 (fr) * 2001-12-21 2003-07-17 Alcon, Inc. Combinaisons de produits viscoelastiques a l'usage de la chirurgie
WO2003059391A2 (fr) * 2001-12-21 2003-07-24 Alcon, Inc. Produits viscoelastiques pour chirurgie oculaire
US20040241155A1 (en) * 2001-12-21 2004-12-02 Shah Mandar V. Dilution resistant viscoelastic compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ARSHINOFF S: "USING THE DISPERSIVE-COHESIVE VISCOELASTIC SOFT-SHELL TECHNIQUE WITH DIFFERENT OPHTHALMIC VISCOSURGICAL DEVICES", OPHTHALMIC PRACTICE, MEDICOPEA INTERNATIONAL, MONTREAL, CA, vol. 18, no. 5, 2000, pages 224 - 226, XP009009473, ISSN: 0832-9869 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2617576A (en) * 2022-04-12 2023-10-18 Hyaltech Ltd Ophthalmological viscoelastic composition
WO2023198737A1 (fr) * 2022-04-12 2023-10-19 Hyaltech Ltd. Composition ophtalmologique viscoélastique

Similar Documents

Publication Publication Date Title
US8529938B2 (en) Combinations of viscoelastics for use during surgery
WO2005097225A1 (fr) Nouvelle composition viscoelastique, procede d'utilisation et conditionnement
US20060110459A1 (en) Triple natural polymer viscoelastic composition
US7578809B2 (en) Surface modified viscoelastics for ocular surgery
US7060297B2 (en) Carrageenan viscoelastics for ocular surgery
JP2010070556A (ja) 外科手術間の使用のための粘弾性剤の組み合わせ
AU2005231687B2 (en) New free-radical scavenger containing viscoelastic composition, methods of use and package
JP2008308503A (ja) 改良された流動特性を有する眼内潅流溶液
AU2005216946B2 (en) Alginate viscoelastic composition, method of use and package
US7363928B2 (en) Dilution resistant viscoelastic compositions
WO2003059391A2 (fr) Produits viscoelastiques pour chirurgie oculaire
US20060003964A1 (en) Dilution resistant viscoelastic compositions
WO2006012155A1 (fr) Composition viscoelastique a base de gomme xanthane pour la viscochirurgie
WO2007008206A1 (fr) Compositions viscoelastiques resistantes a la dilution
JP2004530452A (ja) 外科手術において使用するための非吸引性遷移粘弾性物質

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05774793

Country of ref document: EP

Kind code of ref document: A1