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
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

• the present invention is directed to the field of intraocular surgery. More specifically, the invention is directed to the irrigation of intraocular tissues during cataract surgery, vitrectomy surgery, and other intraocular surgical procedures.
• the invention provides intraocular irrigating solutions that have improved physical properties (e.g., flow characteristics) relative to prior ophthalmic irrigating solutions.
• the present invention has resulted from an effort to improve the fluid dynamics of intraocular irrigating solutions, so as to provide greater protection for delicate intraocular tissues, while at the same time enhancing the ability of ophthalmic surgeons to perform surgical procedures more efficiently.
• various techniques have been used previously to remove the natural crystalline lens of the eye when it becomes afflicted with a cataract, the majority of cataract surgeries today are performed by using a procedure known as "phacoemulsification". This procedure involves the use of a surgical handpiece having a tip that vibrates at an ultrasonic frequency. The vibrating tip of the handpiece is utilized to disintegrate or "emulsify" the cataractous lens.
• This process necessarily generates lens fragments or particles within the eye that can cause irreparable physical damage to corneal endothelial cells if those cells are left unprotected.
• the corneal endothelial cells are normally protected during the phacoemulsification procedure by injecting a viscoelastic material (e.g., hyaluronic acid) into the eye to form a protective barrier over the corneal endothelial cells.
• a viscoelastic material e.g., hyaluronic acid
• lens particles continue to move in the eye, particularly when the viscoelastic material is removed by a combined irrigating/aspiration handpiece following the phacoemulsification of the lens, prior to insertion of an artificial lens.
• damage may result directly from the turbulent flow of fluids intraocularly or from bubbles generated in the intraocular fluids by the phacoemulsification handpiece.
• Air bubbles generated during intraocular surgery have been shown to result in severe injury to the comeal endothelium in as little as twenty seconds.
• the turbulent flow of fluids may also cause tissue fragments to impact the delicate comeal endothelial cells or other intraocular tissues, thereby causing mechanical trauma to such tissues.
• the fluid dynamics of intraocular irrigating solutions is also important during vitrectomy procedures and various other types of intraocular surgical procedures. Turbulence in intraocular fluids may also result from the movements of reciprocating vitrectomy handpieces, the alternating vacuum and irrigation modes of irrigation/aspiration handpieces and movements of other surgical handpieces and devices utilized in such procedures. The elimination or reduction of such turbulence helps to protect the retina and other tissues located in the posterior segment of the eye, as well as tissues located in the anterior segment of the eye, such as the corneal endothelial cells.
• intraocular irrigating solutions having improved physical properties that: (1) reduce the potential for turbulence within the anterior and posterior chambers of the eye, (2) help to contain the movement of tissue fragments and air bubbles within the eye, and (3) facilitate the removal of lens fragments and other tissue fragments by making it easier for the surgeon to track the fragments with the tip of the surgical handpiece.
• the present invention is directed to fulfilling this need. Specifically, the present invention is directed to the provision of an irrigating solution that provides for greater control of the movement of tissue fragments, air bubbles and other particles during phacoemulsification, vitrectomy and other intraocular surgical procedures.
• the irrigating solution of the present invention is designed to provide a protective effect beyond that obtained by means of viscoelastic agents.
• the present invention is directed to the provision of intraocular irrigating solutions that help to prevent the risk of damage to intraocular tissues, while facilitating the efficiency of the surgical procedures.
• the irrigating solutions of the present invention are low viscosity solutions that exhibit less turbulence in the presence of phacoemulsification handpieces and other intraocular surgical devices. These solutions also restrain the movement of air bubbles and tissue fragments within the eye, and generally dampen the impact of ultrasonic handpieces, liquefracture handpieces, irrigation/aspiration handpieces, microscissors, vitrectomy handpieces and other surgical devices on intraocular tissues.
• the restrained movement of lens fragments within the eye protects ophthalmic tissues, and facilitates a more efficient surgical procedure by enabling the ophthalmic surgeon to locate and remove lens fragments more readily.
• the intraocular irrigating solutions of the present invention have a viscosity greater than that of aqueous humor, but preferably have a surface tension similar to that of aqueous humor.
• Existing irrigating solutions generally have a viscosity similar to that of aqueous humor, but have surface tension higher than that of aqueous humor.
• the present inventors have found that a slight enhancement of the viscosity of intraocular irrigating solutions greatly improves the ability of the solutions to protect intraocular tissues by containing the movement of tissue fragments and generally reducing the turbulence of the intraocular fluids, thereby making it easier for the fragments to be tracked and removed via aspiration.
• This slight enhancement of irrigating solution viscosity is also beneficial in vitrectomy procedures because it reduces the pulsatile movement of the retinal tissue and limits collateral tissue damage in the eye. The reduction of pulsatile movement of retinal tissue is particularly important in cases where the retina is partially detached.
• the overall performance of the irrigating solutions of the present invention can be further enhanced by including an agent which reduces the surface tension to a level comparable to that of aqueous humor, thereby making the solutions more physiological.
• Figure 1 is a graph showing the effect of viscosity on flow rate; and Figure 2 is a graph showing the relationship between HPMC concentration and accumulation rate.
• the irrigating solutions of the present invention comprise a balanced electrolyte solution and an amount of a biologically compatible viscosity-adjusting agent sufficient to enhance the viscosity of the electrolyte solution.
• the electrolyte solution utilized in the present invention will typically be a balanced salt solution, such as BSSTM (Balanced Salt Solution) Sterile Irrigating Solution manufactured by Alcon Laboratories, Inc., or BSS PLUSTM (Balanced Salt Solution) Sterile Irrigating Solution, also manufactured by Alcon Laboratories, Inc.
• BSSTM Battery Salt Solution
• BSS PLUSTM Balanced Salt Solution
• Sterile Irrigating Solution also manufactured by Alcon Laboratories, Inc.
• the invention is not limited relative to the types of balanced salt solutions or other electrolyte/nutrient solutions that may be utilized as a building block for the solutions of the present invention.
• the agents utilized to adjust the viscosity of the electrolyte solution will comprise one or more compounds that are compatible with intraocular tissues, such as: chondroitin sulfate, sodium hyaluronate or other proteoglycans; cellulose derivatives, such as hydroxypropyl methylcellulose ("HPMC"), carboxy methylcellulose ("CMC”), and hydroxyethyl cellulose ("HEC”); collagen and modified collagens; galactomannans, such as guar gum, locust bean gum and tara gum, as well as polysaccharides derived from the foregoing natural gums and similar natural or synthetic gums containing mannose and/or galactose moieties as the main structural components (e.g., hydroxypropyl guar); xanthan gum; gellan gums; alginate; chitosans; polyvinyl alcohol; carboxyvinyl polymers (e.g., carbomers such as the CarbopolTM brand polymers available from B.F.
• the above-described viscosity-adjusting agents will be utilized in an amount sufficient to provide the irrigating solutions of the present invention with an enhanced viscosity.
• enhanced viscosity means a viscosity which is greater than the viscosity of aqueous humor and prior irrigating solutions, both of which generally have viscosities of approximately 1 centipoise ("cps").
• the irrigating solutions of the present invention will typically have viscosities of from greater than 1 cps to about 15 cps, preferably from about 2 to about 7 cps.
• the amount of viscosity adjusting agent utilized will vary depending on the degree of viscosity enhancement desired and the specific agent or agents selected. However, the concentration of the viscosity-adjusting agent in the irrigating solutions of the present invention will typically range from about 0.1 to about 1.0 weight/volume percent ("w/v %") for polymers such as HPMC. It should be noted that it is necessary to achieve a balance between: (a) enhancing the viscosity of the solution, and (b) maintaining a solution viscosity that is acceptable for use with the irrigation/aspiration system employed during intraocular surgical procedures.
• Figure 1 of the accompanying drawings is a graph showing the flow rate of irrigating solutions of different viscosities through a normal irrigation/aspiration tip in the Series 20000 LegacyTM (“STTL”) surgical operating system available from Alcon Laboratories, Inc. During generation of these data, all the settings on the STTL system were default instrumental settings. Figure 1 clearly shows the effect of increasing viscosity on flow rate of the irrigating solution, which is usually flowing under gravity.
• aspiration is carried out by applying vacuum through the tip of a surgical handpiece.
• the maximum vacuum or suction capability of the system is such that the irrigation rate is higher than the aspiration rate to maintain positive flow.
• the increase in viscosity of the irrigation solution should be such that the flow rate remains greater than the maximum aspiration rate.
• the preferred viscosity-adjusting agent is hydroxypropylmethylcellulose (“HPMC").
• HPMC HPMC
• E4M HPMC
• the irrigating solutions of the present invention preferably also include an agent to modify the surface tension of the solutions so as to resemble the surface tension of the aqueous humor.
• the surface tension of the aqueous humor is approximately 50 dynes per centimeter ("dynes/cm).
• the irrigating solutions of the present invention will therefore preferably have a surface tension in the range of 40 to 60 dynes/cm or somewhat less.
• viscosity can be increased by an appropriate agent without affecting surface tension, and that surface tension can be reduced to the level of aqueous/vitreous humor by inclusion of an appropriate surface-active agent independent of viscosity.
• the viscosity-adjusting agent may also function as the surface tension reducing agent. This is true with respect to the preferred embodiment of the present invention, wherein HPMC is utilized both as a viscosity-adjusting agent and a surface tension reducing agent.
• a separate agent to the irrigating solution for purposes of reducing the surface tension of the solution.
• Possible agents which can be utilized for this purpose include: Polyoxyl 35 castor oil (CremophoreTM EL and CremophoreTM EL-P, available from BASF Corp.), Polyoxyl 40 Hydrogenated Castor Oil (HCO-40), SolutolTM HS 15 (BASF Corp.), Polysorbate 80, Tocophersolan (TPGS), and other ophthalmically acceptable surface active agents.
• the above-described formulation 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. Then the mixture is stored overnight in an appropriate container to fully hydrate the HPMC. The following day, the remaining ingredients are added to the HPMC solution, additional water for injection is added if needed to bring the solution to final volume, and the final solution is filtered, packaged in bottles and autoclaved.
• Example 3 The above-described formulation may be prepared by means of the method described in Example 1, above.
• Example 3 The above-described formulation may be prepared by means of the method described in Example 1, above.
• BSS Balanced Salt Solution
• the addition of 0.3% HPMC to the BSS solution increased the viscosity from approximately 1 cps to 7 cps, and reduced the surface tension from approximately 71.5 dynes/cm to approximately 48.5 dynes/cm.
• this amount of HPMC increased the viscosity of the balanced salt solution and reduced its surface tension, in accordance with the basic principles of the present invention.
• the addition of 0.05% cremophor to the balanced salt solution had no effect on viscosity, but reduced the surface tension of the balanced salt solution from approximately 71.5 dynes/cm to 43 dynes/cm.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Gastroenterology & Hepatology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Immunology (AREA)
• Ophthalmology & Optometry (AREA)
• Biomedical Technology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Zoology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Surgery (AREA)
• Medicinal Preparation (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Detergent Compositions (AREA)
• Prostheses (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Materials For Medical Uses (AREA)

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• 2001
  • 2001-12-11 WO PCT/US2001/048094 patent/WO2002049614A2/en not_active Ceased
  • 2001-12-11 KR KR1020037008262A patent/KR100767159B1/ko not_active Expired - Fee Related
  • 2001-12-11 JP JP2002550956A patent/JP2005502581A/ja active Pending
  • 2001-12-11 PT PT01987379T patent/PT1343474E/pt unknown
  • 2001-12-11 ES ES01987379T patent/ES2339745T3/es not_active Expired - Lifetime
  • 2001-12-11 AU AU2002239601A patent/AU2002239601B2/en not_active Ceased
  • 2001-12-11 CA CA002431368A patent/CA2431368C/en not_active Expired - Lifetime
  • 2001-12-11 DK DK01987379.3T patent/DK1343474T3/da active
  • 2001-12-11 AU AU3960102A patent/AU3960102A/xx active Pending
  • 2001-12-11 KR KR1020077017978A patent/KR20070087252A/ko not_active Ceased
  • 2001-12-11 BR BR0116353-1A patent/BR0116353A/pt not_active Application Discontinuation
  • 2001-12-11 EP EP01987379A patent/EP1343474B1/en not_active Expired - Lifetime
  • 2001-12-11 DE DE60141477T patent/DE60141477D1/de not_active Expired - Lifetime
  • 2001-12-11 AT AT01987379T patent/ATE459337T1/de active
  • 2001-12-19 TW TW090131545A patent/TWI290050B/zh not_active IP Right Cessation
• 2003
  • 2003-05-08 ZA ZA2003/03557A patent/ZA200303557B/en unknown
• 2005
  • 2005-02-11 US US11/056,042 patent/US20050148542A1/en not_active Abandoned
• 2007
  • 2007-10-04 US US11/867,523 patent/US20080020017A1/en not_active Abandoned
• 2008
  • 2008-07-08 JP JP2008177713A patent/JP2008308503A/ja active Pending
• 2010
  • 2010-03-19 CY CY20101100252T patent/CY1110703T1/el unknown

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