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
  • 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
  • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

• This invention relates to aqueous solutions for use in surgical procedures, and is particularly concerned with an ophthalmic irrigating solution useful for irrigating the human eye during surgery.
• EP-A-0076658 provides a stable sterile ophthalmic irrigating solution which, in addition to correct electrolyte balance, provides factors necessary for continued metabolism in the endothelial cells, maintenance of the fluid transport pump system, and consequential maintenance of proper corneal thickness and clarity.
• This problem is stated to be achieved in EP-A-0076658 by providing a two-part solution system which includes a basic solution and an acidic solution which are individually stable and which, on mixing, form an ocular solution which contains the necessary factors to maintain endothelial cell integrity and corneal thickness during ocular surgery.
• the combined solution contains the necessary ions in a bicarbonate-phosphate buffer as well as oxidised glutathione and dextrose (d-glueose) , the latter being present as an energy source.
• a second problem with the solution system of EP-A-0076658 is that its two-part nature can potentially lead to errors in forming the final ocular solution, a procedure which is normally conducted in a hospital .
• HEPES has been proposed, in the 1980 article "Intraocular irrigating and replacement fluid", M.V. Graham et al, Trans. Opht al . Soc . U.K. (1980) 100, p282-285, as a buffer for an intraocular irrigating solution.
• the 1983 article "A Comparison of HEPES and Bicarbonate Buffered Intraocular Irrigating Solutions: Effects on Endothelial Function in Human and Rabbit Corneas", by Dayle H. Geroski et al, J.
• an ocular irrigating solution for irrigating the eye during surgery comprising, a source of bicarbonate ions and a physiologically acceptable organic buffer which is an organic zwitterionic buffer having a buffering capacity within the range pH 6.8 to 8.0.
• the organic buffer preferably maintains the solution at a pH in the range 7.2 to 7.8 to match the physiological pH of 7.4.
• organic buffer Highly preferred as the organic buffer are the zwitterionic amino acids, such as N-2- [hydroxyethyl]piperazine-N' - [2-ethanesulfonic acid] , commonly referred to as HEPES, which has a pKa of 7.55 at 25°C.
• HEPES zwitterionic amino acids
• BES N,N- bis [2-hydroxyethyl] -2-aminoethanesulfonic acid
• MOPS 3- [N-morpholino] propanesulfonic acid
• TES N-tri
• the organic buffer should be present in the solution in an amount sufficient to buffer the solution over the duration of the surgical procedure. In practice, this means that the concentration of the buffer should be about 10 to 50 mmol/1.
• the bicarbonate source is normally sodium bicarbonate.
• the bicarbonate source is preferably present in the solution to give a bicarbonate concentration of about 10 to 50 mmol/1, preferably from 15 to 25 mmol/ml to maintain the fluid pump system in the endothelium of the eye.
• the ocular irrigating solutions of the present invention are preferably free from glutathione, which - 4 - has previously been considered essential for effective performance .
• irrigation solutions of the invention need not contain an energy source . This is of particular significance so far as glucose is concerned which tends to degrade at physiological pH over extended time periods. Therefore, preferred ocular irrigation solutions of the present invention do not contain glucose, or any other energy source which tends to degrade at physiological pH over extended time periods. If an energy source is to be present in an irrigation solution of the invention, a typical concentration is 2-10 mmol/1.
• the solution of the invention preferably also contains other electrolytes necessary to maintain physiological function, such as Na + , K + , Ca 2+ , and Cl " , but not Mg 2+ , which can lead to the formation of magnesium precipitates in some circumstances. These should be present at concentrations which will permit continued cellular integrity and metabolism. Typically, these electrolytes are present in the following concentrations:
• concentration of Ca 2+ is at least 0.05 mmol/1, and preferably no more than 0.1 mmol/1.
• the osmolality should be between approximately 250 - 350 mosmol/kg, preferably 290 - 320 mosmol/kg, to maintain osmotic stability of the cells.
• phosphate ions normally present in the solution will be a source of phosphate ions, although primarily not for buffering purposes, as in EP-A-00766598 , but for normal physiological function.
• concentration of phosphate in the solution is normally about 1 mmol/1.
• the solution of the invention may be prepared by mixing the components together in aqueous solution, in the desired proportions. It may then be bottled and autoclaved in the normal manner.
• One advantage of the invention is that it may be autoclaved without any deleterious effect. For this reason, components which would degrade to a significant extent under the chosen autoclave conditions should be excluded or reduced in amount to a point at which degradation is minimal. Typical autoclave conditions are 121°C for 15 minutes or 134°C for 3 min.
• the ocular solution of the invention should preferably be free from nutrients of the type normally present in tissue culture media, namely: amino acids, vitamins, hormones, proteins, growth factors, lipids, nucleosides, minerals.
• an aqueous solution comprising a source of bicarbonate ions and a physiologically acceptable organic buffer which is an organic zwitterionic buffer having a buffering capacity within the range pH 6.8 to 8.0, for use in a surgical - 6 - method, preferably a surgical method performed on the eye .
• Figure 1A shows the change in corneal thickness during assessment perfusion following 90 minutes exposure to the "UB-M2" solution in accordance with the invention and "BSS Plus";
• Figure IB shows the change in corneal thickness during perfusion with a solution in accordance with the invention "UB-M2" solution and with “BSS Plus”.
• Example 1 A prior art irrigating solution and an irrigating solution in accordance with the invention were tested in a masked laboratory experiment to evaluate their effectiveness.
• BSS Plus (which is in accordance with EP-A-0076658) was obtained as a two part system and made up as directed. The composition of these solutions along with those of aqueous humour and BSS are shown in Table 1.
• endothelial surface was perfused at 2.5 ml/h, a pressure of 15 cm H 2 0 and 35°C. During the first 90 minutes of perfusion, corneas were exposed to the intraocular irrigation solution. This was followed by a further 6 hours of perfusion during which endothelial - 8 - function was assessed.
• Corneal thickness was measured with an ultrasonic pachymeter (DGH Technologies, Inc) , every 30 minutes. The silicone oil was removed briefly to allow the measurements to be made. Each measurement was the mean of readings taken at four different sites of the central cornea.
• Corneal hydration and, thus, thickness are controlled by the endothelium through a pump leak mechanism. Removal of bicarbonate ions from the perfusate suppresses endothelial pump function and causes corneal swelling, although inhibition of the pump is not complete unless C0 2 is also removed from the perfusate. Pump function can be restored and the swelling reversed by returning bicarbonate to the perfusate. After the 90 minute perfusion with one of the irrigation solutions, endothelial function was, therefore, assessed during a further 6 hours of perfusion with Tissue Culture Medium 199 (TC199) . The first 2 hours of perfusion were with TC199 with Earle's salts (Sigma, M3769) .
• This solution contained sodium bicarbonate (26 mmol/1) , and should have supported endothelial pump function. Two hours of perfusion with TC199 with Hanks' salts (Sigma, M3274) then followed. This solution did not contain bicarbonate ions and, thus, should have caused corneal swelling, although the solution was not C0 2 free. For the final 2 hours, perfusion with TC199 Earle's was restored and, providing that the endothelium was undamaged, corneas should have thinned.
• TC199 solutions contained phenol red, and their measured osmolalities (Roebling osmometer) were 290 and 288 mosmol/kg, - 9 - respectively, for TC199 with Earle's salts and TC199 with Hanks' salts.
• Rates of change in corneal thickness both during perfusion with the irrigation solutions and during the three parts of the assessment perfusion were determined by regression analysis. Comparisons were made between groups by t-tests at the 5% level of significance. The results obtained are shown in Table 2 and are also illustrated graphically in Figure 1A. Table 2
• Example 2 An ocular irrigating solution in accordance with the invention was made up as in Example 1.
• Corneas were dissected, mounted on support rings and perfused as in Example 1 except that the corneas were perfused continuously for a period of 7.5 hours with either BSS Plus or the invention. Paired corneas, from a single rabbit, were perfused, one with BSS Plus and the other with the invention. The allocation of - 10 - corneas to each solution was randomized and masked from the person performing the perfusion. Regression analysis showed no overall change (at the 5% level of significance) in thickness during the course of the perfusion nor was corneal thickness influenced by the type of irrigation solution (see Figure IB) .
• Examples 1 and 2 demonstrate that the invention supports endothelial function at least as well as BSS Plus, despite the absence of components, such as glucose and glutathione, that are considered essential constituents of BSS Plus.

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• 1998
  • 1998-04-07 GB GB9807491A patent/GB2336109A/en not_active Withdrawn
• 1999
  • 1999-04-07 AU AU34303/99A patent/AU3430399A/en not_active Abandoned
  • 1999-04-07 DE DE69914066T patent/DE69914066T2/de not_active Expired - Fee Related
  • 1999-04-07 EP EP99915876A patent/EP1067907B1/en not_active Expired - Lifetime
  • 1999-04-07 WO PCT/GB1999/001066 patent/WO1999051204A1/en not_active Ceased
  • 1999-04-07 PT PT99915876T patent/PT1067907E/pt unknown
  • 1999-04-07 DK DK99915876T patent/DK1067907T3/da active
  • 1999-04-07 AT AT99915876T patent/ATE257371T1/de not_active IP Right Cessation
  • 1999-04-07 ES ES99915876T patent/ES2216502T3/es not_active Expired - Lifetime
  • 1999-04-07 JP JP2000541976A patent/JP2002510613A/ja active Pending
• 2006
  • 2006-03-14 US US11/376,431 patent/US20060177524A1/en not_active Abandoned

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