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    • 专利摘要:
    An improved intraocular wash solution is presented. This solution has an elevated viscosity, thereby reducing the turbulence of the solution and reducing the risk of damage to the intraocular tissue during intraocular surgery by inhibiting the movement of tissue debris and air bubbles. The solution also preferably has a controlled surface tension that is closer to the surface tension of the ocular waterproof.
    公开号:KR20030063441A
    申请号:KR10-2003-7008262
    申请日:2001-12-11
    公开日:2003-07-28
    发明作者:만다르 브이. 샤；미카일 보우크니；윌리암 에이치. 가너；케리 엘. 마크와르트；우데이 도시
    申请人:알콘, 인코퍼레이티드；
    IPC主号:
    专利说明:

    Intraocular cleaning solution with improved flow properties {INTRAOCULAR IRRIGATING SOLUTION HAVING IMPROVED FLOW CHARACTERISTICS}
    [1] The present invention relates to the field of intraocular surgery. More specifically, the present invention relates to the cleaning of intraocular tissue during cataract surgery, vitrectomy, and other intraocular procedures. The present invention provides an intraocular wash solution having improved physical properties (eg, flow characteristics) compared to conventional eye wash solutions.
    [2] Over the last two decades, the field of intraocular surgery has been radically advanced. Advances in this field have resulted in significant improvements in the field of surgical methods, surgical equipment and related pharmaceutical products. Despite these advances, intraocular surgery still remains a very demanding process in that both the tissue of the eye and ultimately the vision of the patient are prone to damage and there is little room for error. Therefore, there is a need to continuously improve not only the relevant pharmaceutical products but also ophthalmic surgery methods and equipment.
    [3] The present invention is the result of an effort to improve the fluid dynamics of intraocular lavage solutions in order to better protect sensitive intraocular tissues while at the same time enhancing the ability of the ophthalmologist to perform the surgical procedure more effectively.
    [4] When cataracts have been used, various methods have been conventionally used to remove the natural lens of the eye, but today most cataract surgeries are performed by a method known as "phacoemulsification". This method uses a surgical handpiece having a tip that vibrates at the ultrasonic frequency. The vibrating tip of the handpiece is used to collapse or "emulsify" the cataract lens. This method inevitably produces in the eye debris or particles that can cause irreparable physical damage to corneal endothelial cells when left unprotected. Corneal endothelial cells are usually protected during phacoemulsification by injecting a viscoelastic material (eg, hyaluronic acid) into the eye to form a protective barrier over the corneal endothelial cells. However, despite the presence of viscoelastic material, the lens particles continue to move in the eye prior to the insertion of the intraocular lens, especially when the viscoelastic material is removed by a mixed washing / suction handpiece and phacoemulsification of the lens.
    [5] Due to the continuous washing and aspiration, there is a large number of vortices in front of the non-drained lens fragments that are generally moving inside. In addition, the ultrasonic vibration generated by the tip of the phacoemulsification handpiece pushes the lens fragment away from the tip, making it difficult for the debris to be drawn out through the suction line of the handpiece tip. Movement of these lens debris can cause damage around the tissue.
    [6] In addition to lens debris, it can also be directly damaged by turbulent flow of intraocular fluid or bubbles generated in the intraocular fluid by phacoemulsification handpieces. Air bubbles generated during intraocular surgery have been shown to cause severe damage to the corneal endothelium within a short time. Turbulent flow of the fluid also results in tissue fragments that affect sensitive corneal endothelial cells or other intraocular tissues, which can cause mechanical trauma to such tissues.
    [7] In addition, for background on this issue, see Kim, et al., “Corneal endothelial damage by air bubbles during phacoemulsification,” Archives of Ophthalmology , volume 115, pages 81-88, 1997; Beesley et al., "The effects of prolonged phacoemulsification time on the corneal endothelium", Annals of Ophthalmology , volume 18, no. 6, pages 216-219, 1986; Kondoh et al., "Quantitative measurement of the volume of air bubbles formed during ultrasonic vibration", Folia Ophthalmogica Japan , volume 45, no, 7, pages 718-720, 1994 and Kim, et al. .) Investigative Ophthalmology & Visual Science , volume 37, no. 3, S84, 1996.
    [8] The hydrodynamics of intraocular wash solutions are also important for vitrectomy procedures and other various intraocular procedures. Turbulent flow in the intraocular fluid can also result from the reciprocating movement of the vitrectomy handpiece, the alternating vacuum and cleaning regime of the wash / suction handpiece, and the action of other surgical handpieces and equipment used in this process. Removal or reduction of such turbulence helps protect tissues located in the anterior eye of the eye, such as corneal endothelial cells, as well as retinas and other tissues present in the eye's posterior eye.
    [9] Given this possible problem, (1) it reduces potential turbulence in the anterior and posterior of the eye, (2) helps to inhibit the movement of tissue debris and air bubbles in the eye, and (3) the doctor's surgical hand There is a need for an intraocular wash solution with improved properties that facilitates removal of debris and other tissue debris by making it easier to locate debris using the tip of the piece. The present invention meets these needs. In particular, the present invention relates to the provision of a wash solution that favorably inhibits the movement of tissue debris, air bubbles and other particles during phacoemulsification, vitrectomy and other intraocular procedures. This inhibition of particle motion is fundamentally different from using the layer of viscoelastic material discussed above, which protects the endothelial cells of the cornea by a buffering effect. The wash solution of the present invention is designed to provide a protective effect beyond that obtained by viscoelastic formulations.
    [10] Summary of the Invention
    [11] The present invention provides an intraocular lavage solution that is essential for suppressing the risk of damage to intraocular tissues while promoting the efficiency of the surgical procedure. The wash solution of the present invention is a low viscosity solution that produces less turbulence in the presence of phacoemulsification handpieces and other intraocular surgery equipment. These solutions also impede the movement of air bubbles and tissue debris in the eye, and are generally ultrasonic handpieces, liquefracture handpieces, cleaning / aspirating handpieces, microscissors, vitrectomy handpieces and their Buffers the influence on the guiding tissue of the external surgical equipment. The suppressed movement of lens debris within the eye protects the eye tissue and allows the ophthalmologist to more easily locate and remove the lens debris, thereby enabling a more effective surgical procedure.
    [12] The intraocular wash solution of the present invention has a greater viscosity than the ocular waterproof, but preferably has a surface tension similar to the ocular waterproof. Current cleaning solutions have a viscosity similar to eye waterproofing, but have a higher surface tension than eye waterproofing.
    [13] The present invention provides a slight increase in the viscosity of the intraocular wash solution, as it generally reduces turbulence of the intraocular fluid and inhibits the movement of tissue debris, thereby making it easier to track and aspirate removal of debris. It was found that the protection of the solution was significantly increased. In addition, a slight increase in the viscosity of the wash solution is also beneficial for the vitrectomy procedure because it reduces pulsatile movement of the retinal tissue and limits lateral tissue damage of the eye. Reduction of the pulsatile movement of the retinal tissue is particularly important when the retina is partially detached.
    [14] The overall performance of the cleaning solution according to the present invention can be further improved by preparing a more physiological solution by including a formulation which reduces surface tension to a level equivalent to ocular waterproofing.
    [15] Brief description of the drawings
    [16] 1 is a graph showing the effect of viscosity on flow rate; 2 is a graph depicting the correlation between HPMC and cumulative ratios.
    [17] Detailed description of the invention
    [18] The wash solution of the present invention comprises an equilibrium electrolyte solution and a biologically suitable viscosity modifier in an amount sufficient to elevate the viscosity of the electrolyte solution.
    [19] The electrolyte solution used in the present invention is a BSS ™ (balanced salt solution) sterilized washing solution prepared by Alcon Laboratoris, Inc., or a BSSPLUS ™ (balanced salt solution) sterilized washing solution prepared by Alcon Laboratoris, Inc. Such as conventional balanced salt solutions. However, the present invention is not limited to the type of balanced salt solution or other electrolyte / nutrient solution that can be used as a building block for the solution of the present invention.
    [20] Agents used to control the viscosity of the electrolyte solution include one or more compounds suitable for intraocular tissues, such as chondroitin sulfate, sodium hyaluronate or other proteoglycans; Cellulose derivatives such as hydroxypropyl methyl cellulose ("HPMC"), carboxy methylcellulose ("CMC") and hydroxyethyl cellulose ("HEC"); Collagen and modified collagen; Galactomannans such as guar gum, locust bean gum and tara gum, as well as polysaccharides derived from the natural gums described above and similar natural or synthetic gums containing mannose and / or galactose moieties as main structural components Propyl guar); Xanthan gum; Gellan gum; Alginate; Chitosan; Polyvinyl alcohol; Carboxyvinyl polymers (such as carbomers such as the Carbopol ™ brand available from BFGoodrich; and various other viscosity or viscoelastic materials, and include, but are not limited to, US Pat. No. 5,409,904 to Hecht et al. And all the contents of the cited references are incorporated herein by reference.
    [21] For further details regarding the viscosity raising agents listed above, reference may be made to the following patent publications: US Pat. No. 4,861,760 (gellan gum); US Patent No. 4,255,415 and WIPO Publication WO 94/10976 (polyvinyl alcohol); U.S. Patent 4,271,143 (carboxyvinyl polymer); WIPO Publication No. WO 99/51273 (xanthan gum); And WIPO Publication No. WO 99/06023 (galactomannan). All contents of the structure, chemical properties and physical properties of each of the above-mentioned viscosity raising agents belonging to the above cited documents are incorporated herein by reference.
    [22] The viscosity modifier described above will be used in an amount sufficient to provide an elevated viscosity to the wash solution of the present invention. The expression “elevated viscosity” as used herein generally means a viscosity greater than that of eye waterproof and conventional wash solutions having a viscosity of about 1 centipoise (“cps”). Wash solutions of the present invention typically have a viscosity of about 15 cps or less, in excess of 1 cps, and preferably a viscosity of about 2 cps to about 7 cps.
    [23] The amount of viscosity modifier used will depend upon the degree of viscosity increase desired and the particular formulation or formulation chosen. However, the concentration of the viscosity modifier in the wash solution according to the invention will typically be in the range of about 0.1 to about 1.0 weight / volume ("w / v%"), for example for polymers such as HPMC.
    [24] It should be noted that it is necessary to strike a balance between (a) raising the viscosity of the solution and (b) maintaining the viscosity acceptable for the cleaning / aspiration system applied during the intraocular procedure. 1 of the accompanying drawings is a graph showing the flow rate of the wash solution with distinct viscosity through a standard wash / suction tip in a Series 20000 Legacy ™ (“STTL”) surgical system available from Alcon Laboratories, Inc. . During the calculation of this data, all settings on the STTL system were in accordance with the instrument's default settings. In FIG. 1, the effect of elevated viscosity on the flow rate of the wash solution, generally flowing under gravity, is clearly indicated.
    [25] During the procedure, aspiration is performed through the tip of the surgical handpiece by applying a vacuum. In general, the maximum vacuum or maximum suction capacity of the system allows the cleaning rate to be higher than the suction rate in order to maintain the actual flow. Therefore, the viscosity of the wash solution must be increased to maintain the flow rate higher than the maximum draft rate. Figure 2 of the accompanying drawings illustrates this issue.
    [26] Elevated concentrations of viscosity modifiers increase the viscosity of the solution and, therefore, at the same vessel height, the flow rate of the wash fluid supplied to the eye by standard gravity is reduced. As the final wash rate decreases, the effective withdrawal rate controlled independently by the STTL peristaltic pump increases. Thus, the cumulative rate shifts from positive to negative. A minimum wash rate of 1 ml aspiration per minute is required to prevent tissue depletion. These competitive factors must be balanced. For HPMC, it was determined that HPMC at a concentration of 0.27 w / v% did not interfere with standard wash and aspiration functions and provided the desired level of viscosity rise. It is noted that this ideal concentration was determined using HPMC (E4M) with STTL surgical system and standard phacoemulsification tip. The ideal concentration may vary, depending on the surgical system and the phacoemulsification tip used.
    [27] Preferred viscosity modifiers are hydroxypropylmethylcellulose ("HPMC"). In the present invention, it was found that adding HPMC to a conventional balanced salt solution resulted in a significantly reduced turbulence during intraocular surgery compared to turbulence observed when using only the balanced salt solution. The preferred concentration of HPMC is about 0.2 to 0.3 w / v%, but this range may vary somewhat depending on the particular ophthalmic system and instrument settings of the system used. Wash solutions containing this concentration of HPMC will have a viscosity of about 4 to 6 cps. Most preferred are viscosity modifiers with a concentration of HPMC (E4M) of 0.22 to 0.27 w / v%.
    [28] As mentioned above, the wash solution of the present invention also preferably comprises an agent that adjusts the surface tension of the solution to be similar to the surface tension of the ocular waterproof. The surface tension of eye waterproofing is about 50 dynes per centimeter ("dynes / cm"). Thus, the wash solution of the present invention preferably has a surface tension in the range of 40 to 60 dynes / cm or slightly lower.
    [29] It should be noted that the viscosity may be increased by a suitable formulation that does not affect surface tension, and the surface tension may be reduced to the level of ocular waterproof / vitreous fluid by including an appropriate surface active agent independent of viscosity. Thus, these two physical properties of the wash solution are independent of each other. However, in some cases, viscosity modifiers may also function as surface tension modifiers. This is demonstrated by the preferred embodiment of the present invention, where HPMC is used which functions as both a viscosity modifier and a surface tension modifier.
    [30] In other cases, it may be necessary to add a separator to the wash solution for the purpose of reducing the surface tension of the solution. Possible formulations that can be used for this purpose include polyoxyl 35 castor oil (Cremophore ™ EL and Cremophore ™ EL-P; BASF Corp.), polyoxyl 40 hydrogenated castor oil (HCO- 40), Sollutol ™ HS 15 (BASF Corp.), Polysorbate 80, Tocophersolan (TPGS) and other ophthalmically acceptable surfactants.
    [31] The following examples are provided to further illustrate various features of the present invention.
    [32] Example 1
    [33] ingredient Volume (w / v%) function HPMC (E4M) 0.1 to 0.3 Viscosity and Surface Tensioning Agent Sodium chloride 0.744 Appearance Potassium chloride 0.0395 Essential ions Dibasic Sodium Phosphate (anhydride) 0.0433 Buffer Sodium bicarbonate 0.219% + 20% XS Menstrual buffer Hydrochloric acid pH adjustment pH regulator Sodium hydroxide pH adjustment pH regulator Water for injection 100% Excipient
    [34] The formulations described above can be prepared as follows: First, the water for injection is brought to a near boiling or boiling point. Then slowly add to the water under constant stirring so that the HPMC is completely dispersed in the water. Continue stirring and slowly cool the mixture. As soon as room temperature is reached, the mixture should begin to become clear. The mixture is then stored overnight in a suitable container to fully hydrate the HPMC. The next day, the remaining ingredients are added to the HPMC solution, additional water for injection is added, if necessary, even if the solution has a final volume, the final solution is filtered, put into a container and autoclaved. Example 2
    [35] ingredient Volume (w / v%) function HPMC (E4M) 0.1 to 0.3 Viscosity and Surface Tensioning Agent Sodium chloride 0.64 Appearance Potassium chloride 0.075 Essential ions Calcium Chloride (Dihydrate) 0.048 Essential ions Magnesium Chloride (hexahydrate) 0.03 Essential ions Sodium Acetate (Trihydrate) 0.039 Buffer Sodium Citrate (Dihydrate) 0.17 Buffer Hydrochloric acid pH adjustment pH regulator Sodium hydroxide pH adjustment pH regulator Water for injection 100% Excipient
    [36] The formulations may be prepared according to the methods described in Example 1 above.
    [37] Example 3
    [38] Three solutions were prepared and an experiment was conducted to evaluate the physical properties of the solution of the present invention versus the related solution. The individual properties of the test solution and the solution are as follows:
    [39] solution Molar osmotic pressure mOsm / kg Viscosity (cps) Surface tension dyne / cm 2BSS * 304,305 1.02, 1.06 70,73 BSS + 0.05% Cremophor 305,305 0.99, 1.01 43,43 BSS + 0.3% HPMC (E4M Grade) 320,322 6.9, 7.0 48,49
    [40] * The term " BSS " as used in the table means BSS ™ (Equilibrium Salt Solution) sterilizing wash solution manufactured by Alcon Laboratories, Inc., Fort Worth, Texas.
    [41] As described above, 0.3% of HPMC was added to the BSS solution to increase the viscosity from about 1 cps to 7 cps and to reduce the surface tension from about 71.5 dynes / cm to about 48.5 dynes / cm. Thus, adding HPMC in this amount, according to the basic principles of the present invention, increased the viscosity of the balanced salt solution and reduced its surface tension. Conversely, adding 0.05% cremophor to the balanced salt solution had no effect on the viscosity, but reduced the surface tension of the balanced salt solution from about 71.5 dyne / cm to 43 dyne / cm.
    [42] The above-mentioned solutions were tested in the simulated intraoperative model to see if the addition of cremophor and HPMC to the equilibrium solution affected the performance of the solution in relation to the turbulence of the solution during the intraocular procedure. Cremophore addition to the balanced salt solution was observed to have little effect on the performance of the balanced salt solution, although this was effective for reducing the surface tension of the solution. However, it was proved that solutions containing HPMC showed much less turbulence than in the balanced salt solution alone. This turbulence was determined based on the movement of air bubbles and the movement of lens fragments.
    [43] The rotation and circulation of lens debris observed in the equilibrium salt solution alone was significantly reduced by including HPMC in the solution. It was easier to remove the particles from the eye during the simulation procedure due to the inhibition of the lens particles movement. This inhibitory effect allows for a more effective surgical procedure and reduces the time required for surgery.
    [44] Conversely, there was no difference between the balanced salt solution alone and the balanced salt solution containing cremophors in terms of bubble formation, flow rate or visible fluid dynamics of the wash solution.
    [45] From the above results, it is clear that the addition of a small amount of viscosity improving agent reduces turbulence of intraocular fluid during the surgical procedure, inhibits the movement of air bubbles and lens fragments, and generally allows for a more effective surgical procedure.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] An intraocular wash solution comprising an amount of a viscosity modifier and an ophthalmically acceptable excipient sufficient to elevate the viscosity of the solution.
    [2" claim-type="Currently amended] The wash solution of claim 1 wherein the solution comprises a viscosity modifier in an amount sufficient to provide a solution having a viscosity in excess of 1 cps.
    [3" claim-type="Currently amended] The wash solution of claim 2 wherein the solution comprises a viscosity modifier in an amount sufficient to provide a solution that has a viscosity of greater than 1 cps and a viscosity of 50 cps or less.
    [4" claim-type="Currently amended] 4. The wash solution of claim 3 wherein the solution comprises a viscosity modifier in an amount sufficient to provide a solution having a viscosity of 2 cps to 7 cps.
    [5" claim-type="Currently amended] The method of claim 1 wherein the viscosity modifier is selected from the group consisting of proteoglycans, cellulose derivatives, collagen or modified collagen, galactomannan, xanthan gum, gellan gum, alginate, chitosan, polyvinyl alcohol and carboxyvinyl polymers. Washing solution.
    [6" claim-type="Currently amended] The washing solution of claim 5 wherein the viscosity modifier comprises hydroxypropyl methylcellulose.
    [7" claim-type="Currently amended] The wash solution of claim 1 wherein the solution further comprises a surface tension modifier in an amount sufficient to provide a solution having a surface tension in the range of 40 to 60 dynes / cm.
    [8" claim-type="Currently amended] The wash solution of claim 1 wherein the elevated viscosity of the solution reduces turbulence of the solution during the intraocular procedure.
    [9" claim-type="Currently amended] A method of reducing turbulent flow of intraocular fluid during intraocular surgery, comprising washing intraocular tissue using the solution of claim 1.
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    同族专利:
    公开号 | 公开日
    AU2002239601B2|2005-09-01|
    WO2002049614A2|2002-06-27|
    CY1110703T1|2015-06-10|
    ES2339745T3|2010-05-25|
    HK1055251A1|2010-05-20|
    AU3960102A|2002-07-01|
    TWI290050B|2007-11-21|
    PT1343474E|2010-04-19|
    KR20070087252A|2007-08-27|
    WO2002049614A3|2003-01-23|
    DE60141477D1|2010-04-15|
    DK1343474T3|2010-05-17|
    US20080020017A1|2008-01-24|
    EP1343474B1|2010-03-03|
    JP2005502581A|2005-01-27|
    EP1343474A2|2003-09-17|
    US20050148542A1|2005-07-07|
    AT459337T|2010-03-15|
    CA2431368A1|2002-06-27|
    KR100767159B1|2007-10-15|
    ZA200303557B|2005-05-25|
    CA2431368C|2006-08-08|
    BR0116353A|2005-04-05|
    JP2008308503A|2008-12-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-12-20|Priority to US25757000P
    2000-12-20|Priority to US60/257,570
    2001-12-11|Application filed by 알콘, 인코퍼레이티드
    2001-12-11|Priority to PCT/US2001/048094
    2003-07-28|Publication of KR20030063441A
    2007-10-15|Application granted
    2007-10-15|Publication of KR100767159B1
    优先权:
    申请号 | 申请日 | 专利标题
    US25757000P| true| 2000-12-20|2000-12-20|
    US60/257,570|2000-12-20|
    PCT/US2001/048094|WO2002049614A2|2000-12-20|2001-12-11|Intraocular irrigating solution having improved flow characteristics|
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