MXPA99003868A - Improved intraocular irrigating solution containing a polyamine antagonist - Google Patents

Abstract

Pharmaceutical compositions useful in ophthalmic surgery are described. The compositions include one or more polyamine antagonists, and are useful for preventing or treating excitotoxicity associated with ophthalmic surgery. Methods of using the compositions in connection with ophthalmic surgical procedures are also described.

Description

IMPROVED SOLUTION FOR INTRAOCULAR IRRIGATION CONTAINING AN ANTIGONIST OF POLYAMINE BACKGROUND OF THE INVENTION 1. Field of the invention The present invention relates to the field of ophthalmology. More particularly, the invention relates to an improved solution for maintaining the integrin stability and function of ocular tissues during invasive surgical procedures. 2. Discussion of the related technique The surgery vi reoret inal, ie, the surgery involving the vitreous and the retina of the posterior segment of the eye, became common as a result of the development d instrumentation and sophisticated surgical procedures The retina is a very delicate tissue , affected by a variety of diseases, such as diabetic retinopathy and cancer, as well as physical damage caused by accidental damage to the eye. In a case of emergency reoperational surgery, the doctor sometimes faces certain complications as the surgery proceeds and the degree of damage is revealed. As a result, this surgery can last for several hours, while the surgeon develops a strategy to repair the damage to the retina. This type of surgery requires careful and deliberate decision-making, and surgical precision.

REF .: 29801 save as much tissue from the retina, therefore, visual function, where possible. In any case the surgeon wishes to avoid additional damage due to surgical procedure and tissue management. Because the retina is exposed for some time to a potentially hostile environment while it remains open during the surgical procedure, certain means are needed to protect the tissue of the retina. When the anterior segment of the eye is performed, generally cataract extraction with intraocular lens implantation, similar routine precautions against iatrogenic damage are taken. In addition to using careful surgical techniques, these precautions may involve the use It is also preferred, such as sodium hyaluronate and / or chondroitin sulfate, to protect the endothelium of the cornea and the use of a physiological saline solution to wash the lens fragment (s). The anterior segment is bathed in aqueous humor, while the posterior segment contains vitreous humor. The differences in the nature and composition of these two ocular humors are related to their respective functions and the tissues they favor. For example, the aqueous humor contains ascorbic acid, which is secreted from the ciliary processes and has a consistency like that of water. On the other hand, vitreous humor has a viscous consistency, like gel. The avascular tissues of the anterior segment, i.e., crystalline and the cornea, depend on the aqueous humor for nutrients and oxygen and to eliminate the metabolic products. The retina receives its oxygen and nutrients from copious vascular feeding. In summary, the needs of the anterior and posterior tissue segments of the eye are similar in many ways, but some differ. The excito-toxicity leads to neuronal damage due to excessive stimulation of the excitatory amino acid ("EAA excitatory amino acid.) In the internal retina, glutama is the main EAA that allows the amacrine bipolar cells to communicate with the ganglion cell. In the central nervous system, excito-toxicity results from hypoxia, hypoglycemia, or trauma (See, for example, Beal, MF, "Mechanisms of excitotoxicity in neurological diseases," FASEB J., 6: 3338-3344 (1992). ), and Choi, DW "Excitotoxic cell death," J. Neurobiol., 23: 1261-12 (1992).) Retinal toxicity has been observed after intravitreal injection of EAAs, after application of EAAs to the isolated animal retina or glutamate applied exogenously to the ganglion cells in culture, see, e general, Sattayasai, et al. "Morphology of qui squa the te-induced neurotoxicity and in t chicleen retina", Invest. Ophtaimol. ., 28: 106-1 (1987); Tung et al., "A quantitative analysis of the effee of excitatory neurotoxins on retinal ganglion cells in t chick", Visual Neurosci., 4: 217-223 (1990); Sisk et al "Histological changes in the inner retina of albino ra following intravitreal injection of monosodium L-glutamate Graefe s Arch. Clin. Exp. Ophthalmol., 223: 250-258 (1985 Siliprandi et al.," N-rne t hyl -D-aspar ta-e-neurotoxicity in the adult rat retina, "Visual Neurosci 8: 567-573 (1992); Reif-Lehrer et al.," Effects of monosodium glutamate on chick emb ryo retina in culture ", Inves Ophthalmol, Vis. Sci., 14 (2): i 14-124 (1975); Blanks, JC "Effects of monosodium glutamate on the isolated retina chick embryo as a function of age: A morphol ogi cal study Exp. Eye Res. , 32: 105-124 (1981), Olney et al., "The anti-excitotoxic effects of certain anesthetics, analgesics to sedati ve-hypno ti cs", Neurosci Lett., 68: 29-34 (1986); al., CNQX potently and selectively blocks kaina excitotoxicíty in the chick embryo retina ", Soc. Neuros c Absr., 14: 418 (1988); David et al.," Involvement excitatory neu r t ransmi te rs in the damage produced in chi embryo ret inas by anoxia and extracellular high potassiu Exp. Eye Res., 46: 657-662 (1988); Caprioli et al., "Lar retinal ganglion cells are more susceptible to excitotox and hypotoxic injury than small cells", Invest. Pphtalmo Vis. Sci. , 34 (Suppl): 1429 (1993); Cummins et al "Electrophysiology of cultured cells to investígate bas mechamos de damage", Giaucoma Update IV. 59-65 (1991); Sucher et al., "N-methyl-D-aspartate antagonists predicts kainate neurotoxicity in rat retinal ganglion cells vitro", J. Neurosci. , 11 (4): 966-971 (1991). The EAA receptors have been characterized with rhodic metabot or rhodic ionot. Activation of a tabotropic receptacle affects cellular processes via G proteins; while the ionotropic receptors affect the translocation of the mono- and divalent cations through the cell membrane. There are at least three ionotropic receptors that have been named by an agonist that preferably stimulates the receptor. Est receivers have been classified as: N-methyl-D-asparta (NMDA); kainato; and AMPA (2-amino-3 - (3-hydroxy-met i i i soxazol-4-yl) propane) acid. These EAA receptors are distributed differentially in specific cells of the retina. (See, for example, Massey, S "Cell types using glutamate as a neurotransmitter in vertebrate retina," NN Osborne and GJ Chader (Eds Progress in Retinal Research, Ch. 9, Pergamon Pres Oxford, 399-425 ( 1990), and Miller et al., "Excitatory ami acid receptors in the vertebrate retina", Retin Transmitters and Modulators: Models for the Brain, (W.

Morgan, Ed.) CRC Press, Inc., Boca Raton, 1: 123-1 (1985)). The location of these receptors would influence the pathologies associated with glaucoma or internal retinal ischem. For example, the death of the retinal cell of the ganglion has been attributed, in large part, to the NMDA receptor. (See, for example, Sucher et al., "N-methyl-aspartate antagonists prevent Kainate neurot oxicity retinal ganglion cells i n vi ro", J. Neurosci., 11 (4): 96 971 (1991)). Accordingly, NMDA receptors antagonists are neuroprotective; However, not all antagonists of the EAA receptors, distributed in different ways, are neuroprotective of the internal retina through antagonism of the NMDA receptor, Zeevalk et al. "Action of the anti-ischemic agent of ifenprodil on methyl- D-aspartate and kainate-mediated excitotoxicity Brain Res., 522: 135-139 (1990) .Glutamic acid is a neurotransmitter of the retina found naturally in that tissue.Ciert cells within the retina have the capacity synthesize, release, capture and metabolize glutamic acid It has been discovered that glutamic acid, excessive amount, is cytotoxic or neurotoxic to some elements of the retina, especially the retinaal cells of the ganglion. origin of optic nerve fibers that favor vision Glutamic acid is released from the retina during periods of ischemia and perfusion, co may occur when the circulation is stopped ion of the sang and re-starts in the retinal blood vessels. The retinal cells of the ganglion, which are close to vitreous hum, are adversely affected by excessive amounts of glutamic acid. Glutámi acid is possibly released from the retinal cells during anterior treinal surgery if the tissue becomes anoxic or physically traumatized. In this case, glutamic acid may damage retinal cells of the ganglion, possibly other types of retinal cells, unless interaction with their receptors located within those target cells is avoided. One means to avoid is to expose the retinal cells to a glutamic acid antagonist during the surgical procedure. Thus, the spectator cells could be protected from the harmful effects of glutamic acid escaping their toxicity. Because it is known that glutamic acid-producing cells do not exist in the tissues of the anterior segment of the eye, but are found in the retina, there is a greater likelihood that excessive damage by glutamic acid occurs during surgery. 1, compared with surgery of the previous segment. This calls for the inclusion of a glutamic acid antagonist in a physiological saline solution projected to be used during the treoretinal surgery. Although it is an antagonist, it may not be useful for anterior segmen surgery, it is unlikely that their presence means any risk to that tissue. Therefore, this physiological saline solution could also be used safely during surgery of the anterior segment. The present invention is directed to satisfy the need for a physiological irrigation solution containing glutamic acid antagonist to protect the retinal cells during the treoretinal surgery.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to providing an improved irrigation solution that is generally useful for the prevention or treatment of excitotoxicity, and particularly useful for the prevention or treatment of this damage associated with ophthalmic surgery. M specifically, the invention is directed to irrigation solutions comprising: one or more polyamine antagonists, electrolytes for maintaining the stability of the ophthalmic tissues, and a buffer.

Description of the preferred modalities. The eliprodil and the polyamine antagonists of the present invention are a subgroup of EAA antagonists that bind to a single location at the NMDA receptor. These compounds do not produce side effects of the CNS (central nervous system). Eiiprodil and other polyamine antagonists are one of four classes of NMD antagonists (See, for example, Ornstein et al., "Antagonists of the NM receptor complex", DN & P, 7 (1): 5-12 (1994)). Classes include competitive antagonists that antagonize glutamate recognition site, non-competitive channel blockers; glycine antagonists polyamine antagonists, the last two modulate glutamate response on the receptor. The glycine and polyamine regulation sites don distinct As mentioned above, EAA receptor antagonists have been used in the CNS to prevent neuronal damage in the animal models of ischemia hypoglycemia and trauma. Pharmacologically competitive and noncompetitive antagonists do not have the ability to cross the blood barrier of the brain and the fact that they produce undesirable side effects (psychotic omotes) Unlike other NMDA antagonists, polyamine antagonists, such as eliprodil, are they divide through the cerebral blood barrier and produce their actions in modulation site without the typical side effects of noncompetitive antagonists. (See, for example, Lipto S.A., "Prospects for clinically tolerated NMDA antagonist open-channel blockers and alternative redox states of nitr oxide", TINS, 16 (12): 527-532 (1993)). The most preferred polyamine antagonists are certain l-phenyl-piperidinoal-acetal derivatives of the following formula (I): where: Rj. represents a hydrogen atom; a halogen atom; trifluoromethyl group; an alkyl group having 1 to carbon atoms; a hydroxyl group; an alkoxy group having 1 to 4 carbon atoms; a benzyloxy group; group to the loxyl canoe having from 1 to 16 carbon atoms a benzyl loxyl group; or, when R2 represents a hydroxyl group or methoxyl in the 4- position; and R3 represents hydrogen atom; R-. it may also represent a hydroxymethyl group; a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in part of the alkoxy group; R. represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group or an alkoxyl group having 1 to 4 carbon atoms; R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R4 represents an alkyl group having from 1 to 4 carbon atoms, in which case the compounds are in the (±) -eritro form; or, when R. represents a hydrogen atom, R, can also represent a hydrogen atom; and R5 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, or a group of three methoxyl groups in 3-3 positions. - and 5-, of the benzyl radical; and pharmaceutically acceptable addition salts of the same. The compounds of the formula (1) / mentioned above are described in US Pat. No. 4,690,931 (i et al.); however, in that patent the ophthalmic indications for these compounds are not mentioned. Wick al., Also describes methods to synthesize these compounds. The total content of US Pat. No. 4,690,931 is incorporated herein by reference. The most preferred compounds are: 2- [4- (fluorobenzyl) -piperidino] -1- (4-chlorophenyl) -ethanol, also known as eliprodil; 2 - (4-benzylpiperidino) -1- (hydroxyphenyl) -propanol, also known as ifenprodil; pharmaceutically acceptable salts thereof. The structures of eliprodil and ifenprodil are shown below.

European Patent Application No. 0 728 480 discloses a composition for reducing intraocular pressure where this composition includes the compound ifenprodil and preservative (eg, chlorobutanol, sodium benzalkonium chloride dehydroacetate, cetyl pyridinium chloride, phenethyl alcohol, paraoxybenzoate). of methyl or bencentonium chloride). We do not claim these compositions here. These compositions are not to be used in the irrigation of ophthalmic tissue during a surgical procedure, if to be used as eye drops or ointments for the eyes. The irrigation solutions of the present invention will typically contain one or more polyamine antagonists at a concentration from about picomolar (pM) to about 1 millimolar (mM preferably from 0.1 nanolar (nM) to 1 micromolar (μM), more preferably 1 nM at 10 μM The solutions further comprise: electrolytes in an amount effective to maintain tissue stability a buffer in an amount sufficient to maintain the pH of the composition in the range of 6.8 to 8.0.The solutions may also include an energy source , like dextrose, in an amount effective to satisfy the metabolic requirements of the endothelial cells of the cornea and other ophthalmic tissues during the surgical procedure, an effective amount of bicarbonate to maintain the pumping system of the endothelial cells of the cornea and other ophthalmic tissues The irrigation solutions of the present invention They may also include an amount of free radical scavenging compound effective to protect the endothelial cells of the cornea and maintain the normal function of those cells. Preferred free radical scavengers include ascorbate, glutathi and cysteine, as well as esters and analogs and other equivalents of these compounds. The most preferred free radical collector is glutathione. The solutions may contain one more free radical scavenger at a concentration from about 0.01 to about 3 mM / L. The present invention can be applied to various types of ophthalmic irrigation formulations, but will generally be provided in the form of an aqueous solution. As will be appreciated by those skilled in the art, some components of the formulations may need to be segregated before use, due to considerations that involve the chemical stability of certain components, potential for adverse chemical interactions between certain components, and sterilization methods. Suitable for certain components. The most preferred embodiment of the present invention is a two-part product, similar to the BSS Plus * Infra-Red Irrigation Solution (Alcon Laboratories, Inc. Forth Worth, Texas). The product is described in USPatent No. 4,550,022 which is incorporated herein by reference. The polyamine antagonist is added to any of the components, the neutral or the acid, of the BSS Plus * product of two parts, depending on the solubility and stability of the polyamine antagonist under any condition, and its compatibility with the other ingredients. The two part compositions are such that each is individually stable and can be stored separately for long periods. When mixed together, the two parts form a tissue irrigation solution that can be used for surgery for the next 24 hours. The mixed solution useful for eye surgery as it contains the necessary factors to maintain the integrity of the endothelial cell and the thickness of the cornea during ocular surgery and protect the tissue of the retina. The combined irrigation solution contains the ions needed for tissue stability, Ca '', Mg '", Na', K * and Cl", in bicarbonate-phosphate buffer, as well as reduced amounts of glutathione and dextrose. Electrolytes provide in proportions that lead to maintaining physical integrity and metabolism of the endothelial cells of the cornea and other ocular tissues. For this purpose, the irrigation solution typically will contain from about 50 to about 5 M Na *, from about 1 to about M K +, from about 0.1 to about M Ca + i, from about 0.1 to about 10 mM Mg ++ and from about 50 to approximately 500 M Cl. "To maintain the osmotic stability of the cells, the osmolality is at approximately 260 and approximately 300 mOsm preferably in the range of approximately 290 to 3 mOsm, so that the pH is closely matched. physiological of 7.4, the pH of the final irrigation solution is between about 6.8 and about 8.0, preferably from about 7.2 to 7.8 To maintain the fluid pumping system, the bicarbonate concentration in the combined irrigation solution is between about 10 and approximately 50 m To stabilize the pH, an additional buffering agent is provided. The buffer medium is preferably phosphate, which is provided in sufficient quantity such that the final phosphate concentration of the irrigation solution is between approximately 1 and approximately 25 mM dextrose between 0.01 and approximately 3 M glutathione. . The neutral solution provides the phosphate and bicarbonate buffer groups, preferably in the form of sodium dibasic phosphate and sodium bicarbonate. The pH solution is adjusted to approximately the physiological 7.4, preferably between approximately 7.2 and approximately 7.8. As mentioned above, the pH of a bicarbonate-containing solution is preferably above 8.0 to avoid decomposition of the bicarbonate. It has been found, however, that the bicarbonate can be stabilized if it is added to a solution with a pH above 8 and from that value, it is adjusted to a pH between 7 and 8. Therefore, when the neutral solution is prepared , add Na; HP04 before the addition of NaHC03, so that NaHCO;, is dissolved in a solution with a pH ent approximately 8 and 9. The solution is subsequently adjusted with dilute acid, such as H ^ S04, H3P04 or HCl, until the desired fine pH, of the neutral solution. Alternatively, carbon dioxide can be added to adjust the pH. Additional potassium and sodium are provided to the basic solution, in the form of sodium and potassium salts, such as sodium, potassium and chloride glucides, citrates, sulfates, acetates, citrates, lactates. Sodium and potassium are compatible with all the groups present in the finished solution of tissue irrigation, and can add sodium chloride and potassium chloride to any of the solutions or be divided among the solutions. However, because the neutral solution provides the buffer system, it can be added to adjust the pH of the irrigation solution.

The acid solution provides Ca ++, in the form of calcium chloride; Mg ++, in the form of magnesium chloride; glutathione dextrose. The pH is adjusted to about 5, less, to provide long-term stability to dextrose and glutathione. Due to the requirement that the acid solution have a low pH, it is preferable that the volume of the neutral solution greatly exceed the volume of the solution, and that the acid solution contains no buffer. The acid solution can be adjusted below a pH of 5, with a relatively small amount of HCl. Because the acid solution is not buffered, its pH is a reflection of the acid concentration and less acid is required to adjust the pH of a small volume. Large volume of the buffered neutral solution can be adjusted very close to the final pH of the irrigation solution and will not be relatively affected by the addition of small volume of the acid solution. Preferably, ratio of the volume of the neutral solution to the volume of acid solution is about 10 to 1 ha at about 40 to 1. The neutral solution and the acid solution are sterilized and packaged separately, or are contained in sterile conditions by of standard techniques, with the use of autoclave, or the use of sterilizing filters but preferably, by sterilization with heat. Typically, the neutral solution, which preferably contains only inorganic groups, undergoes autoclaving process; while the acid solution, which preferably contains the organic components, undergoes microfiltration. To avoid the need for med volumes in the hospital, which can introduce possible errors and / or contamination, it is highly preferable that the particular volumes of the neutral and acid solutions are packaged so that by adding the total content of the the acid solution, to the total container content of the neutral solution, results in the adequately formulated tissue irrigation solution. The solutions can be mixed up to 24 hours before the surgical procedure without a significant change in pH and without the formation of detectable precipitates, and without degradation. The precautions to maintain sterility of the solutions and ensure the correct mixing of the acid and neutral solutions should not be exaggerated. While manufacturer can take all due precautions to maintain quality control, neglect of the technique can make all these precautions worthless. Any opening of the container, regardless of care to make it, increases the likelihood of contamination in the contents. As a method for elimin sely the possibility of improper mixing reduces the possibility of contamination, the solution can be shipped in a container that has a first chamber for the neutral solution; a second isolated chamber for the acid solution and accessories to communicate the cameras without opening the container. Various types of containers can be used for the shipment of medical solutions. As an example, a container may have a lower chamber containing a measured volume of neutral solution, separated by a membrane of a top chamber containing a measured volume of the solution, or a lyophilized powder, formed from the solution. The lid of the container may include a plunger accessor which, when pressed, causes the sharp prick of a sheet, which hangs therefrom, to rupture the membrane. Subsequently, the container is agitated, moving it, to complete the sterile mixing in. the adequate volume of the acid and neutral solutions. Adequate mixing of the acid and neat solutions can also be effected by aseptically removing acidic solution from its packaging with a sterile syringe and water and aseptically adding the acid solution contained in the neutral solution package through the rubber stopper. Alternatively, a sterile double-ended needle can be used, aseptically inserting the end of the needle into the vial containing the solution and then inserting the other end of the needle into the neutral solution packing, whereby the vacuum inside it transfers the acid solution to the neutral solution. and it mixes. A two-compartment syringe can also be used, with the lyophilized powder the acid solution in one compartment, and a diluent for the powder, in the second compartment. The compartments are separated by means of a removable cap or membrane that can be displaced by pressing the plunger of the syringe, thereby allowing the diluent to combine with powder. Once the powder is dissolved, the resulting solution is then added to the bottle containing the buffered neutral solution, by inserting a cannula attached to the front of the syringe through a stopper on the top of the bottle. The two-part solution of the present invention also provides an advantage in terms of safety a technician could not adequately mix the solutions. The largest volume of the physiological neutral solution, so that toxicity is less likely if the basic solution is used without an acid solution mixing with it. The present invention can be applied in various types of formulations. The preferred formulation is described in the following example.

EXAMPLE 1 The following two-part formulation is similar to BSS Plus® Infra-Red Irrigation Solution, available from Alcon Laboratories, Inc., Fort Worth, Texas, USA. The product, which is described in US Pat. No. 4,550,022 (Garabedian, et al.), Consists of two solutions which are referred to as "Part I" and "Part II respectively." The following description illustrates how the product or similar products. can be modified to incorporate the present invention Part I (neutral solution) is obtained by dissolving sodium chloride, potassium chloride, and anhydrous sodium dibasic phosphate in water for injection at a temperature of about 20 ° C. Sodium bicarbonate is dissolved and more water is added for injection to achieve the desired volume, and IN HCl is added to adjust the pH to about 7.4 The solution is then passed through a Millipore 0.45 micron filter and placed in a The bottle is filled, then emptied, and closed tightly The closed bottle is sterilized by using a autoclave at 121 ° C for approximately 23 minutes. II (acid solution) is obtained by dissolving calcium chloride dihydrate, magnesium chloride hexahydrate, dextrose, eliprodil and glutathione in water for injection. The solution is then sterilized by filtration through a 0.22 micron membrane filter and aseptically filled into a previously sterilized bottle sealed with a rubber stopper previously sterilized. Because many free radicals are oxygen sensitive, the container is bubbled with nitrogen gas. Also, a bed of nitrogen is kept on the solution to displace the air and protect the oxidation solution. Immediately after bubbling the container filled with nitrogen gas, it is hermetically sealed by means of a previously sterilized rubber stopper. When combining Parts I and II, the composition of the resulting formulation is as follows: Ingredients Concentration (mM) Reduced Glutathione 0.01-3.0 The iprodi 1 10"6-10" 2 Bi carbonate 1-50 Calcium 0.1-5 Magnes io 0.1-10 Potassium 1-10 Sodium or 50-500 Phosphate 0.1-5 Glucose 1-25 Sodium hydroxide pH and / or hydrochloric acid adjustment pH adjustment Water for injection c. s.

It is noted that, in relation to this date, the best method known by the applicant to carry out the aforementioned invention is the conventional one for manufacturing the objects or substances to which it refers. Having described the invention as above, it claims as property that contained in the following.

Claims (18)

1. CLAIMS 1. A pharmaceutical composition for irrigating the ophthalmic tissue during a surgical procedure, wherein the composition is characterized in that it comprises: pharmaceutically effective amount of a polyamine antagonist; electrolytes in an effective amount p maintain tissue stability; and a buffer in sufficient quantity to maintain the pH of the composition in the range of 6.8 to 8.0.
2. 2. A pharmaceutical composition for irrigating the ophthalmic tissue during a surgical procedure, wherein the pharmaceutical composition is characterized in that it comprises: a first part and a second part, wherein the first part comprises a neutral solution containing bicarbonate and buffer; and wherein the second pair comprises an acid solution containing a free radical scavenger, an energy source, an antagonist the polyamine, and divalent electrolytes and monovalent electrolytes, which are contained in either the first part or the second part.
3. 3. The composition, according to claim 1 2, characterized in that the polyamine antagonist is: < D where: Ri represents a hydrogen atom; a halogen atom; a trifluoromethyl group; an alkyl group q having from 1 to 4 carbon atoms; a hydroxyl group; alkoxy group having from 1 to 4 carbon atoms; benzyloxy group; an alkanoyloxy group containing from 16 carbon atoms or a benzoyl loxy lo group; or, when it represents a hydroxyl or methoxy group in the 4-R position, represents a hydrogen atom, Ri may also represent a hydroxymethyl group, a carbamoyl group or alkoxycarbonyl group having from 1 to 4 carbon atoms in the of the alkoxy group. R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group or a alkoxyl group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or an alkyl group having 1 to carbon atoms. R4 represents an alkyl group having 1 to 4 carbon atoms, in which case the compounds are in the (±) -eritro form; or, when R3 represents a hydrogen atom, RA can also represent a hydrogen atom; and R5 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, or a group of three methoxyl groups in 3-3 positions. - and 5-, of the benzyl radical; and the pharmaceutically acceptable addition salts thereof.
4. 4. The composition, according to claim 1, 2 or 3, characterized in that the polyamine antagonist is Eliprodil.
5. 5. A composition, according to any of the preceding claims, characterized in that the composition comprises: 0.1 to 5 mM of the free radical scavenger; 1 to 25 mM dextrose; 1 pM to 1 mM of the polyamine antagonist; 50 to 500 mM Na '; 1 to 10 mM of K '; 0.1 to 5 mM Ca "'; 50 to 500 mM Cl"; 10 to 50 mM bicarbonate; and 0.1 to 5 mM phosphate.
6. 6. The composition, according to any of the preceding claims, characterized in that free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.
7. 7. A method for the irrigation of ophthalmic tissue last surgical procedures, wherein the method is characterized in that it comprises applying to the affected ocular tissue a composition comprising: a pharmaceutically effective amount of the polyamine antagonist electrolytes in an amount effective to maintain tissue stability; and a buffer in a sufficient amount to maintain the pH of the composition in the range of 6.8 to 8.0.
8. 8. A method for the irrigation of ophthalmic tissue lasts the surgical procedures, characterized in that it comprises applying to the affected ocular tissue a composition comprising a first part and a second part; The first part comprises a neutral solution containing bicarbonate and a buffer; and the second part comprises an acid solution containing a free radical scavenger, a source of energy, a polyamine antagonist; and divalent electrolytes are monovalent electrolytes in either the first pair or the second part.
9. 9. The method, according to claim 7, characterized in that the polyamine antagonist is: (D where: i represents a hydrogen atom; a halogen atom; a trifluoromethyl group; an alkyl group q having from 1 to 4 carbon atoms; a hydroxyl group; alkoxy group having from 1 to 4 carbon atoms; benzyloxy group; an alkanoyloxy group containing from 16 carbon atoms or a benzoyl loxy lo group; or, when it represents a hydroxyl or methoxy group in the 4-R position; represents a hydrogen atom, Rx can also represent a hydroxymethyl group, a carbamoyl group or alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy group part. R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group or a alkoxyl group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or an alkyl group having 1 to carbon atoms. R represents an alkyl group having 1 to 4 carbon atoms, in which case the compounds are in the (±) -eritro form; or, when R3 represents a hydrogen atom, R4 can also represent a hydrogen atom; and R5 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a group of three methoxyl groups in 3-3 positions. - and 5-, of the benzyl radical; and the pharmaceutically acceptable addition salts thereof.
10. 10. The method, according to claims 7, or 9, characterized in that the polyamine antagonist The iprodi 1.
11. 11. EJ. method, according to claims 7, 9 or 10, characterized in that the composition comprises: 0.1 to 5 mM of the free radical scavenger; 1 to 25 M dextrose; 1 pM to 1 mM of a polyamine antagonist; 50 to 500 mM Na '; 1 to 10 M of K '; 0.1 to 5 mM of Ca "; 50 to 500 M of Cl"; 10 to 50 mM bicarbonate; and 0.1 to 5 mM phosphate.
12. 12. The method according to any of claims 7 to 11, characterized in that the free radical collection is selected from the group consisting of ascorbate, glutathione and cysteine.
13. 13. The use of a polyamine antagonist for the manufacture of a medicament for the irrigation of ophthalmic tissue during surgical procedures, wherein the medicament is characterized in that it further comprises electrolytes in an amount effective to maintain tissue stability; and a buffer, in a quantity sufficient to maintain the pH of the composition in the range of 6.8 to 8.0.
14. 14. The use of a polyamine antagonist, for the manufacture of a two-part medicament, for irrigating phlegm tissue during the surgical procedures where the polyamine antagonist is characterized in that it comprises, in a second part, an aci solution containing a dust collector. free radicals, a source of energy and divalent electrolytes; and in a first part a neutral solution containing bicarbonate and buffer, wherein the first part or the second pair additionally comprises monovalent electrolytes.
15. 15. The use, according to claims 13 or 1 'characterized in that the polyamine antagonist is: < D where: Rx represents a hydrogen atom; a halogen atom; a trifluoromethyl group; an alkyl group q having from 1 to 4 carbon atoms; a hydroxyl group; alkoxy group having from 1 to 4 carbon atoms; benzyloxy group; an alkanoyloxy group containing from 16 carbon atoms or a benzoyl group 1 oxyloyl; or, when it represents a hydroxyl or methoxy group in the 4-R: position. represents a hydrogen atom, R! it may also represent a hydroxymethyl group, a carbamoyl group or alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy group part. R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group or a alkoxyl group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or an alkyl group having 1 to carbon atoms. R4 represents an alkyl group having 1 to 4 carbon atoms, in which case the compounds are in the (±) -eritro form; or, when R3 represents a hydrogen atom, R4 can also represent a hydrogen atom; and R5 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a group of three methoxyl groups in 3-3 positions. - and 5-, of the benzyl radical; and the pharmaceutically acceptable addition salts thereof.
16. 16. The use, according to claims 13, 14 15, characterized in that the polyamine antagonist Eliprodil.
17. 17. The use, according to claims 13, 15 or 16, characterized in that the composition comprises: 0.1 to 5 mM of the free radical scavenger; I at 25 mM dextrose; 1 pM to 1 mM of a polyamine antagonist; 50 to 500 mM Na '; 1 to 10 mM of K *; 0.1 to 5 mM Ca "; 50 to 500 mM Cl"; 10 to 50 mM bicarbonate; and 0.1 to 5 mM phosphate.
18. 18. The use, according to any of claims 13 to 17, characterized in that the free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.