HK1081455B - Ophthalmologic irrigation solutions and method - Google Patents

Description

Ophthalmic irrigating solutions and methods

I. Field of the invention

The present invention relates to surgical irrigating solutions and methods, particularly irrigating solutions used in ophthalmic procedures.

Background of the invention

Ophthalmic surgery typically requires the application of a physiological irrigating fluid to protect and maintain the physiological integrity of the intraocular tissue. Examples of ophthalmic surgical procedures that typically require irrigating fluids are cataract surgery, corneal transplantation surgery, vitreoretinal surgery, and trabeculectomy for glaucoma.

Solutions for ophthalmic surgical irrigation include normal saline, lactated ringer's solution and Hartmann's lactated ringer's solution, but these solutions are not optimal due to potential adverse corneal and endothelial effects. Other aqueous solutions include agents such as electrolytes, buffers for pH adjustment, glutathione and/or energy sources such as dextrose, which better protect the eye tissue, but do not address other surgical-related physiological processes. One solution often used for ophthalmic irrigation is the two-part buffered electrolyte and glutathione solution disclosed by Garabedian et al in U.S. patent No. 4,550,022, the disclosure of which is specifically incorporated herein by reference. The two parts of the solution were mixed just before use to ensure stability. These solutions are formulated to maintain the health of ocular tissues during surgery.

It has been proposed to modify conventional aqueous irrigation solutions by the addition of therapeutic agents. For example, Gan et al, in U.S. patent No. 5,523,316, disclose irrigation solutions with the addition of one or more intraocular pressure controlling drugs. Specific examples of agents useful for controlling intraocular pressure in the patents disclosed by Gan et al (the disclosures of which are all incorporated herein by reference) are beta-blockers (e.g., beta adrenergic receptor antagonists) and alpha-2 adrenergic receptor agonists. Muscarinic agonists, carbonic anhydrase inhibitors, angiostatic (angiostatic) steroids and prostaglandins are also included as classes of drugs that control intraocular pressure. Drugs designed to control intraocular pressure only.

Another example of a modified solution is disclosed in International PCT application WO94/08602, entitled Gan et al, which is incorporated herein by reference. This application discloses the inclusion of mydriatic agents, such as epinephrine, in ophthalmic irrigating solutions. Another example is provided by International PCT application WO95/16435 (the name of the inventor is Cagle et al) which discloses the inclusion of non-steroidal anti-inflammatory drugs (NSAIDs) in ophthalmic irrigating solutions.

Thomas, in U.S. patent No. 5,811,446, discloses topical ophthalmic solutions that may include histidine and that may include at least one other active drug such as an anti-glaucoma drug (e.g., timolol or phenylephrine), a steroid, or an NSAID. This reference teaches the use of a composition to inhibit inflammation caused by ophthalmic procedures. The solution was administered by instillation into the cul-de-sac of the eye.

U.S. patent No. 5,624,893 to Yanni includes compositions containing an agent that repairs damage, such as a steroid or a growth factor, and/or a pain mediator, such as an NSAID, a bradykinin antagonist, or a neurokinin-1 antagonist. The composition is intended for the treatment and prevention of corneal clouding associated with laser radiation and photoablation (photoablation).

While many topically applied drugs are available or have been planned for treating inflammation of the eye, mydriasis (a typical requirement for performing various types of ophthalmic surgery), or for controlling intraocular pressure, there has been no attempt in the past to apply combinations of these drugs in perioperative ophthalmic irrigating solutions that are applied to ocular tissue throughout the procedure in a delivery manner that enables them to provide sustained, controlled delivery of multiple therapeutic drugs that can act on multiple molecular targets to perform multiple physiological functions.

Various ophthalmic drug delivery methods are routinely used, each of which has limitations. These limitations may include corneal and conjunctival toxicity, tissue damage, perforation of the eye, optic nerve damage, retinal middle artery and/or middle vein occlusion, immediate retinal drug toxicity, and systemic side effects. For example, topical drugs for instillation are often prevented from reaching the eye site of the target organ due to the natural protective appearance of the eye. In many cases, only a small percentage of the drug applied to the exterior of the eye will accurately reach the desired treatment site of action.

One difficulty with ophthalmic drug delivery in surgical procedures is achieving the desired therapeutic concentration levels with proper temporal control. The most desirable pharmacokinetic effect is to be able to quickly reach a therapeutic concentration range and later to maintain the drug concentration at a constant level. Conventional methods of drug delivery by eye are not able to achieve the desired results. The challenges of achieving the same pharmacokinetic effect are compounded to a large extent when it is desired to deliver more than one drug simultaneously. A unique set of factors that can exert the effect of a drug that permeates the corneal epithelium includes the size of the molecule, its chemical structure and its solubility characteristics.

In order to achieve effective delivery concentrations of the drug to the posterior part of the eye, the drug is often administered systemically in very high doses. These levels are necessary to overcome the blood-retinal barrier that protects the back of the eye when acted upon by selected drug molecules from the blood stream. For surgical procedures, injectable drug solutions are sometimes injected directly into the posterior portion of the eye. Subconjunctival and periocular injections are used when higher local concentrations are required and when poorly permeable drugs are to be delivered. In cataract operation, the liquid medicine is directly injected into the front of the atrioventricular by adopting the injection in the atrioventricular. While injection in the chamber provides a rapid means of achieving concentration, associated corneal toxicity may arise. However, this method faces the fact that the drug can be removed rapidly due to the natural circulatory processes of the eye. Thus, injectable solutions quickly lose their therapeutic benefit, often necessitating the use of frequent, large dose injections that can pose a toxic risk. Sustained release formulations, such as viscous gels containing microcapsules, can be injected into the eye for a longer duration of action. However, there may be some delay in achieving a local therapeutic concentration of the drug. Thus, there is a need for a controlled method of delivering ophthalmic drugs in ophthalmic procedures.

Summary of the invention

The present invention provides solutions for the topical delivery of multiple active agents to the eye that act on multiple different molecular targets, which may inhibit inflammation, inhibit pain, effectively mydriasis (pupil dilation), and/or reduce intraocular pressure during perioperative periods. The solutions and methods described herein employ at least first and second therapeutic agents selected from the class of anti-inflammatory agents, analgesics, mydriatic agents, and physiological functions of intraocular pressure-lowering agents (IOP-lowering agents), with the second agent providing at least one physiological function different from the function or functions provided by the first agent. The solution is preferably applied to continuously irrigate ocular tissue at the surgical site during most of the surgical procedure.

The solution of this aspect of the invention may comprise: (a) one or more anti-inflammatory agents in combination with one or more analgesic agents, and optionally further comprising one or more IOP lowering and/or mydriatic agents; (b) one or more anti-inflammatory agents in combination with one or more IOP lowering agents, and optionally one or more analgesics and/or mydriatics; (c) one or more anti-inflammatory agents in combination with one or more mydriatic agents, and optionally one or more analgesic agents and/or IOP lowering agents; (d) one or more analgesic drugs in combination with one or more IOP lowering drugs, and optionally one or more anti-inflammatory and/or mydriatic drugs; (e) one or more analgesic drugs in combination with one or more mydriatic drugs, and optionally one or more anti-inflammatory and/or IOP lowering drugs; or (f) one or more mydriatic agents in combination with one or more IOP-lowering agents, and optionally one or more anti-inflammatory and/or analgesic agents.

The present invention provides a solution that constitutes a low concentration mixture of multiple drugs in a physiological electrolyte carrier fluid that directly inhibits local pain mediators, inflammatory mediators, lowers intraocular pressure, and/or causes mydriasis. The present invention also provides methods for perioperative delivery of irrigation fluids containing these agents, i.e., directly to the surgical site where the irrigation fluid presupposes pain and inflammation limiting, intraocular pressure reducing and/or mydriasis at the local receptor and enzyme levels. Due to the local perioperative delivery method of the present invention, it is desirable to immediately achieve therapeutic effects that can be achieved with lower doses of drug than are required for systemic delivery methods (e.g., intravenous, intramuscular, subcutaneous, and oral) or injection. When continuous irrigation is used during most surgical procedures, in accordance with a preferred aspect of the present invention, the drug concentration used may be lower than the drug concentration used with instillation or intraocular injection alone.

The present invention has several advantages over other types of compositions and methods for delivering active agents during intraocular surgery. The application of topical instillation perfusion liquid compositions to the eye does not always provide an accurate method of delivering a limited dose, since a portion of the drops may be expelled by blinking or by drainage during application. In addition, the delivered dose delivered to the eye by instillation prior to the start of the surgical procedure in an intraocular or topical ophthalmic procedure can effectively dilute and expel the normal irrigating fluid applied subsequently in advance, thus reducing the therapeutic effect of the drug.

In addition, the increased time-out of the drug deliverable by irrigation in an intraocular or topical ophthalmic procedure according to the invention allows for lower concentrations of the drug to be applied as an irrigation solution, which reduces the risk of eye toxicity. For pharmacokinetic reasons, a dose of drug delivered only prior to surgery will be administered at a variety of concentrations and exhibit effects as a function of time, reaching a peak in potency for a period of time after initial application, and then diminishing in effect immediately due to the gradual decline in concentration. The unique pharmacokinetic parameters upon topical instillation of drugs will vary depending on the dissolution profile of each drug, the vehicle composition and pH, osmolality, tonicity and viscosity of the formulation. An advantage of the present invention is that the irrigation fluid provides a constant concentration of active agent at the surgical site of the eye, thereby maintaining a constant therapeutic effect.

The present invention provides controlled, site-specific drugs for delivery to the eye that have the dual purpose of increasing the effectiveness of ophthalmic treatments and reducing side effects. A therapeutic concentration range can be rapidly achieved during rinsing and subsequently maintained at an effective constant concentration.

The present invention also provides a method of preparing a pharmaceutical composition for use in a dilute irrigant solution for use in the continuous irrigation of a surgical site or wound during a surgical procedure. The method defines a majority of the analgesic, anti-inflammatory, mydriatic and/or intraocular pressure-lowering drugs (IOP-lowering drugs) dissolved in a physiological electrolyte carrier liquid, preferably comprising each drug at a concentration no greater than 100,000 nanomolar, and more preferably no greater than 10,000 nanomolar, in addition to the local anesthetic, and is applicable to concentrations no greater than 100,000,000 nanomolar, preferably no greater than 10,000,000 nanomolar, more preferably no greater than 1,000,000 nanomolar, and still more preferably no greater than 100,000 nanomolar, in local anesthesia.

The present invention provides methods for delivering diluted combinations of various receptor antagonists and agonists, as well as enzyme inhibitors and enzyme activators, directly to a wound or surgical or operative site of the eye during surgery for the purpose of inhibiting pain and inflammation, reducing or controlling intraocular pressure, and/or facilitating therapeutic or diagnostic procedures for mydriasis. Since the active ingredient in the solution is applied directly to the tissues of the eye in a sustained manner during the procedure, the medicament can be effectively applied at extremely low doses relative to those required to achieve a therapeutic effect when the same medicament is applied systemically (e.g., orally, intramuscularly, subcutaneously or intravenously), or separately, e.g., by instillation or injection through the eye.

The term "topical" as used herein includes the application of a drug in and around a wound or other surgical or operative site, and includes oral, subcutaneous, intravenous and intramuscular administration. As used throughout this document, the term "irrigation" means primarily irrigation of a wound or anatomical structure with a flow of liquid. The term "sustained" as used herein includes uninterrupted application, repeated application at frequent intervals, with a frequency of application sufficient to substantially maintain a locally predetermined therapeutic concentration of the drug used, and with the exception of brief interruptions such as allowing the application of other drugs or operating equipment or due to surgical techniques, the application is continuous such that a substantially constant predetermined local therapeutic concentration is maintained locally at the wound or surgical site.

The term "wound" as used herein is meant to include surgical wounds, surgical/interventional sites, and traumatic wounds, unless otherwise indicated.

As used herein, unless otherwise indicated, each of the terms "procedure" and "operation" is meant to encompass surgical, therapeutic, and diagnostic operations.

Irrigating solutions containing selected therapeutic agents are applied topically and perioperatively to ocular tissue at the surgical site, e.g., intraocular for intraocular procedures and external for topical procedures. The term "perioperative" as used herein includes both pre-operative and intra-operative applications, both intra-operative and post-operative applications, and pre-, intra-and post-operative applications. Preferably, the solution is applied before and/or after the operation and during the operation. Most preferably, the irrigating fluid is applied to the wound or surgical site prior to the initiation of the procedure, or prior to significant tissue trauma, and is applied continuously during the procedure to pre-block pain and inflammation, inhibit increased intraocular pressure, and/or induce mydriasis. In a preferred aspect of the invention, irrigation is continued throughout the major portion of the procedure, both before and during a substantial portion of the surgical trauma, and/or during periods when mydriasis may be required and/or intraocular pressure control may be required.

The advantages of low dose application of the drug rinsed with the method and solution of the present invention are threefold. Systemic side effects, which often limit the use of these drugs, are avoided. In addition, the drugs selected for a particular application in the solution of the invention are highly specific with respect to the medium by which they act. This specificity can be maintained by low dose application. Finally, these active agents are low cost per surgical procedure.

More particularly: (1) local application ensures a known concentration of the targeted site without concern for inter-patient variability in metabolism, blood flow, etc.; (2) due to the mode of direct delivery, therapeutic concentrations are obtained almost instantaneously and thus provide improved dose control; and (3) the direct topical application of an active agent to a wound or surgical site also substantially reduces degradation of the agent during passage outside the cell, such as first-pass (first-pass) metabolism and second-pass metabolism, which would occur if the agent were administered systemically (e.g., orally, intravenously, subcutaneously, or intramuscularly). This is particularly true for those active peptide drugs that are metabolized extremely rapidly. Thus, topical application allows for the use of compounds or drugs that would otherwise not be therapeutically useful. Local, sustained delivery to the wound or surgical site minimizes degradation or metabolism of the drug, while also providing sustained replenishment of the portion of the drug that may have degraded to ensure that a local therapeutic concentration is maintained throughout the surgical procedure sufficient to maintain receptor occupancy.

According to the invention, the perioperative topical application of the solution throughout the surgical procedure can produce pre-analgesic, anti-inflammatory and/or intraocular pressure controlling effects (if IOP lowering drugs are used), as well as maintenance of mydriasis (if mydriatic drugs are used). To maximize the effects of pre-anti-inflammatory, analgesic (for some applications), intraocular pressure reduction (for some applications), and mydriasis (for some applications), it is most preferred to apply the solutions of the present invention pre-, intra-and post-operatively. By occupying the target recipient or unactivated target organ or activated target organ enzymes before the onset of a locally significant surgical trauma, the drug of the present solution can tailor specific pathways to pre-inhibit the pathological processes of the target organ. Before inflammatory mediators and processes can produce tissue damage, the benefits are more than delivered after these processes have begun if the inflammatory mediators and processes are previously inhibited in accordance with the present invention, and the mediators that increase intraocular pressure are also previously inhibited.

The irrigation solutions of the present invention include a combination of drugs, each of which acts on multiple receptors or enzymes. The medicament may therefore simultaneously exert its effect against pathological processes, including pain and inflammation, and/or regulatory processes that increase intraocular pressure. It is expected that the effects of these drugs will be synergistic such that the various receptor antagonists and inhibitory agonists of the invention, when used in combination, provide a disproportionate (disproportionatory) increase in effect to that of the drug alone.

For perioperative use, the solution should produce a clinically significant reduction in surgical site pain and inflammation associated with current irrigation fluid applications, thereby reducing the need for post-operative analgesia in the patient and, where appropriate, allowing the patient to recover earlier. It is also desirable to pre-control intraocular pressure to reduce the therapeutic need for the intraocular pressure-elevating process after surgery.

IV detailed description of the preferred embodiments

The present invention provides perioperative, topically applied irrigation solutions to ocular tissues, including intraocular and topical applications, the solutions including a plurality of drugs that act to inhibit inflammation, inhibit pain, effectively dilate mydriasis (pupil dilation), and/or reduce or control intraocular pressure, wherein the plurality of drugs are selected to act on a plurality of different target molecules to achieve a plurality of different physiological functions. The irrigation solution of the present invention is a dilution of various pain/inflammation inhibitors, IOP lowering agents, and/or mydriatic agents in a physiological fluid irrigation vehicle. Suitable such carriers are aqueous solutions which may include physiological electrolytes, such as physiological saline or lactated ringer's solution. More preferably, the carrier includes sufficient electrolyte to provide a physiologically balanced salt solution, a cellular energy source, a buffer, and a free radical scavenger.

Solutions according to the present invention may include (a) one or more anti-inflammatory agents in combination with one or more analgesic agents, and may also optionally include one or more intraocular pressure-lowering (IOP-lowering) agents and/or mydriatic agents; (b) one or more anti-inflammatory agents in combination with one or more IOP lowering agents, and optionally further comprising one or more analgesics and/or mydriatics; (c) one or more anti-inflammatory agents in combination with one or more mydriatic agents, and optionally further comprising one or more analgesics and/or IOP lowering agents; (d) one or more analgesics in combination with one or more IOP lowering agents, and may optionally further comprise one or more anti-inflammatory and/or mydriatic agents; (e) one or more analgesics in combination with one or more mydriatic agents, and may optionally further include one or more anti-inflammatory agents and/or IOP lowering agents; or (f) one or more mydriatic agents in combination with one or more IOP-lowering agents, and may optionally further comprise one or more anti-inflammatory agents and/or analgesics.

Any of these solutions of the present invention may also include one or more antibiotics. Antibiotics suitable for use in the present invention include tendrilysin, gentamicin, tobramycin and picolinase. Other antibiotics suitable for perioperative intraocular use are also encompassed by the present invention. Suitable rinsing solutions according to the invention contain an antibiotic (tendomycin) in a suitable concentration of 0.01mM to 10mM, preferably 0.05mM to 3mM, most preferably 0.1mM to 1 mM. Different antibiotics will be applied in different, e.g. easily definable, concentrations.

In each of the surgical solutions of the present invention, the drug is contained therein at low concentrations and is delivered locally at low doses relative to the concentrations and doses required to achieve the desired therapeutic effect with conventional methods of administration. It is not possible to deliver the same dose of drug by systemic (e.g. intravenous, subcutaneous, intramuscular or oral) routes of administration to achieve equivalent therapeutic effect because systemic administration is subject to first and second pass metabolism.

May be determined in part by the dissociation constant K for each drug_dThe concentration thereof was determined on the basis. The term "dissociation constant" as used herein is intended to include both the equilibrium dissociation constant for their respective agonist receptor or antagonist receptor interactions and the equilibrium inhibition constant for their respective enzyme activator or enzyme inhibitor interactions. Preferably, each drug is included at a low concentration of 0.1 to 10,000 times K_dExcept for the cyclooxygenase inhibitor, which may require greater concentrations depending on the particular inhibitor selected. Preferably, each drug is included at a concentration of 1.0 to 1,000 times K_dAnd most preferably about 100 times K_d. These concentrations are adjusted as required by the amount of dilution at the local site of delivery without metabolic switching. The exact drug and concentration of drug selected for the solution will vary depending on the particular application.

Surgical solutions constitute a new treatment by combining multiple agents that act on different receptor and enzyme molecular targets. Pharmacological strategies to date have focused on the development of highly specific drugs that can selectively target individual receptor subtypes and enzyme isoforms, thereby mediating responses to individual neurotransmitter and hormone signals. This standard pharmacological strategy, although widely accepted, is not perfect, as many other drugs can simultaneously contribute to the initiation and maintenance of physiological efficacy. Furthermore, despite the inactivation of individual receptor subtypes or enzymes, activation of other receptor subtypes or enzymes and the resulting signaling can often trigger a range of actions. This suggests that it is quite difficult to block the pathophysiological processes that are effected by multiple transmitters with a single receptor-specific drug. Thus, targeting only specific individual receptor subtypes may be ineffective.

The treatment with surgical solutions is based on the principle that a combination of drugs acting on different molecular targets simultaneously is required to suppress all events leading to the development of pathophysiological states, as opposed to standard pharmacological treatments. Furthermore, instead of targeting specific receptor subtypes alone, the surgical solution is composed of drugs that target common molecular mechanisms that play a role in different cellular physiological processes involving the development of pain and inflammation, the reduction of intraocular pressure, and the promotion of mydriasis. In this way, additional receptor and enzyme cascades in the nociceptive, inflammatory, and increased intraocular pressure pathways can be minimized from the surgical solution. In these pathophysiological pathways, the surgical solution is able to inhibit both "upstream" and "downstream" cascades (i.e. at two points of divergence and convergence of the pathophysiological pathways).

Preferred solutions of the present invention for use during ophthalmic surgery comprise one or more anti-inflammatory agents in combination with one or more mydriatic agents. Such preferred solutions may also contain one or more analgesics and/or one or more IOP depressants, respectively, depending on the surgical procedure being administered or whether the condition being treated is associated with increased pain or incidence of increased IOP.

These agents are included in diluted concentrations in a physiological aqueous carrier, such as a balanced salt solution, of any of the carriers described above. The solution may also contain viscosity enhancing agents, such as biocompatible and biodegradable polymers, to increase residence time in the eye. The concentration of the agent is determined according to the teachings of the present invention and is applied topically directly to ocular tissue during a surgical procedure. The application of the solution is performed perioperatively, i.e.: in surgery; pre-and intra-operative; during and after surgery; or before, during and after surgery. The drug may be provided as a stable one-part or two-part solution, or may be provided in lyophilized form, to which one-part or two-part carrier liquid is added prior to use.

The functional classification of ophthalmic drugs, which will benefit perioperative use of the ophthalmic irrigating solutions of the present invention, will now be further described.

A. Anti-inflammatory agents

Preferred anti-inflammatory agents for use in the ophthalmic solutions of the present invention include topical steroids, topical non-steroidal anti-inflammatory agents (NSAIDs) and particular types of anti-inflammatory agents suitable for intraocular use, such as topical antihistamines, mast cell inhibitors and Inducible Nitric Oxide Synthase (iNOS) inhibitors. The present invention is also intended to include other anti-inflammatory agents described below as pain/inflammation inhibitors, as well as other anti-inflammatory agents suitable for ophthalmic use not disclosed herein.

Examples of steroids considered suitable for use in the present invention include dexamethasone, fluorometholone and prednisolone. Examples of NSAIDS deemed suitable include flurbiprofen, suprofen, diclofenac, ketoprofen and ketorolac. The choice of NSAID depends in part on the determination that excessive bleeding does not result. Examples of antihistamines deemed suitable include levocabastine, emedastine and olopatadine. Examples of mast cell inhibitors deemed suitable include cromolyn sodium, lodoxamide, and nedocromil. Examples of drugs useful as antihistamines and mast cell inhibitors for use in the present invention include ketotifen and nitrogenA statin. Suitable iNOS inhibitors include N^G-monomethyl-L-arginine, 1400W, diphenylene iodine(diphenyleneiodium), S-methylisothiourea, S- (aminoethyl) isothiourea, L-N⁶- (1-iminoethyl) lysine, 1, 3-PBITU and 2-ethyl-2-thiopseudourea (thiopseudourea).

B.Analgesic agent

The term "analgesic" as used herein with respect to ophthalmic solutions and methods is intended to include both drugs that provide analgesia and drugs that provide local anesthesia. Preferred analgesics for use in the ophthalmic solutions of the present invention include topical anesthetics and topical opioids. The present invention is also intended to include other analgesics described below as pain/inflammation inhibitors, as well as other analgesics not disclosed herein but suitable for ophthalmic use.

Examples of local anesthetics considered suitable for use in the present invention include lidocaine, tetracaine, bupivacaine, and proparacaine. Examples of opioids considered suitable for the use of the present invention include morphine, fentanyl, and hydromorphone.

C.Mydriasis agent

Preferred mydriatic agents for use in the ophthalmic solutions of the present invention (to dilate the pupil during surgery) include sympathomimetic agents (including alpha-1 adrenergic receptor agonists) and anticholinergic agents (including antimuscarinics). Anticholinergic drugs may be chosen when a longer effect is desired, since they provide both cycloplegia (muscular paralysis of the eyelashes) and mydriasis, e.g. topiramide shows a half-life of approximately 4-6 hours. However, for many procedures, alpha-1 adrenoceptor agonists will be preferred because they only provide mydriasis and not cycloplegia. Thus, alpha-1 adrenoceptor agonists are less effective, causing mydriasis during a surgical procedure and allowing the pupil to return to its normal state shortly after the procedure is completed. Examples of suitable adrenoceptor agonists acting at the α -1 receptor include neosynephrine, epinephrine, and oxymetazoline. Examples of suitable anticholinergic agents include tropicamide, cyclopentadien, atropine and homatropine. The present invention is also intended to include other mydriatic inducing agents, particularly short acting mydriatic agents.

D.Intraocular pressure lowering agent

Preferred intraocular pressure-lowering agents for use in the ophthalmic solutions of the present invention include beta adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha-2 adrenergic receptor agonists, and prostaglandin agonists. Examples of beta adrenergic receptor antagonists deemed suitable include timolol, metiprolol, and levobunolol. Examples of carbonic anhydrase inhibitors considered suitable include brinzolamide and dorzolamide. Examples of alpha-2 adrenoceptor agonists considered suitable include apraclonidine, brimonidine, and oxymetazoline. Other alpha-2 adrenoceptor agonists suitable for ophthalmic use and the inflammation/pain inhibitors described below may also suitably function as IOP lowering agents in the solutions of the present invention. Prostaglandin agonists considered suitable include latanoprost, travoprost and bimatoprost. Where inhibition of inflammation is the primary effect desired for a solution and control of IOP is desired, suitable IOP lowering agents other than prostaglandin agonists may be selected; to avoid the possibility that prostaglandins may enhance post-operative inflammation. The present invention is also intended to include other intraocular pressure-reducing agents.

E.Pain/inflammation inhibitors

The following drugs (referred to herein as pain/inflammation inhibitors) may be suitable for use as analgesics and/or anti-inflammatory agents in the ophthalmic solutions and methods of the present invention. Those skilled in the art can readily determine the particular class of drugs for a particular ophthalmic application, as well as the individual drugs in a class of drugs, in accordance with the present invention.

For example, the ophthalmic inflammatory model of rabbits has been studied by comparing the inflammatory response caused by the topical application of several irrigating fluids, in particular carrageenan, Freund's adjuvant, alkali and croton oil. The method comprises measuring the following detectable parameters after applying various stimuli to the eyes of white, new zealand female rabbits: corneal edema and tyndall's effect (slit lamp live microscopy), corneal thickness (biometrical), and levels of prostaglandin E2 of the aqueous humor (r.i.a), total protein (Weichselbaum technique), albumin/globulin ratio (Doumas technique), and white blood cells (coulter granulometer).

Validation studies found that 1-4% croton oil (40 μ l) produced edema and a Yander's effect, and showed that the proportion of edema and Yander's effect increased with croton oil concentration. The ultrasonic pachymeter showed a dose-dependent response from hour 8 to hour 168 (p < 0.01) in the measurement of corneal thickness changes (3-168 hours). After 24 hours of topical application of 3% croton oil (40. mu.l), uveitis was found, as well as prostaglandin E2 levels in aqueous humor (4.50. + -. 0.40pg/0.1ml vs. 260.03. + -. 2.03pg/0.1ml), total protein (0.25. + -. 0.05g/l vs. 2.10. + -. 0.08g/l), albumin/globulin ratios, and white blood cells were all found to be considerably increased. All data obtained were statistically significant (p < 0.01).

Topical application of 3% croton oil (40 μ l) was most suitable for assessing inflammatory processes in the anterior chamber and for detecting penetration effects in the eye. The inflammatory mechanism in this model is believed to involve activation of the arachidonic acid pathway, with breakdown of the blood-ocular aqueous humor barrier leading to high molecular weight proteins entering the aqueous humor.

The above model can be used to determine the effects of topically applied drugs, such as by irrigation, in inhibiting inflammatory processes and in exerting other ophthalmic functions. After each stimulus was applied to the eyes of the rabbit, a given drug or combination of drugs to be evaluated was applied to the eyes of the rabbit.

The solution may suitably comprise a drug selected from the following classes of receptor antagonists and agonists, and enzyme activators and enzyme inhibitors, each of which exerts pain and inflammation inhibitory effects via a different molecular mechanism of action: (1) 5-hydroxytryptamine receptor antagonists; (2) a 5-hydroxytryptamine receptor agonist; (3) a histamine receptor antagonist; (4) bradykinin receptor antagonists; (5) a vasorelaxin inhibitor; (6) tachykinin receptor antagonists, including neurokinins₁And neurokinins₂A subtype receptor antagonist; (7) calcitonin Gene Related Peptide (CGRP) receptor antagonists; (8) an interleukin receptor antagonist; (9) inhibitors of active enzymes in the synthetic pathway of arachidonic acid metabolism, including (a) phospholipase inhibitors, including PLA₂Isoform inhibitors and PLCs_γAn isoform inhibitor, (b) a cyclooxygenase inhibitor, and (c) a lipoxygenase inhibitor; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 subtype receptor antagonists and thromboxane subtype receptor antagonists; (11) leukotriene receptor antagonists include leukotriene B₄Subtype receptor antagonists and leukotriene D₄A subtype receptor antagonist; (12) opioid receptor agonistsIncluding mu-, delta-and kappa-opioid subtype receptor agonists; (13) purine receptor agonists and antagonists, including P_2XReceptor antagonists and P_2YA receptor agonist; (14) adenosine Triphosphate (ATP) -sensitive potassium channel openers; (15) a local anesthetic; and (16) alpha-2 adrenoceptor agonists. Each of the above drugs has a function as an anti-inflammatory agent and/or a function as an analgesic agent such as an analgesic. Drugs selected from these classes of compounds are particularly useful for specific applications.

1.5-hydroxytryptamine receptor antagonists

5-hydroxytryptamine (5-HT) is believed to be produced by stimulating 5-hydroxytryptamine on peripheral nociceptive neurons₂(5-HT₂) And/or 5-hydroxytryptamine₃(5-HT₃) The receptor causes pain. Most researchers agree on 5-HT in peripheral nociceptive neurons₃The receptors mediate the direct sensation of pain produced by 5-HT. In addition to inhibiting pain caused by 5-HT, 5-HT₃Receptor antagonists may also inhibit neurogenic inflammation by inhibiting the activation of nociceptive neuronal receptors. 5-HT₂Activation of receptors may also play a role in peripheral pain and inflammation of neurogenic origin. One goal of the solutions of the present invention is to block most of the pain and inflammation processes. Thus, 5-HT₂And 5-HT₃Both receptor antagonists may be suitably employed, either individually or together, in the solutions of the present invention. Consider amitriptyline (Elavil)^TM) Are potential, suitable 5-HT useful in the present invention₂A receptor antagonist. Metoclopramide (Reglan)^TM) Is clinically used as an antiemetic, but shows a 5-HT interaction with₃The moderate affinity of the receptor and the ability to inhibit the action of 5-HT at this receptor may inhibit pain caused by 5-HT released from platelets. Therefore, it can also be suitably applied in the present invention.

Other potential, suitable 5-HT₂Receptor antagonists include imipramine, trazodone, desmopressin, ketanserin. Other suitable 5-HT₃Antagonists include cisapride and ondansetron. The therapeutic and preferred concentrations of these drugs used in the solutions of the present invention are listed in table 1.

TABLE 1

Treatment and preferred concentrations of pain/inflammation inhibitors

2.5-hydroxytryptamine receptor agonists

Known 5-HT_1A、5-HT_1BAnd 5-HT_1DThe receptor inhibits adenylate cyclase activity. Thus including these low doses of 5-hydroxytryptamine in solution_1A5-hydroxytryptamine_1BAnd 5-hydroxytryptamine_1DReceptor agonists should inhibit neuronal-mediated pain and inflammation. Because of the 5-hydroxytryptamine_1EAnd 5-hydroxytryptamine_1FReceptor agonists also inhibit adenylate cyclase and therefore these receptor agonists are expected to have the same effect.

Buspirone is a potential, suitable 1A receptor agonist for use in the present invention. Sumatriptan is a potential and suitable 1A, 1B, 1D and 1F receptor agonist. A potential and suitable 1B and 1D receptor agonist is dihydroergotamine. A suitable 1E receptor agonist is ergometrine. Table 2 provides therapeutic and preferred concentrations of these receptor agonists.

TABLE 2

Treatment and preferred concentrations of pain and inflammation inhibitors

3.Histamine receptor antagonists

Can be combined into oneAn amine receptor antagonist is effectively included in the rinse solution. Promethazine (Phenergan) commonly used as an antiemetic^TM) Can effectively block H₁Receptor, and become a potential and suitable drug for use in the present invention. Other potential, suitable H₁Receptor antagonists include terfenadine, diphenhydramine, amitriptyline, mepyramine and triprolidine. Since amitriptyline is also an effective 5-hydroxytryptamine₂Receptor antagonists, so it has dual efficacy in the applications of the present invention. Each of said H₁Suitable therapeutic and preferred concentrations of the receptor antagonists are listed in table 3.

TABLE 3

Treatment and preferred concentrations of pain and inflammation inhibitors

4.Bradykinin receptor antagonists

Bradykinin receptors are generally classified as bradykinins₁(B₁) Bradykinin₂(B₂) Two subtypes. These drugs are peptides (small proteins) because they are digested away and therefore they cannot be used orally. B is₂Antagonists of the receptor block acute pain and inflammation caused by bradykinin. B is₁Receptor antagonists inhibit pain in chronic inflammatory conditions. Depending on the application, the solutions of the invention may suitably comprise bradykinin B₁And bradykinin B₂Either or both of the receptor antagonists are included. Potential, suitable bradykinin peptides for use in the invention₁Receptor antagonists include: D-Arg- (Hyp)³-Thi⁵-D-Tic⁷-Oic⁸) [ des-Arg ] of-BK¹⁰]Derivatives ([ des-Arg ] of "HOE 140)¹⁰]Derivatives ", available from Hoechst Pharmaceuticals); and [ Leu ]⁸]des-Arg⁹-BK. Latent, suitable bradykinin₂Receptor antagonists include: [ D-Phe ]⁷]-BK；D-Arg-(Hyp³-Thi^5，8-D-Phe⁷)-BK(“NPC 349”)；D-Arg-(Hyp³-D-Phe⁷) -BK ("NPC 567") and D-Arg- (Hyp)³-Thi⁵-D-Tic⁷-Oic⁸) -BK ("HOE 140"). Table 4 provides suitable treatments and preferred concentrations.

TABLE 4

Treatment and preferred concentrations of pain/inflammation inhibitors

5.Novel vasorelaxin inhibitors

The peptides bradykinin are important mediators of pain and inflammation. Bradykinin is a cleavage product produced from high molecular weight kininogen in plasma under the action of kallikrein. Thus, it is believed that bradykinin inhibitors have a therapeutic effect in inhibiting bradykinin production and the resulting pain and inflammation. A potential, suitable angiostatin inhibitor for use in the present invention is aprotinin. The effective, preferred concentrations for use of the solutions of the present invention are listed in table 5 below.

TABLE 5

Treatment and preferred concentrations of pain/inflammation inhibitors

6.Tachykinin receptor antagonists

Tachykinins (TKs) are a family of structurally related peptides including substance P, neurokinin a (nka), and neurokinin b (nkb). Peripheral neurons are the major source of TKs. One important and common effect of TKs is neuronal stimulation, but other effects include endothelium-dependent vasodilation, plasma protein extravasation, mast cell recruitment and degranulation, and stimulation of inflammatory cells. Due to the combined effects of the above physiological effects mediated by activation of the TK receptor, targeting of the TK receptor is a rational approach to promote analgesia and to treat neuronal inflammation.

a.Neurokinins ₁ Subtype receptor antagonists

Substance P activation is called NK₁Neurokinin subtype receptors of (1). A potential and suitable substance P antagonist is ([ D-Pro)⁹[ gamma-helix-lactams]Leu¹⁰，Trp¹¹]Eudragine- (1-11)) ("GR 82334"). Other potential, suitable actions on NK for use in the present invention₁Antagonists of the receptor are: 1-imino-2- (2-methoxy-phenyl) -ethyl) -7, 7-diphenyl-4-perhydroisoindolone (3aR, 7aR) ("RP 67580"); and 2S, 3S-cis-3- (2-methoxybenzylamino) -2-benzhydrylquinuclidine ("CP 96,345"). Suitable concentrations of these drugs are listed in table 6.

TABLE 6

Treatment and preferred concentrations of pain/inflammation inhibitors

b.Neurokinins ₂ Subtype receptor antagonists

Neurokinin a is a peptide that is co-localized (colocalized) with substance P to sensory neurons and can also promote inflammation and pain. Neurokinin A activation is termed NK₂Specific neurokinin receptors of (1). Potential, suitable NK₂Examples of antagonists include: (S) -N-methyl-N- [4- (4-acetylamino-4-phenylpiperidinyl) -2- (3, 4-dichlorophenyl) butyl]Benzamide ("(±) -SR 48968"); Met-Asp-Trp-Phe-Dap-Leu ("MEN 10,627"); and cyc (Gln-Trp-Phe-Gly-Leu-Met) ("L659,877"). Table 7 provides a list of these agentsThe appropriate concentration.

TABLE 7

Treatment and preferred concentrations of pain/inflammation inhibitors

7.CGRP receptor antagonists

Calcitonin gene-related peptide (CGRP) is also a peptide which is co-localized to sensory neurons with substance P and has vasodilatory and substance P-potentiating effects. An example of a potential, suitable CGRP receptor antagonist is I-CGRP- (8-37), a truncated variant of CGRP. Such polypeptides inhibit the activation of CGRP receptors. Table 8 provides suitable concentrations of this drug.

TABLE 8

Treatment and preferred concentrations of pain/inflammation inhibitors

8.Interleukin receptor antagonists

The classification of interleukins is a cytokine, a family of peptides produced by leukocytes and other cells responsive to inflammatory mediators. Interleukins (IL) can be effective peripheral hyperalgesic drugs. An example of a potential, suitable IL-1 β receptor antagonist is Lys-D-Pro-Thr, which is a truncated variant of IL-1 β. This tripeptide inhibits the activation of the IL-1 beta receptor. Table 9 provides suitable concentrations of this drug.

TABLE 9

Treatment and preferred concentrations of pain/inflammation inhibitors

9.Inhibitors of enzymes that function in the metabolic synthetic pathway of arachidonic acid

a.Phospholipase inhibitors

By phospholipase A₂(PLA₂) The resulting production of arachidonic acid leads to a cascade of reactions that produce a number of inflammatory mediators known as eicosanoids. There are many stages in the overall process of this pathway that can be inhibited, thereby reducing the production of these inflammatory mediators. Examples of suppressing these different stages are given below.

PLA₂Inhibition of the enzyme isoforms inhibits the release of arachidonic acid from the cell membrane, thereby inhibiting the production of prostaglandins and leukotrienes, resulting in a reduction in inflammation and pain. Latent, suitable PLA₂An example of an isoform inhibitor is manoalide. Suitable concentrations of this drug are included in table 10. Inhibition of the phospholipase c (plc) isoform will also result in a reduction in the production of prostanoids and leukotrienes and will therefore result in a reduction in pain and inflammation. An example of an isoform of the PLC isomer is 1- [6- ((17 β -3-methoxyestra-1, 3, 5(10) -trien-17-yl) amino) hexyl]-1H-pyrrole-2, 5-dione.

Watch 10

Treatment and preferred concentrations of pain/inflammation inhibitors

b.Cyclooxygenase inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as anti-inflammatory and analgesic drugs. The molecular targets of these drugs are type I and type II cyclooxygenase enzymes (COX-1 and COX-2). Both the constitutive activity of COX-1 and the inducible activity of COX-2 lead to the synthesis of prostaglandins that can cause pain and inflammation.

Currently marketed NSAIDs (diclofenac, naproxen, indomethacin, ibuprofen, etc.) are generally non-selective inhibitors of both COX isoforms, but may exhibit greater selectivity for COX-1 than for COX-2, although this ratio varies from compound to compound. Blocking prostaglandin formation using COX-1 and COX-2 inhibitors represents a better therapeutic strategy than attempting to block the interaction of the natural ligand with the 7 described prostanoid receptor subtypes.

Potential, suitable cyclooxygenase inhibitors for use in the present invention are ketoprofen, ketorolac, and indomethacin. Table 11 provides the therapeutic and preferred concentrations of these drugs for use in the solutions. For some applications, it may also be appropriate to use a COX-2 specific inhibitor (e.g., COX-1 is more selective than COX-2) as an anti-inflammatory/analgesic agent. Potential, suitable COX-2 inhibitors include rofecoxib (MK 966), SC-58451, celecoxib (SC-58125), meloxicam, nimesulide, diclofenac, NS-398, L-745,337, RS 57067, SC-57666, and flusuamine.

TABLE 11

Treatment and preferred concentrations of pain/inflammation inhibitors

c.Lipoxygenase inhibitors

Inhibition of lipoxygenase inhibits leukotrienes such as leukotriene B₄Leukotrienes are known to be an important inflammatory and pain mediator. An example of a potential, suitable 5-lipoxygenase antagonist is 2, 3, 5-trimethyl-6- (12-hydroxy-5, 10-dodecacarboalkynyl) -1, 4-benzoquinone ("AA 861"), suitable concentrations of the listed drugs are provided in table 12.

TABLE 12

Treatment and preferred concentrations of pain/inflammation inhibitors

10.Prostanoid receptor antagonists

Specific prostanoids produced as metabolites of arachidonic acid mediate their inflammatory effects by activating prostanoid receptors. Examples of specific prostanoid antagonists are eicosanoid EP-1 and EP-4 subtype receptor antagonists and thromboxane subtype receptor antagonists. A potential and suitable prostaglandin E2 receptor antagonist is 8-chlorodibenzo [ b, f][1，4]Oxazazem(oxazepine) -10(11H) -carboxylic acid, 2-acetylhydrazide ("SC 19220"). A potential and suitable thromboxane subtype receptor antagonist is [15- [1 alpha, 2 beta (5Z), 3 beta, 4 alpha ]]-7- [3- [2- (phenylamino) -carbonyl]Hydrazine radical]Methyl radical]-7-oxobicyclo- [2, 2, 1]-hept-2-yl]-5-heptanoic acid ("SQ 29548"). Suitable concentrations of these drugs are listed in table 13.

Watch 13

Treatment and preferred concentrations of pain/inflammation inhibitors

11.Leukotriene receptor antagonists

Leukotrienes (LTB)₄、LTC₄And LTD₄) Are products of the 5-lipoxygenase pathway in arachidonic acid metabolism, which is produced enzymatically and has important biological properties. Leukotrienes relate toMany pathological conditions include inflammation. Latent, suitable leukotrienes B₄An example of a receptor antagonist is SC (+) -S-7- (3- (2- (cyclopropylmethyl) -3-methoxy-4- [ (methylamino) -carbonyl]Phenoxy (propoxy) -3, 4-dihydro-8-propyl-2H-1-benzopyran-2-propionic acid ("SC 53228"). Table 14 provides potential, suitable concentrations of this drug for use in the practice of the present invention. Other potential, suitable leukotrienes B₄The receptor antagonist comprises [3- [2- (7-chloro-2-quinolyl) ethenyl]Phenyl radical][ [3- (dimethylamino-3-oxopropyl) thio ]]Methyl radical]Thiopropionic acid ("MK 0571") and the drugs LY 66,071 and ICI 20,3219. MK 0571 is also used as LTD₄A subtype receptor antagonist.

TABLE 14

Treatment and preferred concentrations of pain/inflammation inhibitors

12.Opioid receptor agonists

Activation of opioid receptors results in anti-nociceptive effects and, therefore, agonists of these receptors are desirable. Opioid receptors include the mu-, delta-and kappa-opioid subtype receptors. Examples of potential, suitable mu-opioid receptor agonists are fentanyl and Try-D-Ala-Gly- [ N-MePhe]-NH(CH₂) -OH ("DAMGO"). An example of a potential, suitable delta-opioid receptor agonist is [ D-Pen²，D-Pen⁵]Enkephalin ("DPDPE"). An example of a potential, suitable kappa-opioid receptor agonist is (trans) -3, 4-dichloro-N-methyl-N- [2- (1-pyrrolidino) cyclohexyl]-phenylacetamide ("U50,488"). Suitable concentrations of each of these drugs are listed in table 15.

Watch 15

Treatment and preferred concentrations of pain/inflammation inhibitors

13.Purine receptor antagonists and agonists

Through with P₂The interaction between purine receptors (purinoceptors), extracellular ATP, acts as a signaling molecule. One of the main types of purine receptors is P_2XPurine receptor which controls Na in internal ion channels⁺、K⁺And Ca²⁺The permeated ligand gates the ion channel. Potential, suitable P for use in the present invention_2XATP purine receptor antagonists include, for example, suramin and pyridoxal phosphate-6-azophenyl-2, 4-disulfonic acid ("PPADS"). Table 16 provides suitable concentrations of these drugs. Known as P_2YReceptor (a G-protein coupled receptor) agonists have smooth muscle relaxant action via inositol triphosphate (IP)₃) Increased levels and subsequent increases in intracellular calcium ions. A P_2YAn example of a receptor agonist is 2-me-S-ATP.

TABLE 16

Treatment and preferred concentrations of pain/inflammation inhibitors

14.Adenosine Triphosphate (ATP) -sensitive potassium channel opener

Potential, suitable Adenosine Triphosphate (ATP) -sensitive K for use in the practice of the present invention⁺The channel openers include: (-) pinacidil; chromaffin; nicorandil; minoxidil; N-cyano-N' - [1, 1-dimethyl- [2, 2, 3, 3-³H]Propyl radical]-N "- (3-pyridyl) guanidine (" P1075 "); and N-cyano-N' - (2-nitroxylethyl) -3-pyridinecarboxyiminoacylAmine (pyridinecarboximidamide) monomethanesulfonate ("KRN 2391"). The concentrations of these drugs are listed in table 17.

TABLE 17

Treatment and preferred concentrations of pain/inflammation inhibitors

15.Local anesthetic

The solution of the present invention is preferably applied by continuous perfusion throughout the surgical procedure in order to previously inhibit pain and inflammation. Local anesthetics (such as lidocaine, bupivacaine, etc.) are used clinically as analgesics and are known to reversibly bind to sodium ion channels on the membrane of the neural axis, thereby inhibiting axonal conduction and transmission of pain signals from the periphery to the spinal cord. Local delivery of local anesthetic lidocaine at very low or sub-clinical concentrations has been shown to inhibit firing of nerve lesions (Bisla K and Tanalian DL, concentration-dependent effects of lidocaine in healing corneal epithelial lesions, Invest Ophthalmol Vis Sci 33(11), p. 3029-3033, 1992). Thus, in addition to reducing pain signals, local anesthetics also have anti-inflammatory properties when delivered at very low concentrations.

The inclusion of very low or "sub-anesthetic" concentrations of local anesthetic in the irrigation fluid can provide a beneficial anti-inflammatory effect while avoiding exposing the patient to systemic toxic reactions associated with currently clinically used doses of local anesthetic. Thus, at very low concentrations, local anesthetics are suitable for use in the present invention. Examples of representative local anesthetics for use in the practice of the present invention include, but are not limited to, benzocaine, bupivacaine, chloroprocaine, cocaine, etiodocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, tetracaine, dibucaine, QX-222, ZX-314, RAC-109, HS-37, and pharmaceutically active enantiomers thereof. While not wishing to be bound by any particular theory, certain local anesthetics are believed to act by inhibiting voltage-gated sodium ion channels (see Guo X et al, "comparison of inhibition of voltage-gated cation channels by local anesthetics", ann.n.y.acad.sci.625: 181-199 (1991)). Particularly useful pharmaceutically active enantiomers of local anesthetics include, for example, the R-enantiomer of bupivacaine. For purposes of the present invention, the concentration of anesthetic agent used for local delivery is generally in the range of about 125 to about 100,000,000nM, more preferably about 1,000 to about 10,000,000nM, and most preferably about 225,000 to about 1,000,000 nM. In one embodiment, the solution of the invention contains at least one local anesthetic delivered at a local concentration of no more than 750,000 nM. In another embodiment, the solution of the invention contains at least one local anesthetic delivered at a local concentration of no greater than 500,000 nM. The following are representative of useful concentrations of specific local anesthetics.

Watch 18

Treatment and preferred concentrations of specific local anesthetics

16.Alpha-2 adrenergic receptor agonists

All the individual 9 receptors containing the adrenergic amine receptor family belong to the G-protein related receptor superfamily. The classification of the adrenergic family (dividing it into three distinct subfamilies, namely alpha₁(alpha-1)、α₂(alpha-2) and β (beta)) are based on the number of connections, function and study of second messengers. Each adrenergic receptor subfamily itself consists of three homologous receptor subtypes, defined by the cloning and pharmacological characterization of recombinant receptors. In different subfamilies (alpha)₁For alpha₂P.beta.) the identity of the amino acids in the transmembrane domain is in the range of 36-73% amino acid identity between adrenergic receptorsInside the enclosure. However, in the same subfamily member (. alpha.)_1AFor alpha_1B) The identity between membrane domains is typically 70-80%. These different receptor subtypes modulate the action of two physiological agonists, epinephrine and norepinephrine.

Different adrenergic receptor types couple to a unique group of G-proteins and are therefore capable of activating different signal transduction effectors. Alpha is alpha₁、α₂And the β subfamily, not only define receptors associated with signal transduction mechanisms, but also give rise to differences in their ability to recognize a variety of natural and synthetic adrenalines. In this regard, a number of selective ligands have been developed and used to identify the pharmacological properties of each of these receptor types. The functional response of the alpha-1 receptor has been shown in certain systems to stimulate phosphatidylinositol renewal and promote intracellular calcium ion (via G)_q) While stimulation of the alpha-2 receptor inhibits adenylyl cyclase (via G)_i). In contrast, the functional response of the beta receptor is associated with an increase in adenylyl cyclase activity and an increase in intracellular calcium ions (via G)_s) Are combined together.

It is currently accepted that there are three distinct alpha-1 receptor subtypes, all of which exhibit high affinity (sub-nanomolar) for the antagonist prazosin. The alpha-1 adrenergic receptor is subdivided into three groups called alpha_1A、α_1BAnd alpha_1DAre based primarily on studies of the binding of a large number of ligands to intrinsic receptors and cloned receptors. The pharmacological properties of the cloned receptor lead to a revision of the original classification, originally called alpha_1CCorresponds to a pharmacologically defined alpha_1AA receptor. Alpha is alpha_1A-DOccupancy of the receptor subtype by agonists leads to activation of phospholipase C, stimulation of PI breakdown, production of IP as a second messenger₃And an increase in intracellular calcium ions.

Three distinct alpha-2 receptor subtypes, respectively designated alpha, have been cloned, sequenced and expressed in mammalian cells_2A(α₂-C10)、α_2B(α₂-C2)、α_2C(α₂-C4). These subtypes differ not only in their amino acid composition, but also in their pharmacological pattern and distribution. An additional alpha was originally proposed based on studies of radioligand binding in rodent tissues₂Receptor subtype, α_2D(Gene rg20), but is presently believed to represent a human alpha_2AThe species of receptor homology.

All three alpha_2AThe functionality of the signal transduction pathways of the receptor subtypes is identical; each through G_i/oNegatively coupled with adenylyl cyclase. In addition, α has also been reported_2AAnd alpha_2BReceptor modulation activates the coupling of G-proteins to potassium ion channels (receptor-open) while inhibiting the association of G-proteins with calcium ion channels.

The α -2 adrenergic receptor is pharmacologically defined as high affinity for the antagonists cotinine (Ki ═ 0.5-25 μ M), altemezole (Ki ═ 0.5-2.5 μ M) and imidazole clozene (Ki ═ 21-35 μ M), and low affinity for the α -1 receptor antagonist prazosin. Agonists that are more selective for the alpha-2 adrenergic receptor class than the alpha-1 adrenergic receptor class are UK14,304, BHT920, and BHT 933. Oxymetazoline and alpha_2AHigh affinity and high selectivity binding of the receptor subtype (K)_D3 μ M) but otherwise also bind to the α -1 adrenergic receptor and the 5-HT1 receptor with high affinity. An additional complicating factor is that the alpha-2 adrenergic receptor ligands, which are imidazolines (clonidine, idazoxan) and others (oxymetazoline and UK14304), also bind with high affinity (nM) to the binding sites of the non-adrenergic receptor imidazolines. Further, α_2A-the pharmacological presence of adrenergic receptors population variability. To date, ligands for subtype-selective alpha-2 adrenergic receptors have shown only little or no selectivity for other specific receptors, and therefore therapeutic properties of subtype-selective drugs are still under development.

One area of treatment where alpha-2 receptor agonists are thought to have potential utility is as an adjunct to anesthetics for the control of pain and the blockade of neurogenic inflammation. Tissue damage is followed by stimulation of the sympathetic nervous system to release norepinephrine and thus affect the activity of nociceptors. Alpha-2 receptor agonists, such as clonidine, inhibit the release of norepinephrine at the nerve fiber terminals and thus may directly produce analgesia at peripheral sites (without the action of the CNS). The ability of primary afferent neurons to release neurotransmitters from their centres and endings enables them to perform a dual, sensory-transmitting and "efferent" or "local effector" function. The term "neurogenic inflammation" is used to describe the efferent function of sensory nerves, which includes the release of neuropeptides that transmit sensations associated with inflammatory processes in a "feed forward" mode. Drugs that cause sensory-transmitting neuropeptides to be released from the periphery of sensory nerves, such as capsaicin, can produce pain, inflammation and can increase vascular permeability, leading to plasma extravasation. Drugs that block neuropeptide release from sensory nerve endings (substance P, CGRP) are predicted to have analgesic and anti-inflammatory effects. This mechanism of action has been established in other drugs that exhibit peripheral analgesic and anti-inflammatory effects, such as sumatriptan and morphine, which act on 5-HT1 and the mu-opioid receptor, respectively. Both drugs are agonists of the activation receptor and share a common mechanism of signal transduction with the alpha-2 receptor. UK14304, like sumatriptan, has been shown to block plasma extravasation in the dura mater (spine) membrane by a pre-binding effect on the-2 receptor.

Evidence supporting the analgesic effect of clonidine endings was obtained in studies of the effect of intra-articular injection of the drug after the end of knee arthroscopic surgery ((Gentili, M et al (1996) Pain 64: 593-596)). Clonidine is believed to exhibit the anti-nociceptive properties of non-opiates, which would likely allow its use as a replacement for post-operative analgesics. In studies that have been conducted to evaluate the analgesic effects of intravenously administered clonidine during post-operative procedures, it was found that clonidine can delay the onset of pain and reduce pain scores. Thus, numerous studies have demonstrated that drugs acting on alpha-2 adrenergic receptors can exert analgesic effects both during and after surgery, indicating that these receptors are good therapeutic targets for new drugs for pain management.

Alpha-2 receptor agonists, such as UK14304, are defined by the molecular and cellular mechanisms of action, and these compounds are expected to exhibit anti-nociceptive effects at the distal ends of primary afferent nerves when irrigation fluids are applied directly to tissues during surgery.

Alpha-2 receptor agonists are suitable for use in the present invention, either as single agents or in combination with other anti-pain and/or anti-inflammatory agents to inhibit pain and inflammation. Representative alpha-2 receptor agonists for use in the practice of the present invention include, for example: (ii) clonidine; dexmedetomidine; oxymetazoline; ((R) - (-) -3 '- (2-amino-1-hydroxyethyl) -4' -fluoro-methanesulfonyl aniline (NS-49); 2- [ (5-methylbenzo-1--4-oxazin-6-yl) imino]Imidazoline (AGN-193080); AGN 191103 and AGN 192172 as described by Munk.S et al (J.Med.chem.39: 3533-3538 (1996)); 5-bromo-N- (4, 5-dihydro-1H-imidazol-2-yl) -6-quinoxalinamine (UK 14304); 5,6, 7, 8-tetrahydro-6- (2-propenyl) -4H-thiazole [4, 5-d]Aza derivatives-2-amine (BHT 920); 6-Ethyl-5, 6, 7, 8-tetrahydro-4H-oxapyrrolo (oxazolo) [4, 5-d]Aza derivatives-2-amine (BHT933), 5, 6-dihydroxy-1, 2, 3, 4-tetrahydro-1-naphthyl-imidazoline (a-54741).

Watch 19

Treatment and preferred concentrations of alpha-2 adrenergic receptor agonists

F.Multifunctional medicine

In another aspect of the invention, the preferred drugs for inclusion in the ophthalmic irrigating solution are selected taking into account the specific drugs that exhibit more than one of the above-mentioned functional types of effects. The α -2 adrenergic receptor agonists described above provide this example because they can serve the dual function of both IOP-lowering agents and agents that inhibit inflammation and pain. For example, oxymetazoline inhibits inflammation of the eye by inhibiting the release of neurotransmitters that transmit sensations (Fuder H., J.Oul.Pharmacol., 10: 109-. Oxymetazoline can also function like a mydriatic agent through stimulation at alpha-1 adrenergic receptors and can also lower IOP through stimulation at alpha-2 adrenergic receptors (Chu t. et al, Pharmacology, 53: 259-. In addition to anti-inflammatory effects, NSAIDs are also useful for inhibiting intraoperative miosis and thus have the property of dilating the pupil. When such a multifunctional drug is combined with another drug or drugs that can provide at least one additional ophthalmic function not provided by the multifunctional drug, the drug may be suitable for use in the ophthalmic irrigating solution of the present invention.

In addition to the selection of multifunctional drugs, it is also important to avoid the toxic side effects of these topically applied drugs. One advantage of topical application is that systemic side effects are significantly reduced. However, local effects of these drugs must be taken into account, for example, with high concentrations of local anesthetics or steroids can reduce wound healing. Thus, it is preferred that a low concentration of a local anesthetic effective to inhibit neuronal firing while avoiding wound healing problems be used in the present invention (Bisla K, et al, Invest Ophthalmol. Vis. Sci.33: 3029-. Since NSAIDs have proven to be as effective as steroids in controlling inflammation following ophthalmic surgery (Dadeya s. et al, j.pediatr.ophthalmol.stratismus., 39: 166-168(2002)), NSAIDs are preferred to avoid potential non-specific adverse effects of steroids.

Depending on the particular needs of different ophthalmic surgical procedures, a variety of suitable irrigating solutions of the present invention comprising two or more drugs may be formulated according to the present invention, but each solution may not include drugs taken from all of the named functional classes (e.g., analgesics, anti-inflammatory agents, mydriatic agents, and IOP-lowering agents). For example, an irrigation fluid formulated in accordance with the present disclosure for cataract surgery may not require an analgesic because the procedure is not as painful as a vitrectomy.

G.Rinsing carrier

The active agents of the present invention are soluble in physiological fluid wash vehicles. The carrier is suitably an aqueous solution which may contain physiological electrolytes, such as physiological saline or lactated ringer's solution. More preferably, the carrier includes one or more adjuvants, and preferably all of the following adjuvants: sufficient electrolyte to provide a physiologically balanced salt solution; an energy source for the cells; buffers and free radical scavengers. One suitable solution (referred to as a "preferred balanced salt solution" in the examples below) includes: from 50 to 500mM sodium ions, from 0.1 to 50mM potassium ions, from 0.1 to 5mM calcium ions, from 0.1 to 5mM magnesium ions, from 50 to 500mM chloride ions and from 0.1 to 10mM phosphate; bicarbonate buffer at a concentration of from 10 to 50 mM; an energy source of cells selected from dextrose and glucose at a concentration of 1 to 25 mM; and glutathione as a radical scavenger (e.g., antioxidant) at a concentration of from 0.05 to 5 mM. It is suitable when the pH of the rinsing liquid is controlled between 5.5 and 8.0, preferably 7.4.

V.Application method

The solutions of the present invention have been used in a variety of surgical/interventional procedures, including surgical, diagnostic and therapeutic techniques. The irrigating solution is applied perioperatively in ophthalmic surgery. As defined above, the term "perioperative" includes both intra-operative applications, pre-operative and intra-operative applications, intra-operative and post-operative applications, and pre-operative, intra-operative and post-operative applications. Preferably, the solution is applied before and/or after the operation and during the operation. Most preferably, the irrigating fluid is applied to the wound or surgical site prior to the initiation of the procedure, preferably prior to significant tissue trauma, and is continuously applied during the procedure or for most of the time to preferentially block pain and inflammation, inhibit increased intraocular pressure, and/or cause mydriasis. As previously defined, the continuous application of the irrigating fluid of the present invention may be carried out without interruption, or the wound or operation site may be repeatedly and frequently irrigated frequently to adequately maintain the predetermined local therapeutic concentration of the drug used, or the flow of irrigating fluid may be intermittently interrupted during application as required by the surgical technique. At the end of the procedure, additional amounts of the therapeutic drug may be added, for example by intraocular injection of an irrigation solution containing the same or a higher concentration of the active drug, or by intraocular injection or topical application of the drug in a viscoelastic gel.

In the absence of metabolic conversion, the concentration of each drug listed in the solutions of the present invention is the concentration of the drug delivered locally to the surgical site to achieve a predetermined effective level at the surgical site. Since in operation the drug is applied topically directly to the surgical site, this solution applies very low doses of these pain and inflammation inhibitors.

The drug is included in low concentrations in each of the surgical solutions of the present invention and is delivered locally at a lower dose relative to the concentration and dose required to achieve the desired therapeutic effect at the site of the procedure using systemic administration methods.

VI.Examples

The following are exemplary formulations suitable for ophthalmic procedures in accordance with the present invention.

Example 1

Exemplary ophthalmic solutions of the present invention for use during cataract extraction are described in tables 20, 21, and 22. Such solutions, as well as the solutions of tables 23-25 below, are provided by way of example only and are not intended to limit the present invention. The anti-inflammatory effects of the solutions of the present invention are believed to be particularly useful in cataracts, and may be effective in reducing the occurrence of, or promoting resolution of, cystoid edema (CME) after surgery. These exemplary solutions and other exemplary ophthalmic irrigating solutions described herein below are provided according to the concentration of each drug contained in the aforementioned preferred balanced salt solution. By way of non-limiting example, the solution may be adapted to be supplied in 500ml bags, which is a typical amount of rinse applied in operation.

Watch 20

Exemplary cataract solutions

TABLE 21

Alternative exemplary cataract solutions

TABLE 22

Alternative exemplary cataract solutions

Example 2

Table 23 provides similar irrigating solutions containing various drugs effective in reducing inflammation and providing mydriasis for invasive ophthalmic surgery, such as drapery resection.

TABLE 23

Exemplary drape resection solution

Example 3

Irrigation solutions suitable for use in a wide range of ophthalmic procedures or posterior chamber procedures, such as vitrectomy, provide increased analgesia through the addition of a local anesthetic. Tables 24 and 25 provide such local anesthetic-containing solutions of the present invention.

Watch 24

Exemplary ophthalmic solutions for local anesthesia

TABLE 25

Alternative exemplary topical anesthetic ophthalmic solutions

While the preferred embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made in the disclosed solutions and methods without departing from the spirit and scope of the invention. For example, alternative pain suppressants, inflammation suppressants, IOP lowering agents and mydriatic agents may be found, which may be in addition to or in place of the drugs contained in accordance with the disclosure herein. It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto.

Claims (7)

1. Use of a solution comprising at least a first and a second drug in a liquid irrigation carrier for the manufacture of a medicament for inhibiting inflammation and effective mydriasis perioperatively by irrigating intraocular tissue with said solution in ophthalmic intraocular surgery, wherein the first drug is ketorolac as an anti-inflammatory agent and the second drug is neoforskolin as a mydriatic agent.

2. The use of claim 1, wherein the concentration of said anti-inflammatory agent is no greater than 100000nM and the concentration of said mydriatic agent is no greater than 500000 nM.

3. The use of claim 1, wherein the liquid irrigation carrier further comprises an adjuvant selected from the group consisting of electrolytes sufficient to provide a physiologically balanced salt solution, a cellular energy source, a buffer, a free radical scavenger, and mixtures thereof.

4. An intraocular perioperative irrigating solution for inhibiting inflammation and effective mydriasis in ophthalmic intraocular procedures, comprising at least a first and a second drug in a liquid irrigating carrier, wherein the first drug is ketorolac as an anti-inflammatory agent and the second drug is neoforskolin as a mydriasis agent, and wherein the concentration of the anti-inflammatory agent is no greater than 100000nM and the concentration of the mydriasis agent is no greater than 500000 nM.

5. The solution of claim 4 wherein said liquid irrigation carrier further comprises electrolytes sufficient to provide a physiological balanced salt solution, a cellular energy source, a buffering agent, and a free radical scavenger.

6. The solution of claim 5 wherein: if an electrolyte is selected, it contains 50 to 500mM of sodium ions, 0.1 to 50mM of potassium ions, 0.1 to 5mM of calcium ions, 0.1 to 5mM of magnesium ions, 50 to 500mM of chloride ions, and 0.1 to 10mM of phosphate; if a buffer is selected, it contains bicarbonate at a concentration of 10 to 50 mM; if a cellular energy source is chosen, it is dextrose and it is present at a concentration of 1 to 25 mM; and if a radical scavenger is selected, it contains glutathione at a concentration of 0.05 to 5 mM.

7. The solution of claim 5 wherein: if an electrolyte is selected, it contains 50 to 500mM of sodium ions, 0.1 to 50mM of potassium ions, 0.1 to 5mM of calcium ions, 0.1 to 5mM of magnesium ions, 50 to 500mM of chloride ions, and 0.1 to 10mM of phosphate; if a buffer is selected, it contains bicarbonate at a concentration of 10 to 50 mM; if a cellular energy source is chosen, it is glucose and it is present in a concentration of 1 to 25 mM; and if a radical scavenger is selected, it contains glutathione at a concentration of 0.05 to 5 mM.