This application is a continuation-in-part of U.S. Patent Application Serial No. 08/355,461, filed December 13, 1994, which is a continuation of U.S. Patent Application Serial No. 08/137,232, filed October 14, 1993, now abandoned.

Background of the Invention

Local anesthetics, such as proparacaine (Alcaine ^® , available from Alcon Laboratories, Inc.), which nonspecifically stabilize neuronal membranes successfully suppress the transmission of pain stimuli to the CNS. Although useful in many situations, these agents have a relatively short duration of action and can impair the wound healing process. Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase dependent prostaglandin synthesis, have also been used to treat pain; but, these compounds modulate pain perception at the CNS level and, therefore, topical application of these compounds provides analgesia only after systemic absorption of effective concentrations. The NSATD, diclofenac (Voltaren ^® , available from Ciba Vision Ophthalmics), has moderate analgesic properties independent of its effects on prostaglandin synthesis. It is frequently used to alleviate ocular pain.

The perception of pain at the level of the central nervous system (CNS) requires the transmission of pain stimuli by peripheral sensory nerve fibers. These sensory fibers can be activated by mechanical, chemical, pressure, and thermal stimuli. Substance P is a neuropeptide released by pain sensory neurons and is known to participate in the transmission of pain stimuli to the CNS. Substance P receptor antagonists have been proposed as potential analgetic agents. However, the efficacy of this class of compounds as topical, ocular, analgetic agents has not been established.

GB 2 274 777 A discloses compositions containing a combination of NK1 and NK2 receptor antagonists. On page 64 of the application the combination is disclosed for the treatment of a host of diseases and pain of traumatic, post-surgical, menstrual, or cranial origin. In addition, the combination is said to be useful in the treatment of ocular

inflammatory disorders. U.S. Patent No. 5,434,158 discloses neurokinin-3 receptor antagonists to treat CNS disorders, inflammatory diseases, pain, migraine, asthma, and emesis. The compounds are said to be useful in treating ophthalmic diseases such as conjunctivitis and vernal conjunctivitis (col. 16, lines 47, 48). U.S. Patent No. 5,360,820 discloses substance P receptor antagonists for the treatment of emesis. Their usefulness in treating inflammation of the eye is also disclosed (col. 17, lines 59, 60). EP 0 659 409 A2 discloses substance P receptor antagonists for inhibiting angiogenesis and at page 42 mentions their use in treating proliferative retinopathy. None of these references disclose the use of a substance P antagonist for treating ocular pain.

Summary of the Invention

The present invention is directed to compositions for topical, ocular use containing a substance P receptor antagonist, particularly (2S,3S)-3-(2-methoxybenzyl)amino-2- phenylpiperidine, with the structure set forth below ("Compound"). Methods for treating persons suffering from ocular pain with the compositions are also described.

Detailed Description of the Preferred mbodiments

The cornea is highly inervated with sensory afferents which transmit pain stimuli to the CNS. Anything that stimulates these neurons, such as, surgical procedures, accidental trauma, dry eye, and various inflammatory conditions can elicit pain. The Compound of the present invention has proved to be an extremely potent analgesic when dosed topically to the eye and compositions of the Compound are therefore useful in treating painful eye conditions resulting from the above listed events or conditions. In particular the Compound is useful in treating

ocular pain arising from surgical procedures, such as, photo refractive keratotomy (PRK), radial keratotomy, cataract extraction and irritating conditions, including, uveitis, conjunctivitis, dry eye, contact lens intolerance, and trauma.

The Compound is disclosed in U.S. Patent No. 5,364,943 which discloses the preparation of certain substance P receptor antagonists. The Compound is also disclosed in WO 91/09844 which is directed to the treatment of pain, but does not include the treatment of ocular pain. Both publications are incorporated herein by reference.

The Compound, or any pharmaceutically acceptable salts or esters of the Compound, can be incorporated into various types of ophthalmic formulations for topical delivery to the eye. It may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride and water to form aqueous, sterile, ophthalmic suspensions or solutions. Ophthalmic solution formulations may be prepared by dissolving the Compound in a physiologically acceptable isotonic aqueous buffer. The ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound. Also, the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the medicament in the conjunctival sac. In order to prepare sterile ophthalmic ointment formulations, the Compound is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the Compound in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.

The Compound is preferably formulated as a topical ophthalmic suspension or solution, with a pH of about 5.0 to 8.0, preferrably 6.0 to 7.0. The Compound will normally be contained in these formulations in an amount of 0.05 to 2.0 percent by weight (wt.%), but preferably in an amount of 0.1 to 1.0 wt.%. Thus, for topical administration, 1 to 3 drops of

these formulations are delivered to the surface of the eye 1 to 4 times a day according to the routine discretion of a skilled clinician.

Example 1

Ophthalmic Formulation

Ingredient Weight %

Compound 0.5%

Tyloxapol 0.01%

BAC 0.01%

Carbopol 0.1%

Disodium EDTA 0.1%

NaCl 0.45%

Dibasic Sodium Phosphate 0.1%

Monobasic Sodium Phosphate 0.1%

H ₂ O pH = 7.4