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US5760077.Pdf IIIIUSOO5760.077A United States Patent (19) 11) Patent Number: 5,760,077 Shahinian, Jr. 45) Date of Patent: *Jun. 2, 1998 54 TOPICAL OPHTHALMIC ANALGESIC Jean Daniel Arbour, M.D., et al, Should We Patch Corneal PREPARATIONS FOR SUSTANED AND Erosions?. Arch Opgthalmol., vol. 115, 313-317. (Mar. EXTENDED CORNEALANALGESA 1997). 76) Inventor: Lee Shahinian, Jr. 1506 Country Club A K Brahma, et al., Topical Analgesia For Superficial Dr., Los Altos, Calif. 94024 Corneal Injuries, J Accid Emerg Med, 13:186-188. (1996). * Notice: The term of this patent shall not extend beyond the expiration date of Pat. No. Steve A. Arshinoff, M.D.. et al., Pharmacotherapy of Pho 5,610,184. torefractive Keratectomy, J. Cataract Refract Sur. vol. 22. 1037-1044 (Oct. 1996). 21 Appl. No.: 816,762 22 Filed: Mar 11, 1997 Primary Examiner-Zohreh Fay Related U.S. Application Data Attorney, Agent, or Firm-Hana Verny 63 Continuation-in-part of Ser. No. 415,184, Apr. 3, 1995, Pat. 57 ABSTRACT No. 5,610,184, which is a continuation-in-part of Ser. No. 183,186, Jan. 14, 1994, abandoned. A preparation suitable for sustained and extended corneal (S1) Int. Cl. ............... A61K 31/24 analgesia and for repeated administration consisting of 52 U.S. Cl. ........................... 514/540: 514/563; 514/912 ultralow nontoxic subanaesthetic concentrations of local 58 Field of Search ..................................... 514/540, 563. anesthetic agents. A method for corneal analgesia has a fast 514/912 onset of pain relief and extended duration of the corneal 56) References Cited analgesia for several months without accompanying toxic PUBLICATIONS symptoms by administering to a patient an ophthalmic analgesic solution containing a local anesthetic agent in Steve Arshinoff, M.D., Use of Topical Nonsteroidal Anti inflammatory Drugs in Excimer Laser Photorefractive Kera Subanesthetic concentration. tectomy, J. Cataract Refract Sur, vol. 20.216-222. (Supple ment 1994). 21 Claims, 1 Drawing Sheet U.S. Patent Jun. 2, 1998 5,760,077 & 3 O O) o () am to 2 N. s an d () o E O He ss O O O S. S. S S25O 38 to 95 Ol n O t O O (uu u buippe, ue euose used uuz'O) AAISueS oeuoo efDueAW 5,760.077 1 2 TOPCAL OPHTHALMIC ANALGESC it forms the front part of the eye's outer wall and thus PREPARATIONS FOR SUSTA NED AND protects structures inside the eye. Second, with its curved EXTENDED CORNEAL ANALGESA shape, the cornea acts like a camera lens to transmit light and focus images on the retina at the back of the eye. The This is a continuation-in-part application of application 5 epithelium (outermost layer) of the cornea is heavily inner Ser. No. 08/415,184 filed on Apr. 3, 1995, issued as U.S. Pat. wated. Therefore, the cornea is very sensitive, and any No. 5,610.184 on Mar. 11, 1997 which is a continuation-in damage to the surface epithelium can cause severe pain. part application of the application Ser. No. 08/183.186 filed A common cause of such pain is a break in the corneal on January 14, 1994 now abandoned. epithelium. Such epithelial defects can be caused by corneal 10 drying, infection and inflammation which damage epithelial BACKGROUND OF THE INVENTION cells, by corneal dystrophies with loosely adherent 1. Field of Invention epithelium, or by mechanical removal of the corneal epi The current invention concerns a topical ophthalmic anal thelium in traumatic abrasions or surgical procedures. In gesic preparations containing ultralow nontoxic Subanaes most cases, the pain persists until the epithelial defect has thetic concentrations of local anesthetic agents for sustained 15 healed, and extended corneal analgesia by repeated administration. At present, in order to provide immediate but short-term In particular, the invention concerns a topical ophthalmic alleviation of the severe pain experienced by patients suf preparation for corneal analgesia having a fast onset of pain fering from corneal epithelial defects, commercially avail relief and extended duration of the corneal analgesia. The able local anesthetics can be applied topically to the eye, preparation may be administered for several months without providing rapid onset of short-acting corneal anesthesia. accompanying toxic symptoms. The topical analgesic prepa Two commonly used topical anesthetics are proparacaine in ration contains a local anesthetic agent in ultralow suban a concentration of 0.5% (5,000 ug/ml) and tetracaine 0.5% aesthetic concentration. The analgesic microdose system (5,000 pg/ml). Lidocaine 4% (40,000 ug/ml) is also occa contains concentration between about 0.001 and 1.0% of the sionally used. anesthetic agent per 1-10 ul. 25 While short-term relief from pain accompanies the appli 2. Background Art and Related Art Disclosers cation of these anesthetics, there are conditions of the cornea Trauma to the eye, particularly corneal injury and where such short term relief from pain is not sufficient and abrasion, tends to be excruciatingly painful. While many where prolonged analgesia is necessary and desirable. This anesthetic agents such as proparacaine. cocaine, procaine, is especially true for relief of pain associated with corneal tetracaine, hexylcaine. bupivacaine, lidocaine, benoximate. epithelial defects. In these instances, the toxicity associated mepivacaine, prilocaine and etidocaine, to name a few, are with repeated use of topical anesthetics for achieving sus well known to attain temporary anesthesia and suppression tained corneal analgesia has been well documented. In of pain, concentrations of these agents needed to achieve Ocular Pharmacology. Fifth Edition, C. V. Mosby, St. corneal anesthesia are between 0.25% and 4%. At these 35 Louis, pages 75-76 (1983), the repeated use of anesthetic concentrations, these agents can only be administered for a concentrations of topical anesthetics was found to be detri very short period of time necessary to achieve local anes mental to the cornea, and the article states that the repeated thesia and permit performance of ophthalmic procedures use of anesthetics is prohibited because of their toxicity. such as examination of a painful eye. measurement of Thus, the toxicity of these anesthetic agents precludes their intraocular pressure, gonioscopic examination, removal of 40 repeated use for prolonged corneal analgesia. At this time, foreign bodies and sutures from the cornea, diagnostic therefore, acceptable methods for long-term relief of corneal conjunctival and corneal scrapings, radial keratotomy, and pain are limited to patching and oral analgesics. other surgical procedures. The onset of the anesthesia is very Patching provides partial pain relief in some patients by rapid, typically under 15 seconds, and typically lasts for reducing eyelid movement over the corneal surface and about 10-30 minutes. Unfortunately, application of local 45 limiting exposure to the outside environment. However, anesthetics to the cornea at these concentrations causes the patching has many disadvantages. It is difficult for the development of temporary superficial corneal epithelial patient to reapply the patch properly when it becomes loose lesions. Upon repeated application for prolonged anesthesia, or soiled. Patching restricts the frequent use of topical these lesions progress to extensive erosions of the corneal medications. It raises the temperature of the eye surface and epithelium and grayish infiltrates of the corneal stroma 50 thus supports the growth of microorganisms. Finally, many which can lead to permanent scarring and loss of vision. patients are uncomfortable with an eye patched. While Prolonged application of local anesthetics is further associ patching with a bandage soft contact lens may overcome ated with delayed corneal reepithelialization after wounding, some of these problems, patching provides incomplete pain altered lacrimation and tear film stability, corneal swelling. relief in most patients and is no substitute for sustained and disruption of epithelial cell mitosis and migration. 55 analgesia in patients suffering from corneal epithelial It is therefore clear that the use of local anesthetics in their defects, where the pain can persist for several days to several normal and intended manner is limited to short-term anes weeks or months. thesia and cannot be safely utilized for sustained decrease or Oral agents are reasonably effective in reducing corneal elimination of pain over several hours or days. pain. However, onset of action is gradual and slow rather Anesthesia, which is a partial or total loss of the sense of than immediate. Doses adequate for corneal analgesia are pain, temperature, and touch, is very different from high and usually cause significant generalized sedation, analgesia, a state in which the individual does not feel pain occasionally accompanied by nausea and vomiting and but feels other sensations, such as touch or temperature. rarely by life-threatening allergic reactions. Sustained ophthalmic analgesia is very difficult to It would therefore be highly desirable and advantageous achieve. This is particularly true with respect to corneal 65 to have available a method for treatment of acute and analgesia. The cornea is the clear dome-shaped window in chronic corneal pain without exposing a patient to the the front of the eye. The cornea serves two functions. First, undesirable side effects of currently available oral 5,760.077 3 4 analgesics, to the inadequate analgesia and inconvenience "Microdose" or "microdrop” means a measurable amount associated with patching, or to the toxic effects of repeated of the ophthalmic
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