(12) United States Patent
`Gil et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006294553Bl
`US 6,294,553 Bl
`Sep.25,2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) METHOD FOR TREATING OCULAR PAIN
`
`(75)
`
`Inventors: Daniel W. Gil, Corona Del Mar;
`Michael E. Stern, Mission Viejo; John
`E. Donello, Dana Point, all of CA (US)
`
`(73) Assignee: Allergan Sales, Inc., Irvine, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/783,160
`
`(22) Filed:
`
`Feb. 14,2001
`
`(52) U.S. Cl. .............................................................. 514/314
`(58) Field of Search ............................................... 514/314
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,242,442
`6,248,741
`
`6/2001 Dean eta!. ....................... 514/222.8
`6/2001 Wheeler eta!. ..................... 514/249
`
`Primary Examiner-Raymond Henley, III
`(74) Attorney, Agent, or Firm-Robert 1. Baran; Martin A
`Voet; Carlos A Fisher
`
`(57)
`
`ABSTRACT
`
`Related U.S. Application Data
`(60) Provisional application No. 60/182,609, filed on Feb. 15,
`2000.
`
`The invention relates to the use of brimonidine for treating
`ocular pain.
`
`(51)
`
`Int. Cl? ..................................................... A61K 31/47
`
`11 Claims, 1 Drawing Sheet
`
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`US 6,294,553 Bl
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`1
`METHOD FOR TREATING OCULAR PAIN
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`This patent application claims priority from provisional 5
`patent application 60/182,609 which was entitled
`"METHOD FOR TREATING OCULAR PAIN" and was
`filed on Feb. 15, 2000.
`
`FIELD OF THE INVENTION
`
`This invention relates to the topical application of bri(cid:173)
`monidine for treating ocular pain and neurogenic inflamma(cid:173)
`tion and compositions useful for such application.
`
`BACKGROUND OF THE ART
`
`Pain is a well known phenomenon as an indicator of
`injury or tissue damage due to inflammation, ischemia,
`mechanical or other irritation.
`The first step leading to the sensation of pain is the 20
`activation of nociceptive primary afferents by intense
`thermal, mechanical or chemical stimuli. Indirect studies of
`nociceptive transduction (activation) indicate that it involves
`chemical mediators that are released or synthesized in
`response to tissue damage. These chemical mediators 25
`include lactic acid, hypertonic saline, histamine,
`5-hydroxytyptamine, potassium chloride, acetylcholine,
`purines, bradykinin and substance P which are referred to as
`algesic agents. In recent years it has been shown that
`prostaglandins and leukotrienes can contribute to the acti- 30
`vation of primary afferent nociceptors. Prostaglandins are
`uniquely distinguished from the other chemical mediators in
`that they induce a state of hyperalgesia by elevating the
`sensitivity of pain receptors to other painful or algesic
`stimuli.
`The stimulation of primary afferents leads to action poten(cid:173)
`tials in their axons which propagate to the spinal cord. In
`addition, excited primary afferents release neuropeptides
`(substance P, calcitonin gene-related peptide, neurokinin A)
`at their peripheral terminals. Neuropeptides enhance inflam- 40
`matory reactions in the injured tissue, contributing to
`vasodilation, edema, and increased vascular permeability,
`this phenomenon is called 'neurogenic inflammation'.
`In the spinal cord, the nociceptors enter the gray matter of
`the superficial dorsal horn to synapse on nerve cells con- 45
`tributing to pain-transmission pathways such as the
`spinothalamic and spinoreticulothalamic tracts which termi(cid:173)
`nate in two separate regions in the thalamus. The two
`thalamic regions in turn project to different cortical sites.
`The pain transmitting and modulating system depicted so
`far depends on numerous chemical moieties for its inte(cid:173)
`grated function.
`Anesthetics block neuronal transmission and affect sen(cid:173)
`sation as well as pain. Analgesics act by interfering with the
`activity of chemical mediators of nociception without affect(cid:173)
`ing sensory input.
`According to Remington's Pharmaceutical Sciences, 17th
`Ed., analgesics can be classified as falling into at least three
`loose groups: 1) the opiate-based (narcotic) analgesics; 2)
`the non-opiate analgesics; and 3) analgesics and antipyret(cid:173)
`Ics.
`The opiate-based analgesics include opium derived
`alkaloids, including morphine, codeine, and their various
`derivatives, opiate antagonists, the several morphine deriva(cid:173)
`tives which have morphine antagonist activity, but have
`analgesic activity.
`
`2
`Since these narcotic type drugs are addictive, a number of
`nonaddictive, non-opiate analgesics have been developed in
`an attempt to produce an analgesic which is highly efficient
`but not addictive.
`In the third broad category, the analgesics and
`antipyretics, are the salicylates and acetamide-containing
`compounds and the so-called non-steroidal anti(cid:173)
`inflammatory drugs. They are non-addictive pain killers.
`As to their mode of action, drugs that block perception of
`10 pain may be said to act either centrally (such as narcotics) or
`peripherally.
`The non-steroidal anti-inflammatory agents (NSAIAs)
`have been described as peripheral pain relievers. It was
`15 further suggested that the analgesic properties of these drugs
`are independent of their antiedema or anti-inflammatory
`actions.
`The action of NSAIAs as pain relievers is associated with
`the biosynthesis of prostanoids.
`Inflammation or trauma and resultant tissue injuries cause
`the release of arachidonic acid which is degraded by cyclo(cid:173)
`oxygenase and lipoxygenase. The cyclo-oxygenase pathway
`leads to the synthesis of prostaglandin E2 (PGE2) and other
`mediators. PGE2 release increases the cyclic AMP and ionic
`calcium levels at the nociceptor membrane resulting in a
`lowered activation threshold, resulting in the relay to the
`central nervous system of augmented pain perception
`(hyperalgesia). Inhibitors of prostaglandin synthesis, such as
`NSAIAs, act by avoiding the sensitizing effects of prostag(cid:173)
`landins on nociceptive endings and therefore, the decrease in
`pain threshold.
`In animal models and human studies non-steroidal anti(cid:173)
`inflammatory agents have been shown to inhibit inflamma(cid:173)
`tory pain.
`Ophthalmic applications of various NSAIAs are also
`known, including the utilization of their anti-inflammatory
`properties for control of various ocular inflammations.
`NSAIAs have been used for the treatment of non(cid:173)
`inflammatory, localized pain, such as non-inflammatory
`ocular pain.
`Calcium channel blockers have been suggested as useful
`for treating pain, including ocular pain.
`
`35
`
`SUMMARY OF THE INVENTION
`
`55
`
`As will be appreciated from the above, various
`peripherally-acting analgesics, anesthetics, etc. have been
`used to treat ocular pain. However, nowhere is it suggested
`that the compound utilized in the method of the present
`50 invention, i.e. brimonidine that is a centrally-acting analge(cid:173)
`sic in animal models, may be used to treat ocular pain.
`The present invention is based on the unexpected finding
`that brimonidine efficiently relieves ocular pain, including
`ocular pain associated with corneal injuries.
`The use of a topical composition, including brimonidine,
`for the relief of eye pain offers several benefits over the use
`of systemic agents because of the decreased systemic
`absorption, which may decrease side-effects, and increased
`60 ocular absorption that can increase efficacy.
`Alpha-2 agonists including brimonidine have been shown
`to alleviate systemic pain in animal models, including hot
`plate, tail flick and nerve ligation. One alpha-2 agonist,
`clonidine, is administered epidurally for treating chronic
`65 pain in humans.
`The sites of action are presumed to be in the spinal cord
`and in the brain, where they can reduce the perception of
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`pain. One potential mechanism for the alleviation of pain at
`the level of the spinal cord is the inhibition of release of the
`chemical mediators of pain, including substance P and
`calcitonin gene-related peptide. This mechanism has been
`demonstrated in vitro for the alpha-2 agonist,
`dexmedetomidine, acting on rat spinal cord slices (M.
`Takano, Y. Takano and T. Yaksh, 1993, Release of calcitonin
`gene-related peptide, substance P, and vasoactive intestinal
`polypeptide from rat spinal cord: modulation by alpha-2
`agonists, Peptides 14, 371-378), and for brimonidine (UK
`14304) acting on cultured dorsal root ganglion cells (S.
`Supowit et al., 1998, Alpha-2 adrenergic receptor activation
`inhibits calcitonin gene-related peptide expression in cul(cid:173)
`tured dorsal root ganglia neurons, Brain Res. 782, 184-193).
`Accordingly, the present invention relates to a method for
`treating ocular pain in a mammal afflicted by such pain,
`which method comprises applying to the eye of said mam(cid:173)
`mal an effective amount of brimonidine in a pharmaceuti(cid:173)
`cally acceptable vehicle.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`FIG. 1 shows a recording of the rabbit eye response to
`O.SM NaCl, alone, and in the presence of brimonidine.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Brimonidine has the structure
`
`and is also known as 5-bromo-6(2-imidazolin-2-ylamino)
`quinoxaline. It is available from Allergan, Inc. as the
`D-tartrate salt and used for treating glaucoma.
`An effective dose, when it comes to topical, ocular pain,
`is a matter of broad therapeutically effective dose require(cid:173)
`ments. This figure is one controlled by a number of factors:
`the inherent activity of the drug itself; the vehicle in which
`it is administered, primarily topical delivery being antici(cid:173)
`pated; the size of the area to be treated; and the intensity of 45
`the pain. Exact dosing data have not been determined but it
`is anticipated that a topical formulation having between
`0.01% and 0.5% (weight/volume) of a brimonidine will
`provide relief from ocular pain. The determination of the
`effective dose for any selected compound is well within the 50
`skill of an ordinary skilled physician.
`In the practice of this invention, brimonidine may be
`administered in any manner which will deliver the drug
`directly to the locale of the pain to be treated. It is anticipated
`that this will be by application to the immediate area of 55
`distress. For example, the drug could be applied topically, or
`by some similar means which delivers the drug directly to
`the affected area. It is not intended that this invention be
`practiced by administering the drug in such a way as to
`insure that it gets to the central nervous system. In fact, that
`would defeat the whole purpose of this invention which is
`focused on treating the pain at its source.
`For ophthalmic application, preferably solutions are pre(cid:173)
`pared typically containing from about 0.01% to about 0.5%
`of active ingredient, and a physiological saline solution as a
`major vehicle. The pH of such ophthalmic solutions should
`preferably be maintained between 6.5 and 7.2 with an
`
`4
`appropriate buffer system. The formulations may also con(cid:173)
`tain conventional, pharmaceutically acceptable
`preservatives, stabilizers and/or penetration enhancers.
`The preferred vehicle that may be used in the ophthalmic
`5 solutions of the present invention is purified water, more
`preferably a physiological saline solution. Additional suit(cid:173)
`able vehicles include but are not restricted to, viscosity
`agents such as polyvinyl alcohol, povidone, hydroxypropyl
`methyl cellulose, poloxamers, carboxymethyl cellulose, car-
`lO bomer and hydroxyethyl cellulose.
`Preferred preservatives that may be used in the oph(cid:173)
`thalmic formulations of the present invention include, but
`are not limited to, benzalkonium chloride, chlorobutanol,
`thimerosal, phenylmercuric acetate and phenylmercuric
`15 nitrate.
`Penetration enhancers may, for example, be surface active
`agents; certain organic solvents, such as dimethylsulfoxide
`and other sulfoxides, dimethylacetamide and pyrrolidone;
`certain amides of heterocyclic amines, glycols (e.g., propy-
`20 lene glycol); propylene carbonate; oleic acid; alkyl amines
`and derivatives; various cationic, anionic, nonionic, and
`amphoteric surface active agents; and the like.
`Tonicity adjustors may be added as needed or convenient.
`They include, but are not limited to, salts, particularly
`25 sodium chloride, potassium chloride, mannitol and glycerin,
`or any other suitable opthalmically acceptable tonicity
`adjustor.
`Various buffers and means for adjusting pH may be used
`so long as the resulting preparation is ophthalmically accept-
`3D able. Accordingly, buffers include acetate buffers, citrate
`buffers, phosphate buffers and borate buffers for ophthalnic
`use.
`In a similar vein, an ophthalmically acceptable antioxi(cid:173)
`dant for use in the present invention includes, but is not
`35 limited to, sodium metabisulfite, sodium thiosulfate,
`acetylcysteine, butylated hydroxyanisole and butylated
`hydroxytoluene.
`Other excipient components which may be included in the
`ophthalmic preparations are chelating agents. The preferred
`40 chelating agent is edetate disodium, although other chelating
`agents may also be used in place or in conjunction with it.
`The invention is further illustrated by the following
`non-limiting examples.
`
`EXAMPLE 1
`
`A clinical study is performed to compare the analgesic
`effect of topically administered brimonidine and placebo
`following radial keratotomy surgery. One hundred and
`twenty-four male and female subjects, 21 to 45 years of age,
`undergo routine, elective, unilateral radial keratotomy for
`the correction of myopia and brimonidine is administered as
`a 0.03% ophthalmic solution.
`Each subject receives one drop of the assigned study
`medication every four hours while awake one day prior to
`surgery and again every 20 minutes for the two hours just
`before surgery. Each subject then undergoes unilateral radial
`keratotomy. Following surgery, each subject receives one
`drop of the study medication in the operated eye every four
`60 hours while awake for 14 consecutive days. Postoperative
`examinations occur at days 1, 3, 7 and 14.
`Efficacy is assessed by evaluation of pain intensity, pain
`relief, subjective global analgesic efficacy. Symptoms of
`ocular inflammation (burning/stinging, tearing, etc.) are also
`65 recorded.
`The results of this study show greater pain relief at hours
`2, 3 and 4 in the brimonidine group over the group treated
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`with placebo. This appears to suggest that brimonidine,
`administered preoperatively, blocks the perception of pain.
`
`EXAMPLE 2
`
`A 54 year old woman, hard contact lens wearer, has a one
`day history of sharp shooting pain in both eyes. Brimonidine
`is prescribed as a sole treatment of pain. On instillation of
`the medication, the patient reports relief of pain for appro xi(cid:173)
`mately two and a half hours. Upon recurrence of pain, a
`second dose of brimonidine provides pain relief.
`
`EXAMPLE 3
`
`A 32 year old female patient with a history of gas(cid:173)
`permeable contact lens wear has a two-to-three day history
`of pain in her left eye. The patient is treated with brimoni(cid:173)
`dine for pain. The patient reports relief of pain for two hours.
`
`EXAMPLE 4
`
`The effect of brimonidine on ocular pain is also studied
`using the Corneal Nerve Conduction Model. This model is
`performed in rabbits as a way to determine the types and
`quantity of nerve traffic generated as the cornea is exposed
`to various stimuli. In this model, a rabbit under deep
`anesthesia is placed in a stereotaxic apparatus. The retro(cid:173)
`orbital space is surgically exposed and a hook electrode is
`placed around the ciliary nerve that sits adjacent to the optic
`nerve. The ocular surface is fitted with a chamber through
`the use of a conjunctival pharyngeal ring into which test
`formulations can be added.
`A dose range of an ophthalnic formulation ofbrimonidine
`(0.01% to 0.5% for instance) as well as a vehicle is filled into
`the chamber and the resultant nerve traffic from the cornea
`is recorded. In this way the effects of brimonidine on ocular
`surface sensation is determined. This study is also performed
`in the presence of an ocular surface sensory challenge such
`as topical capsaicin, potassium chloride or fine hairs.
`Ocular responses characteristic of neurogenic
`inflammation, including redness and pupillary constriction,
`are also observed in rabbits following external stimuli. The
`ability of an ophthalmic solution of brimonidine at concen(cid:173)
`trations ranging from 0.01% to 0.5% to reduce the neuro(cid:173)
`genic response at 5, 10, 15, 30 and 60 minutes following
`administration is determined. Brimonidine is effective in
`reducing such neurogenic responses.
`
`EXAMPLE 5
`
`It has been found that the rabbit neurophysiological model
`is a predictor of actions on the corneal nerves that are 50
`associated with the sensation of corneal irritation and pain in
`humans. Thus, this experiment is carried out in the anesthe(cid:173)
`tized rabbit and enables one to make decisions as to the
`effect on the human eye. By comparison with the human
`psychophysical studies it has been determined when the
`corneal nerves are activated in the rabbit model-pain would
`be sensed in the human. When the amount of neural activity
`is decreased the amount of pain or sensory irritation in the
`human would decrease. In the rabbit neurophysiological
`model, one records from the primary sensory axons so the
`results reflect what is occurring at the sensory receptor in the
`corneal epithelium.
`The FIGURE shows a response at the top, a control
`response to mechanical stimulation, this is carried out to
`ensure that the preparation is lively. Test solutions are put
`into a chamber, about 1 cc, over the surface of the cornea.
`The test solution is blocked from reaching the axons where
`
`60
`
`6
`the recording is made. Application of a standard stimulus,
`O.SM NaCl for 30 seconds elicits rapid action potential
`activity which lasts beyond the end of the stimulus. The
`NaCl is washed away by several applications of saline.
`5 Brimonidine, as Allergan, Inc.'s Alp hagan® pharmaceutical
`composition, was put into the chamber for 1 minute, and not
`washed before retesting with the O.SM NaCl. This was
`repeated at several intervals and resulted in a decrease in the
`response for the O.SM NaCI. Overall, three runs were made
`and the response decreased by about 35% at 5 mins and then
`continued to decrease at 10 mins by about 50%. The
`interpretation of this result is that the sensory response to the
`human cornea would be decreased. At 60 mins it was found
`that the response to O.SM NaCl had returned to about that of
`the pretest solution. In each record, the top part indicates the
`15 raw data and the bottom record the integrated response.
`Also, at the beginning of each record there is a response to
`mechanical stimulation. Brimonidine does not alter that
`response to any real extent. It is commonly found that the
`chemical thermal response is more labile to drug applica-
`20 tion. At the same time, preservation of the mechanical
`response is important for the health of the cornea. In
`contrast, a topical anesthetic would rapidly decrease the
`response to mechanical and chemical modalities.
`While further experiments would be desirable to validate
`25 these results, these results are indicative that brimonidine
`may be useful to decrease corneal sensory irritation and
`pain.
`The foregoing description details specific formulations
`and methods that can be employed to practice the present
`invention. Having detailed specific compositions for the
`topical formulations of the present invention and specific
`instructions for their use in the treatment of ocular pain, the
`art skilled will well enough know how to devise other
`formulations and how to adapt the treatment (formulations,
`doses) to a special situation. Thus, however detailed the
`foregoing may appear in text, it should not be construed as
`limiting the overall scope hereof; rather, the ambit of the
`present invention is to be governed only by the lawful
`construction of the appended claims.
`What is claimed is:
`1. A method for alleviating ocular surface pain in a
`mammalian eye comprising administering to a mammalian
`eye having ocular surface pain an amount of brimonidine
`effective to alleviate the ocular surface pain.
`2. The method of claim 1 wherein said mammalian eye is
`a human eye.
`3. The method of claim 1 wherein said administration is
`topical administration directly to said eye.
`4. The method of claim 1 wherein said brimonidine is
`administered in solution in a pharmaceutically acceptable
`ophthalmic vehicle.
`5. The method of claim 1 wherein said effective amount
`is from about 0.005 to about 1 mg per eye per day.
`6. The method of claim 4 wherein said vehicle contains
`55 from about 0.05 to about 5 mg per ml of said brimonidine.
`7. The method of claim 1 wherein said pain is associated
`with a wound or inflammation in said eye.
`8. The method of claim 1 wherein said pain is associated
`with radial keratotomy.
`9. The method of claim 1 wherein said pain is associated
`with treatment by a laser.
`10. The method of claim 9 wherein said laser is an
`excimer laser.
`11. The method of claim 1 wherein said pain is associated
`65 with corneal abrasion.
`* * * * *
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