WO1997044062A1

WO1997044062A1 - The use of 5-ht1b/1d agonists to treat ocular pain

Info

Publication number: WO1997044062A1
Application number: PCT/US1997/005465
Authority: WO
Inventors: Daniel A. Gamache; Najam Sharif
Original assignee: Alcon Laboratories, Inc.
Priority date: 1996-05-23
Filing date: 1997-04-02
Publication date: 1997-11-27
Also published as: AU2434297A

Abstract

Compositions and methods for treating ocular pain are disclosed. In particular, the invention discloses compositions and methods of using 5-HT1B/1D agonists for the prevention or alleviation of ocular pain.

Description

The Use of 5-HT,_B/1D Agonists to Treat Ocular Pain

The present invention relates to the pharmaceutical treatment of pain. In particular,

the present invention relates to the use of 5-HT_{1 B/1 D} receptor agonists and partial agonists

for the prevention or alleviation of pain in the eye.

Background of the Invention

Pain is a perceived nociceptive response to local stimuli in the body. The perception

of pain at the level of the central nervous system requires the transmission of painful stimuli by peripheral sensory nerve fibers. Upon stimulation of tissue (i.e., thermal, mechanical or

chemical), electro-chemical signals are transmitted from the sensory nerve endings to the

spinal column, and hence to the brain where pain is perceived.

The cornea is highly innervated with sensory afferents which transmit various

painful stimuli to the central nervous system. Pain conditions involving the eye, therefore,

can arise in numerous instances such as, foreign body stimulus, inflammation, dry eye

syndrome, accidental trauma, surgical procedures and post-surgical recovery. For example,

ocular pain can result from photorefractive keratotomy (PRK), a vision correcting, surgical

procedure whereby a laser is used to shape the cornea. This process involves the

photoablation of Bowman's membrane and the stromal levels of the cornea. As a result, the denuding of the nerve-containing epithelial layers of the cornea can cause some patients to

experience pain following laser surgery until the epithelium regenerates.

Various therapies have been attempted for the alleviation of pain. The use of non-

steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, have been developed to

treat pain. These agents inhibit cyclooxygenase dependent prostaglandin synthesis.

Prostaglandins can modulate pain perception at the level of the central nervous system and

systemic administration of NSAIDs is known to provide analgesia. However, the use of

NSAIDs can involve undesired side effects including gastrointestinal bleeding and kidney

dysfunction.

Opiates are another class of compounds used to treat pain. Opiates can be

administered in a number of ways. For example, opiates can be administered systemically, by intravenous injection or oral dosage, or locally, by subcutaneous, intramuscular or

topical application. Opiates, however, have been associated with several problems including

dose escalation (tolerance), addiction, respiratory depression and constipation.

Local anesthetics are another class of pain modulators which relieve pain by directly

inhibiting nerve cellular function. One problem of local anesthetic therapy is the short

duration of action. Furthermore, as local anesthetics cause non-specific membrane

stabilization, they can have the undesired coincident effect of also inhibiting other

biological functions, such as fibroblast and surrounding neuronal activity. Therefore, even

though pain sensation can be abated with local anesthetic treatment, healing and normal

function of the tissue may be significantly compromised.

Other agents have also been suggested for use in treating pain. Such agents include tricyclic antidepressants such as imipramine and desipramine, alpha-2 adrenergic agonists, serotonin uptake blockers, such as prozac, and other analgesics such as paracetamol, as

described in United States Patent No. 5,270,050 (Coquelet et al.). Some of these therapies,

however, have been associated with side-effects such as dryness of mouth, drowsiness,

constipation, and low potencies and efficacies.

A class of agents which potently and specifically inhibit the transmission of painful

stimuli by sensory afferents without local anesthetic activity following topical ocular

application has yet to be described.

Serotonin, or 5-hydroxytryptamine ("5-HT'), is an endogenous peripheral and

central neurotransmitter. Activation of serotonin receptors elicits the transduction of

specific intracellular signals which lead to various physiological responses, depending on

the receptor sub-type activated and the tissue stimulated. Certain classes of molecules have

been discovered which bind to 5-HT receptors and either elicit 5-HT agonist or antagonist responses. Researchers have pursued the use of various 5-HT receptor agonists and

antagonists in an effort to modulate cellular activity, and hence, effect various therapies to

the afflicted tissues.

A number of different sub-types of 5-HT receptors have been discovered, based on differential agonist/antagonist sensitivities, second messenger coupling and protein structures. Such sub-types include, for example, 5-HT_1B, 5-HT_{1 D}, 5-HT_1Λ and 5-HT_2A

(Hoyer et al., VII. International Union of Pharmacology Classification of Receptors for 5-

Hydroxytryptamine (Serotonin), Pharmacological Reviews, volume 46, No. 2, Pages 157-

170 (1994)). While all serotonin receptors bind serotonin, different sub-types of serotonin

receptors, which demonstrate a selective sensitivity to different agonists and antagonists,

exist in various tissues and species. As noted by Hoyer et al. (1994), there are significant W /

differences in the types of serotonin receptors evident among various species. For example,

the 5-HT_1B receptor exists in rodents, while the homolog of this receptor, the

pharmacologically defined 5-HT_1D receptor, exists in canine, pig and human species

(Adham et al., 1992 and Hoyer et al., 1994).

Numerous therapies involving the manipulation of various serotonin receptors have

been attempted. For example, the use of 5-HT₃ antagonists to treat emesis in cancer

chemotherapy patients is disclosed in U.S. Patent No. 5,446,050 (Rosen); the use of certain

5-HT, agonists to treat a myriad of ailments is disclosed in U.S. Patent No. 5,409,941

(Nowakowski); and the use of 5-HT₂ antagonists to treat CNS disorders such as anxiety

have been disclosed in U.S. Patent No. 5,393,761 (Perregaard et al.). However, nowhere in

these publications has it been disclosed to use 5-HT_1B or 5-HT_1D agonists for the treatment

of ocular pain.

Summary of the Invention

The present invention is directed to compositions and methods for treating ocular

pain. The present invention is based in part on the finding that compounds which bind to

certain serotonin receptor subtypes in the eye inhibit ocular pain. More specifically, the

present invention provides compositions containing 5-HT_1D and/or 5-HT_1B agonists for the

treatment of ocular pain.

The methods of the present invention involve the topical dosage of the compositions described above. One advantage of this therapy is that the inhibition of pain is receptor-

specific, as contrasted with non-specific therapy, such as local anesthetic treatment. This specific activity may reduce greatly the number of dosings per day, and also reduce the

drawbacks of short duration of action and inhibition of wound healing which are associated

with local anesthetics. Additionally, serotonin receptor binding agents acting locally within

ocular tissue avoid the problems of tolerance, addiction and constipation associated with the

chronic, systemic administration of opiates.

Detailed Description of the Invention

The present invention is directed to the use of 5-HT_1D and/or 5-HT_1B receptor

agonists for the prevention or alleviation of pain. It has now been found that 5-HT_{1B/1 D}

agonists potently prevent or alleviate ocular pain. The 5-HT_{] D} ("ID") receptor is found in

human tissue such as cerebral arteries and parts of the brain, such as the basal ganglia, raphe

and the cerebral cortex (Hoyer et al, (1994)). The 5-HT_1B ("IB") receptor, thus far, has

been found in the CNS and peripheral nerves of other species such as rat, mouse and

hamster. However, the IB receptor has been shown to possess similar homology, and thus similar sensitivity, as the ID receptor (Hoyer et al., Pharmacological Reviews, at 167-170).

It has now been found that IB receptor agonists will activate ID receptors.

The compounds of the present invention are ID agonists, IB agonists or IB/ ID

agonists. As used herein, a "IB agonist" refers to a compound which activates a IB

receptor, a "ID agonist" refers to a compound which activates a ID receptor, and a "IB/ ID

agonist" refers to a compound which activates either a 1 B or a 1 D receptor.

Preferred IB/ ID compounds of the present invention are:

7-trifluoromethyl-4(4-methyl- 1 -piperazinyl)-pyrrolo[ 1 ,2-a]quinoxaline maleate (CGS-12066A)

Anpirtoline

CP-93129

RU-24969 5-carboxamidotryptamine (5-CT)

5-methoxy-n,n,dimethyl-tryptamine

Sumatriptan (GR43175C)

L-694247

Metergoline LY165163 (PAPP)

BMS- 180048

The most preferred IB/ID agonist is 7-trifluoromethyl-4(4-methyl-l-piperazinyl)- pyrrolo[l,2-a]quinoxaline maleate (CGS-12066A). Other classes of IB/ ID agonists have

been suggested or are known in the art and may be useful in the present invention. For

example, U.S. Patent Nos. 5,504,104 (Glennon) and 5,252,749 (Badorc et al.) disclose

tryptamine analogs and thienocyclopentanone oxime ethers, respectively, and WIPO Patent

Publication No. WO 95/14004 (Halazy et al.) discloses azylpiperazines, for use as IB/ID

agonists. The IB/ID agonists of the present invention are available from commercial

sources or may be synthesized by methods known to those skilled in the art.

The following is an example of the anti-pain efficacy of CGS-12066A, a preferred

IB/ID agonist of the present invention: Example 1

Drug candidates were tested in a formalin-induced model of ocular pain in the rat.

Briefly, 20 μL of a drug candidate or vehicle (maxidex vehicle) were applied topically at

various times between 1 and 30 minutes prior to the administration of formalin. 5 μL of a

0.1% w/v formalin solution (5 μg) was then topically applied using an eppendorf pipette.

Blinking began immediately and the frequency over the first minute was determined. The 5

μg dose of formalin typically yielded about 40-50 blinks in the first minute. The control counts of vehicle animals were compared to the counts of dosed animals and percent

inhibition was then calculated. The results are illustrated in Table 1 below:

Table 1

The IB/ID agonists of the present invention will be contained in topical compositions,

in accordance with formulation techniques known to those skilled in the art. The compounds

may be included in solutions, suspensions and other dosage forms adapted for the particular

IB/ ID agonist and dosing regimen. The present invention is particularly directed to the provision of compositions adapted

for topical treatment of ophthalmic tissues. The ophthalmic compositions of the present

invention will include one or more IB/ID agonists and a pharmaceutically acceptable vehicle

for these agonist(s). Various types of vehicles may be used. The vehicles will generally be

aqueous in nature. Aqueous solutions or suspensions are generally preferred, based on ease of

formulation, as well as a patient's ability to easily administer such compositions by means of

instilling one to two drops of the solutions in the affected eyes. However, the compounds of

the present invention may also be readily incorporated into other types of compositions, such

as suspensions, viscous or semi-viscous gels or other types of solid or semi-solid

compositions. Suspensions may be preferred for IB/ ID agonists which are relatively

insoluble in water. The ophthalmic compositions of the present invention may also include

various other ingredients, such as buffers, preservatives, co-solvents and viscosity building

agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium

borate) may be added to prevent pH drift under storage conditions.

Ophthalmic products are typically packaged in multidose form. Preservatives are thus

required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben,

phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known

to those skilled in the art. Such preservatives are typically employed at a level of from 0.001

to 1.0 percent by weight, based on the total weight of the composition (wt.%).

Some of the compounds of the present invention may have limited solubility in water

and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: polyethoxylated castor oils, Polysorbate 20, 60 and 80; Pluronic®

F-68, F-84 and P-103 (BASF Corp., Parsippany NJ, USA); cyclodextrin; or other agents

known to those skilled in the art. Such co-solvents are typically employed at a level of from

0.01 to 2 wt.%.

Viscosity greater than that of simple aqueous solutions may be desirable to increase

ocular absorption of the active compound, to decrease variability in dispensing the

formulations, to decrease physical separation of components of a suspension or emulsion of

formulation and/or otherwise to improve the ophthalmic formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,

hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,

hydroxypropyl cellulose or other agents known to those skilled in the art. Such agents are

typically employed at a level of from 0.01 to 2 wt.%.

The compounds may also be used for treating irritated tissues following ophthalmic

surgery. The compounds may be used for acute treatment of temporary conditions, or may be

administered chronically. The compounds may also be used prophylactically, especially prior

to ocular surgery or noninvasive ophthalmic procedures, or other types of surgery.

The dosage of IB/ID agonists utilized for any of the above-described purposes will

generally be from about one to two drops of a 0.01 wt.% to 3 wt.% composition, administered

one to four times per day.

The compounds and compositions of the invention will be used to prevent or

ameliorate ocular pain associated with various stimuli. For example, the IB/ID agonists and

compositions of the present invention may be used in treating pain arising from allergens,

inflammation, trauma, dry eye, foreign body sensation, such as from contact lenses and surgery. The compounds of the present invention may be used for the treatment of pain

following PRK surgery. With such treatment, the IB/ID agonists can be individually dosed,

or in combination with other pharmaceutical agents such as by methods disclosed in U.S.

Patent Nos. 4,939,135 and 5,401,510 (Robertson et al.), the entire contents of which are

incorporated herein by reference. The compounds will be utilized in a concentration effective

to prevent or ameliorate ocular pain. As used herein, the term "pharmaceutically effective amount" refers to that amount of one or more IB/ ID agonists which prevents or alleviates ocular pain.

The compositions of the present invention are further illustrated by the following

formulation examples 2-4. The ingredient "IB/ID agonist" denotes a compound of the present invention.

Example 2

Ingredient Amount (wt%)

7-trifluoromethyl-4(4-methyl- 1 -piperazinyl) 0.01-1.0% -pyrrolo[l ,2-a]quinoxaline maleate (CGS-12066A)

Phosphate Buffered Saline 1.0 Polysorbate 80 0.5

Purified water q.s. to 100% Example 3

Ingredient Amount (wt%)

IB/ID agonist 0.01-1.0%

Monobasic sodium phosphate 0.05

Dibasic sodium phosphate 0.15

(anhydrous)

Sodium chloride 0.75

Disodium EDTA (Edetate disodium) 0.05

Cremophor EL 0.1

Benzalkonium chloride 0.01

HCI and/or NaOH pH 7.3 - 7.4

Purified water q.s. to 100%

Example 4

Ingredient Amount (wt%)

IB/ ID agonist 0.01-1.0% Phosphate Buffered Saline 1.0 Hydroxypropyl-β-cyclodextrin 4.0 Purified water q.s. to 100%

Claims

What is claimed is:

1. A composition for treating ocular pain comprising a pharmaceutically effective amount of a IB/ID agonist in a pharmaceutically acceptable vehicle.

2. A composition according to Claim 1, wherein the IB/ID agonist is selected from the group consisting of: 7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[l,2- a]quinoxaline maleate; Anpirtoline; CP-93129; RU-24969; 5-carboxamidotryptamine; 5- methoxy-n,n,dimethyl-tryptamine; Sumatriptan; L-694247; Metergoline; LY 165163; and BMS-180048.

3. A composition according to Claim 2, wherein the IB/ID agonist is 7- trifluoromethyl-4(4-methyl-l -piperazinyl)-pyrrolo[l ,2-a]quinoxaline maleate.

4. A composition according to Claim 2, wherein the 1 B/1D agonist is Anpirtoline.

5. A method for treating ocular pain which comprises administering to a human a composition comprising a pharmaceutically effective amount of one or more 1 B/ 1 D agonists in a pharmaceutically acceptable vehicle.

6. A method according to Claim 5, wherein the IB/ID agonist is selected from the group consisting of: 7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[l,2- a]quinoxaline maleate; Anpirtoline; CP-93129; RU-24969; 5-carboxamidotryptamine; 5- methoxy-n,n,dimethyl-tryptamine; Sumatriptan; L-694247; Metergoline; LY 165163; and BMS-180048.

7. A method according to Claim 6, wherein the 1 B/l D agonist is 7- trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[l ,2-a]quinoxaline maleate.

8. A method according to Claim 6, wherein the IB/1 D agonist is Anpirtoline.

9. A method according to Claim 5, further comprising administering the composition topically.

10. A method according to Claim 6, further comprising administering the composition topically.

1 1. A method according to Claim 5, wherein the ocular pain is the result of PRK surgery.