WO2013180698A1 - Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire - Google Patents

Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire Download PDF

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Publication number
WO2013180698A1
WO2013180698A1 PCT/US2012/039956 US2012039956W WO2013180698A1 WO 2013180698 A1 WO2013180698 A1 WO 2013180698A1 US 2012039956 W US2012039956 W US 2012039956W WO 2013180698 A1 WO2013180698 A1 WO 2013180698A1
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WO
WIPO (PCT)
Prior art keywords
faah
fatty acid
dry eye
pain
eye
Prior art date
Application number
PCT/US2012/039956
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English (en)
Inventor
Martha E GADD
Karen C. David
Original Assignee
Alcon Research, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Alcon Research, Ltd. filed Critical Alcon Research, Ltd.
Priority to PCT/US2012/039956 priority Critical patent/WO2013180698A1/fr
Publication of WO2013180698A1 publication Critical patent/WO2013180698A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the invention relates to the treatment of ocular pain and symptoms of dry eye disorders.
  • the invention relates to the use of certain fatty acid amide hydrolase (FAAH) inhibitors or a fatty acid amide in the treatment of chronic corneal pain and neuropathies associated with dry eye or other ocular disorders.
  • FAAH fatty acid amide hydrolase
  • 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.
  • 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.
  • ocular pain can result from photorefractive keratotomy ("PR "), a vision correcting, surgical procedure whereby a laser is used to shape the cornea.
  • PR photorefractive keratotomy
  • This process involves the photoablation of Bowman's membrane and the stromal levels of the cornea.
  • 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.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • diclofenac diclofenac
  • NS AIDs cyclooxygenase dependent prostaglandin synthesis.
  • Prostaglandins can modulate pain perception at the level of the central nervous system and systemic administration of NS AIDs is known to provide analgesia.
  • NS AIDs can involve undesired side effects including gastrointestinal bleeding and kidney dysfunction.
  • Local anesthetics are another class of pain modulators that relieve pain by directly inhibiting nerve cellular function.
  • One problem with local anesthetic therapy is that the anesthetics exhibit a short duration of action.
  • Another problem with the use of local anesthetics is that their mechanism of action, non-specific membrane stabilization, can have the undesired coincident effect of also inhibiting biological functions of other cells, such as fibroblasts and surrounding neural cells.
  • chronic use of topical ocular anesthetics is undesirable due to the potential for inadvertent, unperceived damage. Therefore, even though pain sensation can be abated with local anesthetic treatment, healing and normal function of the tissue may be significantly compromised. There is a need, therefore, to discover agents which potently and specifically inhibit the transmission of painful stimuli by sensory afferents, without local anesthetic activity, following topical ocular application.
  • Dry eye also referred to as keratoconjunctivitis sicca
  • Dry eye is a common ophthalmological disorder affecting millions of persons each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's syndrome and cicatricial pemphigoid, may also lead to dry eye conditions. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
  • Practitioners have taken several approaches to the treatment of dry eye.
  • One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day.
  • Other approaches include the use of ocular inserts that promote retention of tears (e.g., punctal plugs) or the stimulation of endogenous tear production.
  • Tear film stabilization is also attempted by providing one or more components of the tear film such as phospholipids and oils.
  • Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998).
  • U.S. Patent No. 4,818,537 discloses the use of a lubricating, liposome-based composition
  • U.S. Patent No. 5,800,807 discloses compositions containing glycerin and propylene glycol for treating dry eye.
  • WO 00/03705 Al cyclosporine A (Tauber, J. Adv. Exp. Med. Biol. 1998, 438 (Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2), 969), and mucosecretatogues, such as 15-HETE (Yanni et. al, U.S. Patent No. 5,696,166).
  • Fatty acid amide hydrolase is a membrane protein that hydrolyzes the fatty acid amide (FAA) class of signaling lipids.
  • FAA signaling pathways are involved in such physiological processes as sleep, pain, feeding, and locomotion (Cravatt et al., 2002, Chemistry and Physics of Lipids 121 :135-148).
  • Nichols et al. demonstrated that certain fatty acid amides are present in the eye.
  • oleamide a fatty acid amide that induces sleep in animals and modulates pain perception
  • meibum human meibomian gland secretions
  • Meibum once spread as a thin oil layer over the aqueous tear film, helps prevent evaporation and maintain the stability of the tear film.
  • Nichols et al. postulated that oleamide or the oleamide:oleic acid ratio may play a unique role in ocular surface diseases, such as dry eye, but did not suggest that any other particular fatty acids and amides are involved in such roles.
  • Matsuda et al. demonstrated that anandamide hydrolase, a fatty acid amide hydrolase (FAAH), is expressed in porcine ocular tissues, including the retina, lens, iris, choroid, and the lacrimal gland (Matsuda et al., 1997, Exp. Eye Res. 64:707-711). Matsuda et al. , however, did not discuss the role of fatty acid amides or FAAH in dry eye or pain associated with ocular disorders.
  • FAH fatty acid amide hydrolase
  • modulation of FAAH and/or FAA levels in the eye can effectively reduce ocular pain and reduce symptoms of dry eye.
  • the invention provides methods for the treatment of dry eye symptoms, including symptoms of dry eye associated with refractive surgery such as LASIK surgery.
  • the invention also provides methods for the treatment of ocular pain and inflammation.
  • fatty acid amide hydrolase (FAAH) antagonists or fatty acid amides are administered to a patient to prevent or alleviate chronic corneal pain and neuropathies associated with dry eye or other ocular disorders and or events, such as cataract surgery, LASIK, PRK, accidental trauma, cicatricial pemphigoid, and either idiopathic neuropathies or those coincident with diabetes, and Sjogren's syndrome.
  • FAAH fatty acid amide hydrolase
  • FAAH antagonists or fatty acid amides are administered to a patient suffering from dry eye or corneal pain.
  • the methods of the invention involve the administration of fatty acid amides (FAAs), FAA analogues, FAA derivatives, and/or lipoaminoacids that can modulate FAAH activity and lead to increased levels of FAAs at the ocular surface.
  • FAAs fatty acid amides
  • FAA analogues FAA analogues
  • FAA derivatives FAA derivatives
  • lipoaminoacids that can modulate FAAH activity and lead to increased levels of FAAs at the ocular surface.
  • the FAAH antagonists or fatty acid amides are preferably administered topically to the eye.
  • Specific preferred embodiments of the invention will become evident from the following more detailed description of certain preferred embodiments and the claims.
  • Figure 1 is a graph representing the effects of oleamide and anandamide in a capsaicin blink test conducted on seven week old Sprague-Dawley rats.
  • inhibitors of FAAH are administered to a patient suffering from dry eye.
  • the compounds suitable for use in the present invention inhibit the activity of FAAH by binding to FAAH at the ocular surface of a patient, thereby reducing the perception of pain associated with dry eye.
  • FAAH antagonists are beneficial in treating various ocular pain states and other conditions associated with neuropathic pain.
  • FAAH antagonists can inhibit endogenous FAAH from hydrolyzing FAAs at the ocular surface.
  • FAAH antagonists are administered to a patient to prevent or ameliorate ocular pain associated with various stimuli.
  • the FAAH antagonists and compositions of the present invention may be used in treating pain arising from allergens, inflammation, trauma, dry eye, and/or 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 ocular surgery, such as PRK surgery.
  • the FAAH antagonists 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.
  • the terms "fatty acid amide” and "FAA” include analogs and derivatives thereof.
  • FAAH antagonist and “FAAH inhibitor” include any agent that can inhibit the activity of FAAH.
  • FAAs and FAAH inhibitors useful in the methods of the invention include, but are not limited to, oleamide, stearamide, anandamide, lipoaminoacids, ammonium oleoyl- CoA, ammonium arachidononyl-CoA, oleoylglycine, arachidonoylglycine, N-oleoyl- ⁇ - amino-butyric acid, N-oleyl-alanine N-arachidonoyl-Y-amino-butyric acid, N-arachidonoyl- alanine, 2-octoyl ⁇ -bromoacetone, trifluoromethyl ketones, a-keto ester and amides and aldehydes, sulfonyl fluorides, and fluorophosphonates.
  • FAAH antagonists useful in the methods of the invention include, but are not limited to, FAAH inhibitors described in Boger et al, 2000, Proc. Natl. Acad. Sci. 97:5044-5049; PiomeUi et al. , 2006, CNS Drug Rev. 12(1): 21-28; Sit et al, 2007 Bioorg. Med Chem Lett. 17: 3287-91; US Patent No. 6,462,054; US Patent No. 6,949,574; US Patent No.
  • an FAAH antagonist may have the following structures described by Boger et al, 2000, Proc. Natl. Acad. Sci. 97:5044-5049:
  • compositions comprising one or more of the specified FAAH antagonists or fatty acid amides and a pharmaceutically acceptable carrier for topical ophthalmic administration or implantation into the conjunctival sac or anterior chamber of the eye is administered to a mammal in need thereof.
  • the compositions are formulated in accordance with methods known in the art for the particular route of administration desired.
  • the compositions administered according to the present invention comprise a pharmaceutically effective amount of one or more of the specified FAAH antagonists or fatty acid amides.
  • compositions are intended to be administered topically to the eye in the form of eye drops or eye ointments, wherein the total amount of FAAH antagonist or fatty acid amide will be about 0.001 to 5.0% (w/v).
  • the amount of FAAH antagonists or fatty acid amides is about 0.01 to about 5.0% (w/v).
  • the dosage of an FAAH antagonist used in a method of the invention will be about 200 pM to about 500 ⁇ .
  • compositions administered according to the present invention will be formulated as solutions, suspensions and other dosage forms for topical administration.
  • Aqueous solutions 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.
  • the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for cytokine synthesis inhibitors which are sparingly soluble in water.
  • compositions administered according to the present invention may also include various other ingredients, including but not limited to surfactants, tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm).
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the particular concentration will vary, depending on the agent employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 6.0 - 7.5.
  • Topical ophthalmic products may also be packaged in multidose form. Preservatives may thus be required to prevent microbial contamination during use. Suitable preservatives include: 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 5.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives. The ophthalmic compositions of the present invention may also be provided preservative free and packaged in unit dose form.
  • compositions of the present invention are intended for administration to a human patient suffering from ocular pain or dry eye or symptoms of dry eye.
  • such compositions will be administered topically.
  • the doses used for the above described purposes will vary, but will be in an effective amount to reduce or eliminate ocular pain and/or eliminate or improve dry eye conditions.
  • 1-2 drops of such compositions will be administered one or more times per day.
  • the composition can be administered 2 to 3 times a day or as directed by an eye care provider.
  • the above composition is prepared by the following method.
  • the batch quantities of boric acid, sodium chloride, disodium edetate, and polyquaternium-1 are weighed and dissolved by stirring in 90% of the batch quantity of purified water.
  • the pH is adjusted to 7.4.+-.0.1 with NaOH and/or HC1.
  • the batch quantity of the FAAH antagonist as a stock solution is measured and added.
  • Purified water is added to q.s. to 100%.
  • the mixture is stirred for five minutes to homogenize and then filtered through a sterilizing filter membrane into a sterile recipient.
  • a capsaicin blink test was used to determine the pharmacological effect of two fatty acid amides, oleamide and anandamide. The test measured the pain response of the cornea by the number of times the animal blinked after the application of capsaicin.
  • Lyophilized anandamide was resuspended in an aqueous 10%> cyclodextrin solution that was buffered with an aliquot of 10X phosphate buffered saline (PBS) (Laine et. al, 2001, Pharmaceutical Research. 18:494-499).
  • Capsaicin (5 of 0.0005%>) was dosed in the OD eye. Blinks were counted in the same manner as the OS eye.
  • treatment of anandamide on the eyes of Sprague-Dawley rats resulted in a reduced blink rate elicited by capsaicin by 50%.
  • Treatment with anandamide alone resulted in rapid blinking for approximately one minute, followed by normal rates of blinking for the four minutes remaining before capsaicin application.
  • Oleamide showed only a modest decrease (20% reduction) in capsaicin-induced blinking, which is likely due to the only partial solubility of oleamide in the 10% cyclodextrin vehicle.

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Abstract

La présente invention concerne des méthodes de traitement de symptômes de la kératoconjonctivite sèche par administration d'un amide d'acide gras ou d'inhibiteurs de l'hydrolase d'amide d'acide gras (FAAH). L'invention concerne également des méthodes permettant de prévenir ou de soulager la douleur oculaire par administration d'un amide d'acide gras ou d'inhibiteurs de la FAAH.
PCT/US2012/039956 2012-05-30 2012-05-30 Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire WO2013180698A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2012/039956 WO2013180698A1 (fr) 2012-05-30 2012-05-30 Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire

Applications Claiming Priority (1)

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PCT/US2012/039956 WO2013180698A1 (fr) 2012-05-30 2012-05-30 Utilisation d'antagonistes de la faah pour le traitement de la kératoconjonctivite sèche et de la douleur oculaire

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050009902A1 (en) * 2001-10-22 2005-01-13 Suguru Miyaji Remedies for pruritus
WO2008024139A2 (fr) * 2006-08-18 2008-02-28 N.V. Organon Inhibiteurs d'hydrolase des amides d'acides gras
WO2011071996A1 (fr) * 2009-12-08 2011-06-16 Ironwood Pharmaceuticals, Inc. Inhibiteurs de faah
WO2012015704A2 (fr) * 2010-07-28 2012-02-02 The Regents Of The University Of California Inhibiteurs de la faah à restriction périphérique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050009902A1 (en) * 2001-10-22 2005-01-13 Suguru Miyaji Remedies for pruritus
WO2008024139A2 (fr) * 2006-08-18 2008-02-28 N.V. Organon Inhibiteurs d'hydrolase des amides d'acides gras
WO2011071996A1 (fr) * 2009-12-08 2011-06-16 Ironwood Pharmaceuticals, Inc. Inhibiteurs de faah
WO2012015704A2 (fr) * 2010-07-28 2012-02-02 The Regents Of The University Of California Inhibiteurs de la faah à restriction périphérique

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