WO1998014193A1 - The use of a substance p antagonist for the manufacture of a medicament for the treatment of ocular pain - Google Patents

The use of a substance p antagonist for the manufacture of a medicament for the treatment of ocular pain Download PDF

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Publication number
WO1998014193A1
WO1998014193A1 PCT/US1997/006410 US9706410W WO9814193A1 WO 1998014193 A1 WO1998014193 A1 WO 1998014193A1 US 9706410 W US9706410 W US 9706410W WO 9814193 A1 WO9814193 A1 WO 9814193A1
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WO
WIPO (PCT)
Prior art keywords
substance
antagonist
pain
treatment
compound
Prior art date
Application number
PCT/US1997/006410
Other languages
French (fr)
Inventor
Daniel A. Gamache
John M. Yanni
Original Assignee
Alcon Laboratories, Inc.
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.)
Filing date
Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU24620/97A priority Critical patent/AU2462097A/en
Publication of WO1998014193A1 publication Critical patent/WO1998014193A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine

Definitions

  • NSAIDs Non-steroidal anti-inflammatory drugs
  • the NSATD diclofenac (Voltaren ® , available from Ciba Vision Ophthalmics)
  • Voltaren ® available from Ciba Vision Ophthalmics
  • the perception of pain at the level of the central nervous system 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.
  • the combination is disclosed for the treatment of a host of diseases and pain of traumatic, post-surgical, menstrual, or cranial origin.
  • 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).
  • 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").
  • a substance P receptor antagonist particularly (2S,3S)-3-(2-methoxybenzyl)amino-2- phenylpiperidine
  • 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.
  • 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.
  • PRK photo refractive keratotomy
  • 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.
  • 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.
  • a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like.
  • 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.%.
  • wt.% percent by weight
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Methods and compositions for treating ocular pain using a substance P antagonist are disclosed.

Description

THE USE OF A SUBSTANCE P ANTAGONIST FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF OCULAR PAIN
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.
Figure imgf000004_0001
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%
H2O pH = 7.4

Claims

We Claim:
1. A method for treating ocular pain, which comprises, administering to an affected eye an ophthalmic formulation comprising a pharmaceutically effective amount of a substance P antagonist.
2. The method of Claim 1 wherein the substance P antagonist is (2S,3S)-3-(2- meώoxybenzyl)amino-2-phenylpiperidine.
3. An ophthalmic composition for treating ocular pain, comprising a pharmaceutically effective amount of a substance P antagonist.
4. The composition of Claim 3 wherein the substance P antagonist is (2S,3S)-3-
(2-me oxybenzyl)amino-2-phenylpiperidine.
PCT/US1997/006410 1996-10-04 1997-04-17 The use of a substance p antagonist for the manufacture of a medicament for the treatment of ocular pain WO1998014193A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24620/97A AU2462097A (en) 1996-10-04 1997-04-17 The use of a substance p antagonist for the manufacture of medicament for the treatment of ocular pain

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72689096A 1996-10-04 1996-10-04
US08/726,890 1996-10-04

Publications (1)

Publication Number Publication Date
WO1998014193A1 true WO1998014193A1 (en) 1998-04-09

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1172106A2 (en) * 2000-05-03 2002-01-16 Pfizer Products Inc. Use of fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles as substance P receptor antagonists
WO2009067438A1 (en) * 2007-11-19 2009-05-28 Alcon Research, Ltd. Use of trpv1 receptor antagonists for treating dry eye and ocular pain
WO2019162519A1 (en) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Nk-1 antagonists for use in the treatment of ocular pain
WO2021180885A1 (en) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Treatment of stem cell deficiency
CN114206849A (en) * 2019-05-30 2022-03-18 斯格本斯眼科研究所有限公司 Therapeutic methods for treating non-infectious ocular immunoinflammatory disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742156A (en) * 1985-09-30 1988-05-03 Mcneilab, Inc. Peptide antagonists of neurokinin B and opthalmic solutions containing them
WO1991009844A1 (en) * 1990-01-04 1991-07-11 Pfizer Inc. Substance p antagonists
WO1996014845A1 (en) * 1994-11-10 1996-05-23 Pfizer Inc. Nk-1 receptor antagonists for the treatment of eye disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742156A (en) * 1985-09-30 1988-05-03 Mcneilab, Inc. Peptide antagonists of neurokinin B and opthalmic solutions containing them
WO1991009844A1 (en) * 1990-01-04 1991-07-11 Pfizer Inc. Substance p antagonists
WO1996014845A1 (en) * 1994-11-10 1996-05-23 Pfizer Inc. Nk-1 receptor antagonists for the treatment of eye disorders

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1172106A2 (en) * 2000-05-03 2002-01-16 Pfizer Products Inc. Use of fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles as substance P receptor antagonists
EP1172106A3 (en) * 2000-05-03 2002-05-15 Pfizer Products Inc. Use of fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles as substance P receptor antagonists
WO2009067438A1 (en) * 2007-11-19 2009-05-28 Alcon Research, Ltd. Use of trpv1 receptor antagonists for treating dry eye and ocular pain
WO2019162519A1 (en) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Nk-1 antagonists for use in the treatment of ocular pain
CN111918647A (en) * 2018-02-26 2020-11-10 圣拉斐尔医院有限公司 NK-1 antagonists for the treatment of ocular pain
JP2021514976A (en) * 2018-02-26 2021-06-17 オスペダーレ・サン・ラッファエーレ・エッセエッレエッレ NK-1 antagonist for use in the treatment of eye pain
EP4371613A2 (en) 2018-02-26 2024-05-22 Ospedale San Raffaele S.r.l. Compounds for use in the treatment of ocular pain
EP4371613A3 (en) * 2018-02-26 2024-07-24 Ospedale San Raffaele S.r.l. Compounds for use in the treatment of ocular pain
CN114206849A (en) * 2019-05-30 2022-03-18 斯格本斯眼科研究所有限公司 Therapeutic methods for treating non-infectious ocular immunoinflammatory disorders
EP3976594A4 (en) * 2019-05-30 2023-11-08 The Schepens Eye Research Institute, Inc. A therapeutic approach for treating non-infectious ocular immunoinflammatory disorders
WO2021180885A1 (en) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Treatment of stem cell deficiency

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