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WO1999030717A1 - Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire - Google Patents

Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire Download PDF

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Publication number
WO1999030717A1
WO1999030717A1 PCT/US1998/025481 US9825481W WO9930717A1 WO 1999030717 A1 WO1999030717 A1 WO 1999030717A1 US 9825481 W US9825481 W US 9825481W WO 9930717 A1 WO9930717 A1 WO 9930717A1
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WO
WIPO (PCT)
Prior art keywords
brinzolamide
blood flow
ocular
medicament
manufacture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1998/025481
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English (en)
Inventor
Michael L. Chandler
George Barnes
Thomas R. Dean
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Vision LLC
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 AU18012/99A priority Critical patent/AU1801299A/en
Publication of WO1999030717A1 publication Critical patent/WO1999030717A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • 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

Definitions

  • the present invention is directed to the topical ophthalmic use of brinzolamide to improve ocular blood flow.
  • Brinzolamide is disclosed in commonly assigned U.S. Patent Nos. 5,240,923 and 5,378,703 for its usefulness in controlling intraocular pressure, particularly in the treatment of glaucoma. These patents are incorporated herein by reference.
  • the present invention is directed to the topical use of brinzolamide formulations to improve ocular blood flow, such as to ocular tissues including the optic nerve head.
  • the distribution coefficients for methazolamide, acetazolamide and dorzolamide are 0.64, 0.23, and 1.72 respectively.
  • the IC 50 values (determined against human carbonic anhydrase II) are 12.5 nM, 9.04 nM, and 3.74 nM respectively.
  • the Ki values are 29.3 nM, 33.8 nM, and 0.51 nM respectively.
  • Dorzolamide is significantly more potent than either acetazolamide or methazolamide as measured by Ki and IC 50 and is only slightly, ⁇ 2x, more lipophilic as measured by its distribution coefficient. Thus, it is not expected to efficiently cross the blood retinal barrier. None of these compounds have the requisite characteristics to efficiently improve ocular blood flow. Thus there is a need to identify superior agents to improve blood flow to the back of the eye.
  • brinzolamide is well suited to penetrate into the retina, choroid, and optic nerve head upon topical ocular administration. Moreover, brinzolamide significantly increases blood flow to the back of the eye and in particular the optic nerve head.
  • Brinzolamide (R-(+)-4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H- thieno[3,2,e]l-2-thiazine-6-sulfonamide- 1,1 -dioxide, is a carbonic anhydrase inhibitor which has been found to be effective in lowering the elevated intraocular pressure associated with ocular hypertension and glaucoma.
  • the distribution coefficient, IC 50 and Ki values for brinzolamide are 6-56, 3.19 nM and 0.13 nM respectively. Further studies discussed in the examples show that it penetrates to the back of the eye following topical ocular delivery and is also effective in increasing blood flow in ocular tissues including the optic nerve head.
  • Ocular diseases and conditions which find their etiology in compromised blood flow can be treated with brinzolamide.
  • These diseases and conditions include glaucoma including but not limited to primary open angle glaucoma (POAG) and normal tension glaucoma also known as low tension glaucoma or angle closure glaucoma, occlusion conditions, such as, branch vein occlusion and retinal artery or vein occlusion, diabetic retinopathy, and retinal or iris neovascularization from any cause.
  • POAG primary open angle glaucoma
  • normal tension glaucoma also known as low tension glaucoma or angle closure glaucoma
  • occlusion conditions such as, branch vein occlusion and retinal artery or vein occlusion, diabetic retinopathy, and retinal or iris neovascularization from any cause.
  • Neovascularization of the retinal, choroidal, or iridial tissues arises by the action of angiogenic substance(s).
  • these angiogenic substances are produced in ocular tissue which is suffering from hypoxia.
  • hypoxia hypoxia
  • Brinzolamide is preferably formulated as a topical ophthalmic suspension with a pH of about 4.5-7.8. It will normally be contained in the formulation at a concentration of 0.1%- 10% by weight, preferably 0.25%-5.0% by weight. Thus, for topical presentation 1-3 drops of these formulations would be delivered to the surface of the eye 1-4 times a day according to the routine discretion of a skilled clinician.
  • Example 4 describes the tissue distribution of brinzolamide in the eyes of rabbits.
  • ONH blood flow was then measured by LDF in the anesthetized, spontaneously breathing felines. The experiment was repeated after a one-week interval in the same cats to assess the reproducibility of the technique. Averaging the two blood flow measurements showed that ONH flow was increased by an average of 21.8% over that measured in the control group. In anesthetized, ventilated cats, ONH blood flow was increased on average 16.5% + 8% at 60 minutes following a single topical dose. Intravenous brinzolamide produced a 46 + 17% increase (p ⁇ _0.05) in ONH blood flow; ONH vascular resistance, a measure of vascular tone in the ONH microcirculation, was reduced by 35 + 8% (p ⁇ 0.05).
  • Intravenous administration of 0.5, 2.5, and 5 mg/kg of brinzolamide to anesthetized, ventilated New Zealand albino rabbits produced a significant dose-related increase in total ocular blood which reflected increases in blood flow to the tissues of the eye measured by the colored microsphere technique.
  • Optic nerve head blood flow, measured by LDF was also increased above baseline.
  • Ocular vascular tone was reduced since total ocular vascular resistance was decreased dose-dependently.
  • Baseline blood flow was 657 + 36 ⁇ l/min in the hypofused eye.
  • Intravenous doses of brinzolamide produced similar increases in total ocular blood flows of 29%, 68%, and 90% in normal eyes and increases of 21%, 64%, and 90% in hypofused eyes.
  • the highest intravenous brinzolamide dose returned regional blood flows to the hypofused eye to baseline levels found in the normal eye. Percentage wise, the blood flow increase to the hypofused eye was greatest to iridial, ciliary, and choroidal tissues, respectively.
  • LDF Baseline values for optic nerve head (ONH) blood flow, blood pressure, heart rate, intraocular pressure (IOP), and acid-base balance were determined before treatment began and 7-14 days after completion of a treatment arm; baseline values for the measured variables did not significantly change during the experiment. Treatment measurements were made 90 minutes after the last dose on day eight. Optic nerve head blood flow and measured systemic variables were not changed by vehicle treatment. Minimal disturbance of acid-base balance occurred in brinzolamide treated animals. IOP was decreased by 16.8 + 2.2% (p ⁇ 0.05 versus vehicle; p ⁇ .001 versus baseline) and ONH blood flow was significantly increased by 11.2 + 1.6% (mean + SEM; p ⁇ 0.05) following topical brinzolamide.
  • the tissue distribution of brinzolamide was determined in New Zealand Albino (NZW) and Dutch belted rabbits after a single topical ocular dose of 1 % 14 C- brinzolamide.
  • NZW New Zealand Albino
  • Dutch belted rabbits after a single topical ocular dose of 1 % 14 C- brinzolamide.
  • brinzolamide was found to slowly redistribute into the retina.
  • the T max values in the retina were 20 days and 36 days in the NZW and Dutch belted rabbits respectively. These data demonstrate that brinzolamide is slowly delivered to the retina over time and likely comes for the red blood cells.
  • the C max values were 0.330 and 0.338 ⁇ g equivalents/g in the NZW and Dutch belted rabbits respectively.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des procédés et à des formulations servant à augmenter le flux sanguin oculaire en utilisant du brinzolamide.
PCT/US1998/025481 1997-12-12 1998-12-01 Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire Ceased WO1999030717A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18012/99A AU1801299A (en) 1997-12-12 1998-12-01 Use of brinzolamide for the manufacture of a medicament for improving ocular blood flow

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6965697P 1997-12-12 1997-12-12
US60/069,656 1997-12-12

Publications (1)

Publication Number Publication Date
WO1999030717A1 true WO1999030717A1 (fr) 1999-06-24

Family

ID=22090398

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/025481 Ceased WO1999030717A1 (fr) 1997-12-12 1998-12-01 Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire

Country Status (4)

Country Link
AR (1) AR015494A1 (fr)
AU (1) AU1801299A (fr)
WO (1) WO1999030717A1 (fr)
ZA (1) ZA9811387B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6753009B2 (en) 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5378703A (en) * 1990-04-09 1995-01-03 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
WO1996037203A1 (fr) * 1995-05-22 1996-11-28 Advanced Research & Technology Institute Procede d'augmentation du debit sanguin retinien

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5378703A (en) * 1990-04-09 1995-01-03 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
WO1996037203A1 (fr) * 1995-05-22 1996-11-28 Advanced Research & Technology Institute Procede d'augmentation du debit sanguin retinien

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C.CAMRAS: "A triple-masked primary therapy study of the efficacy and safety of BID and TID-dosed brinzolamide 1% compared to TID-dosed dorzolamide 2% and BID-dosed timolol 0.5%", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 38, no. 4, 15 March 1997 (1997-03-15), pages s560, XP002092853 *
T.DEAN ET AL.: "Brinzolamide (AL-8462) suspension is a new topically active carbonic anhydrase inhibitor in the dutch-belted rabbit and cynomolgus monkey", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 38, no. 4, 15 March 1997 (1997-03-15), pages S813, XP002092854 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6753009B2 (en) 2002-03-13 2004-06-22 Mcneil-Ppc, Inc. Soft tablet containing high molecular weight polyethylene oxide

Also Published As

Publication number Publication date
AU1801299A (en) 1999-07-05
ZA9811387B (en) 1999-07-14
AR015494A1 (es) 2001-05-02

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