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WO2003051351A1 - Suspension ophtalmique de rofecoxib pour le traitement de l'inflammation et de la douleur oculaire - Google Patents

Suspension ophtalmique de rofecoxib pour le traitement de l'inflammation et de la douleur oculaire Download PDF

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Publication number
WO2003051351A1
WO2003051351A1 PCT/MX2002/000116 MX0200116W WO03051351A1 WO 2003051351 A1 WO2003051351 A1 WO 2003051351A1 MX 0200116 W MX0200116 W MX 0200116W WO 03051351 A1 WO03051351 A1 WO 03051351A1
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WIPO (PCT)
Prior art keywords
weight
solution
suspension
treatment
sodium
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Ceased
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PCT/MX2002/000116
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English (en)
Spanish (es)
Inventor
Arturo Jimenez Bayardo
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Priority to AU2002361516A priority Critical patent/AU2002361516A1/en
Publication of WO2003051351A1 publication Critical patent/WO2003051351A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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 relates to a suspension of Rofecoxib for topical ophthalmic use, useful in the treatment of pain and any ocular inflammatory disorder, including inflammation and post-surgical pain.
  • the clinical scope of the Rofecoxib suspension, object of the present invention should include the treatment of pain and / or inflammation of the eye and its annexes, whether due to infectious or non-infectious processes, as well as subsequent to surgical procedures of the anterior segment, posterior segment or both, as well as the surgery of some of the ocular annexes (conjunctiva and extraocular muscles) and as a treatment or adjunct treatment of glaucoma.
  • the dose is 1 drop every 4 to 24 hours depending on the severity of the case and during the time indicated by the doctor, with minimal restrictions for prolonged use given the low incidence of local or systemic reactions considered toxic or unsafe, as well as effects adverse effects attributable to the use of Rofecoxib.
  • the present invention relates to ophthalmological applications of a suspension formula of Rofecoxib (specific inhibitor of cyclooxygenase isoform 2 (COX-2)) useful in the treatment of cystic macular edema in the retina (aphaco and pseudophaco); prevention of intraoperative myosis; definitive or adjuvant treatment of the following conditions with infraocular inflammation: anterior uveitis, ulceris, cyclitis, iridocyclitis, trabeculitis, intermediate uveitis, posterior uveitis (choroiditis, retinitis, chorioretinitis, retinocoroiditis), optic neuritis; as a definitive or adjuvant treatment of all known glaucoma variants, both open-angle and closed-angle, primary or secondary; definitive or adjuvant treatment of allergic conjunctival disease that includes stationary allergic conjunctivitis, spring conjunctivitis, atopic blepharoconjunctivitis
  • Inflammation is an extremely complex process that generally occurs in response to different types of aggressions suffered by tissues.
  • inflammation mediators participate in this process.
  • Pharmacological manipulation of the inflammatory phenomenon is based on the suppression of the release of proinflammatory mediators by the participating cells, or by inhibiting one or more of the key steps in their biosynthesis.
  • spheroids The most potent anti-inflammatory drugs known at the moment are spheroids, these compounds are capable of suppressing an inflammatory reaction by acting at both cellular and humoral levels.
  • synthetic spheroids also leads to the inhibition of substances that in many cases it would be desirable not to do, which is why research in clinical pharmacology has tried to be increasingly selective in the inhibition only of steps considered keys in the development of inflammation, trying to keep the physiological pathways intact so that the incidence of undesirable adverse effects is as low as possible.
  • One of the most important mediator groups in the inflammatory response is prostaglandins. These are derived from the metabolism of arachidonic acid by the enzyme cyclooxygenase (COX).
  • COX-1 which works in physiological situations in all tissues of the body, most obviously in kidney and stomach
  • COX-2 which participates in the production of prostaglandins in the framework of a response inflammatory in any tissue of the body.
  • COX-1 which works in physiological situations in all tissues of the body, most obviously in kidney and stomach
  • COX-2 which participates in the production of prostaglandins in the framework of a response inflammatory in any tissue of the body.
  • the most active metabolic pathway during the inflammatory response is that of cyclooxygenases.
  • Anti-inflammatory drugs are classified into two types, steroids and non-steroids (NSAIDs).
  • Rofecoxib reason for this patent belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), which are specific inhibitors of COX-2 already synthesized.
  • WO 48583 formulations of 5-HT antagonists with COX-2 inhibitors are described, and particularly the use of Rofecoxib in the treatment of migraines is described, by the simultaneous administration of a therapeutically effective amount of a 5-agonist.
  • -HT coordinated with a therapeutically effective amount of a non-spheroidal anti-inflammatory agent (NSAID), particularly a long-acting NSAID in the class of NSAIDs called oxygenase cycle inhibitors, such as Celecoxib, Rofecoxib, Meloxicam, Piroxicam, JTE-522, L -745,337 and NS398.
  • NSAID non-spheroidal anti-inflammatory agent
  • oxygenase cycle inhibitors such as Celecoxib, Rofecoxib, Meloxicam, Piroxicam, JTE-522, L -745,337 and NS398.
  • Dexamethasone is the most used and effective steroidal anti-inflammatory, it acts among many other known mechanisms inhibiting the synthesis of COX-2 but its application produces many undesirable side effects, due to the diversity of biological effects that it has as a spheroid.
  • COX-2 is the soforma responsible for the production of prostaglandins in the framework of the inflammatory response, in addition to being one of those involved in the genesis of pain at the sites of inflammation.
  • Traditional NSAIDs such as Acetyl Salicylic Acid, Indomethacin, Ibuprofen, Naproxen, Diclofenac, etc. they share the same mechanism of action with each other and this is because their effectiveness is based on the inhibition of the action of COX, both in its isoform 1 and in 2.
  • the ocular inflammation is similar to that which can occur in other body tissue and is characterized by its four cardinal signs: hyperemia, protein exudation, pain and cellular response.
  • COX-2 is the COX isoform that actively participates in producing inflammation-mediating prostaglandins at the ocular level.
  • prostaglandins In addition to functioning as mediators of inflammation, prostaglandins perform physiological functions in the eye and this has been proven by identifying receptors for prostaglandins in virtually all eye tissues, such as: retina, ciliary body, pupillary sphincter, mesh trabecular, ciliary muscle, non pigmented epithelium of the ciliary body, corneal epithelium, ciliary processes, etc.
  • the synthesis of prostaglandins in baseline physiological conditions seems to depend mostly, if not entirely on the activity of COX-1.
  • prostaglandins In the eye, after trauma, cataract surgery or laser iridotomy, it has been possible to identify elevated levels of prostaglandins in the aqueous humor. These prostaglandins at concentrations higher than baseline have effects on the ocular level, decrease in infraocular pressure, increased permeability of blood-brain barriers in addition to conjunctival hyperemia. It is worth mentioning that the inflammatory response, regardless of the stimulus that triggers it, can be harmful.
  • topical NSAIDs in Ophthalmology is increasingly common and a sample of this is the presence in this field of salts such as diclofenac, ketorolac, indomethacin and flurbiprofen. Its advantages and disadvantages in the field of ophthalmology are gradually becoming known. Unfortunately, the use of medications such as diclofenac has been associated with disorders of the corneal architecture which are believed to be due to the inhibition of the physiological action of COX-1 at this level.
  • having a non-steroidal anti-inflammatory agent that specifically inhibits the action of COX-2 represents an important advantage since the beneficial effect of the blockade of proinflammatory prostaglandin synthesis would be achieved, without altering homeostasis at the ocular level and without the adverse effects that are inherent in spheroid anti-inflammatory agents.
  • Rofecoxib is a non-steroidal anti-inflammatory agent with activity, analgesic, anti-inflammatory and antipyretic. It is highly specific to inhibit COX-2 activity and its effectiveness has been proven in the treatment of dysmenorrhea, osteoarthritis, rheumatoid arthritis and pain after dental surgery. Rofecoxib represents an advantage over other COX-2 inhibitors such as celecoxib since it lacks sulfamide groups that make its administration safe in people allergic to sulfa drugs. In addition to the absence of allergic reactions, Rofecoxib has other additional advantages, such as the time of the analgesic effect (24 hours against 5 hours of celecoxib) and the time of onset of action (30 minutes. Rofecoxib against 1 hour celecoxib).
  • Another object of the invention is to provide a composition in the form of an aqueous suspension of Rofecoxib for use in the treatment of inflammatory ocular conditions and ocular conditions mediated by cyclooxygenase-2 without the concomitant inhibition of COX-1.
  • a further object of the present invention is to provide a method for the manufacture of an aqueous suspension of Rofecoxib for topical use.
  • Preferred agents for the preparation of the composition are: Sodium chloride as an isotonizing agent to maintain the osmolarity of the suspension; Dibasic sodium phosphate anhydrous and sodium monobasic phosphate monohydrate as buffering or pH regulating agents;
  • Disodium edetate dihydrate as sequestering agent;
  • - Benzalkonium chloride as a preservative agent;
  • Rofecoxib both of topical ocular application (corneal and conjunctival surface).
  • solution B is integrated with solution A and then solution C.
  • the pH is adjusted to 7.2 with 2.5 N NaOH. Stirring is continued for an additional 30 minutes to ensure that it has been perfectly homogenized. It is added to 100 ml with purified USP grade water.
  • composition according to formula 1 is obtained:
  • Solution C In 20 ml of purified water and at room temperature 0.50 g of polysorbate 80 are integrated and then 0.10 g of Rofecoxib previously micronized in mortar are added.
  • Disodium edetate dihydrate 0.10 g 0.1%

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

Abstract

Cette invention se rapporte aux applications ophtalmologiques d'une formulation d'une suspension de Rofecoxib (inhibiteur spécifique de la ciclooxygénase isoforme 2 (COX-2)) s'utilisant dans : le traitement de l'oedème maculaire cystoïde dans la rétine (phakique et pseudophakique); la prévention de myosis transopératoire; dans le traitement définitif ou adjuvant des états pathologiques suivants, qui s'accompagnent d'une inflammation intraoculaire: uvéite antérieure, iritis, cyclite, iridocyclite, trabéculite, uvéite intermédiaire, uvéite postérieure (choroïdite, rétinite, choriorétinite, rétinochoroïdite), neurite optique; le traitement définitif ou adjuvant de toutes les variantes connues de glaucome aussi bien à angle ouvert qu'à angle fermé primaire ou secondaire; le traitement définitif ou adjuvant de la maladie conjonctive allergique comprenant la conjonctivite allergique stationnaire, la conjonctivite printanière, la blépharoconjonctivite atopique, la conjonctivite papillaire géante ainsi que la conjonctivite de contact; le traitement des conjonctivites aiguës et chroniques non spécifiques non infectieuses, ainsi que le traitement symptomatique des conjonctivites infectieuses aussi bien virales, bactériennes, micotiques que par protozoaires et par helminthes, le traitement définitif ou adjuvant de maladies inflammatoires externes, notamment la kératite, l'esclérite (nécrosante et non nécrosante, antérieure et/ou postérieure), l'épisclérite (nodulaire et diffuse) et le traitement symptomatique de la pinguéculite et du ptérygion; ainsi que le traitement postopératoire après toute intervention chirurgicale du globe oculaire et/ou de ses annexes.
PCT/MX2002/000116 2001-12-18 2002-12-17 Suspension ophtalmique de rofecoxib pour le traitement de l'inflammation et de la douleur oculaire Ceased WO2003051351A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002361516A AU2002361516A1 (en) 2001-12-18 2002-12-17 Ophthalmic rofecoxib suspension for the treatment of ocular pain and inflammation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX01013257 2001-12-18
MXPA01013257A MXPA01013257A (es) 2001-12-18 2001-12-18 Suspension oftalmica de rofecoxib para el tratamiento de la inflamacion y el dolor ocular.

Publications (1)

Publication Number Publication Date
WO2003051351A1 true WO2003051351A1 (fr) 2003-06-26

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Country Status (3)

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AU (1) AU2002361516A1 (fr)
MX (1) MXPA01013257A (fr)
WO (1) WO2003051351A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2421193C2 (ru) * 2009-12-07 2011-06-20 Мария Александровна Ковалевская Способ выбора терапии хронических воспалительных заболеваний глазной поверхности на основе управляемого потенцирования экссудативной реакции с помощью механического или иммунного воздействий
RU2533274C1 (ru) * 2013-12-25 2014-11-20 Илья Александрович Марков Фармацевтическая композиция для лечения демодекозного блефарита и блефароконъюнктивита в виде геля
US9017725B2 (en) 2009-06-09 2015-04-28 Aurinia Pharmaceuticals Inc. Topical drug delivery systems for ophthalmic use
US9138467B2 (en) 2005-01-28 2015-09-22 Stipkovits, Laszlo, Dr. Immunologically active compositions
US10265375B2 (en) 2007-10-08 2019-04-23 Aurinia Pharmaceuticals Inc. Ophthalmic compositions
US11622991B2 (en) 2017-05-12 2023-04-11 Aurinia Pharmaceuticals Inc. Protocol for treatment of lupus nephritis

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025771A1 (fr) * 1998-11-04 2000-05-11 Synphora Ab Methode empechant l'accroissement de la pigmentation iridienne pendant un traitement a la prostaglandine
EP1082966A1 (fr) * 1998-05-15 2001-03-14 Wakamoto Pharmaceutical Co., Ltd. Gouttes oculaires anti-inflammatoires
WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
WO2002005848A2 (fr) * 2000-07-13 2002-01-24 Pharmacia Corporation Utilisation d'inhibiteurs de cox-2 pour le traitement et la prevention de troubles oculaires a mediation cox-2
WO2002005815A1 (fr) * 2000-07-13 2002-01-24 Pharmacia & Upjohn Company Preparation ophtalmique d'un medicament inhibiteur selectif de cyclooxygenase-2.
WO2002030395A1 (fr) * 2000-10-10 2002-04-18 Pharmacia & Upjohn Company Composition antibiotique topique destinee au traitement d'une infection oculaire

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1082966A1 (fr) * 1998-05-15 2001-03-14 Wakamoto Pharmaceutical Co., Ltd. Gouttes oculaires anti-inflammatoires
WO2000025771A1 (fr) * 1998-11-04 2000-05-11 Synphora Ab Methode empechant l'accroissement de la pigmentation iridienne pendant un traitement a la prostaglandine
WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
WO2002005848A2 (fr) * 2000-07-13 2002-01-24 Pharmacia Corporation Utilisation d'inhibiteurs de cox-2 pour le traitement et la prevention de troubles oculaires a mediation cox-2
WO2002005815A1 (fr) * 2000-07-13 2002-01-24 Pharmacia & Upjohn Company Preparation ophtalmique d'un medicament inhibiteur selectif de cyclooxygenase-2.
WO2002030395A1 (fr) * 2000-10-10 2002-04-18 Pharmacia & Upjohn Company Composition antibiotique topique destinee au traitement d'une infection oculaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASFERRER J.L. ET AL.: "Cyclooxygenase-2 inhibitors: a new approach to the therapy of ocular inflammation", SURVEY OF OPHTHALMOLOGY, vol. 41, no. SUPPL. 2, February 1997 (1997-02-01), pages S35 - S40, XP002931298 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9138467B2 (en) 2005-01-28 2015-09-22 Stipkovits, Laszlo, Dr. Immunologically active compositions
US10265375B2 (en) 2007-10-08 2019-04-23 Aurinia Pharmaceuticals Inc. Ophthalmic compositions
US10973871B2 (en) 2007-10-08 2021-04-13 Aurinia Pharmaceuticals, Inc. Ophthalmic compositions
US9017725B2 (en) 2009-06-09 2015-04-28 Aurinia Pharmaceuticals Inc. Topical drug delivery systems for ophthalmic use
RU2421193C2 (ru) * 2009-12-07 2011-06-20 Мария Александровна Ковалевская Способ выбора терапии хронических воспалительных заболеваний глазной поверхности на основе управляемого потенцирования экссудативной реакции с помощью механического или иммунного воздействий
RU2533274C1 (ru) * 2013-12-25 2014-11-20 Илья Александрович Марков Фармацевтическая композиция для лечения демодекозного блефарита и блефароконъюнктивита в виде геля
US11622991B2 (en) 2017-05-12 2023-04-11 Aurinia Pharmaceuticals Inc. Protocol for treatment of lupus nephritis

Also Published As

Publication number Publication date
AU2002361516A1 (en) 2003-06-30
MXPA01013257A (es) 2003-06-25

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