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WO2010058166A1 - Utilisation du rimcazole pour le traitement de troubles oculaires - Google Patents

Utilisation du rimcazole pour le traitement de troubles oculaires Download PDF

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Publication number
WO2010058166A1
WO2010058166A1 PCT/GB2009/002700 GB2009002700W WO2010058166A1 WO 2010058166 A1 WO2010058166 A1 WO 2010058166A1 GB 2009002700 W GB2009002700 W GB 2009002700W WO 2010058166 A1 WO2010058166 A1 WO 2010058166A1
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WIPO (PCT)
Prior art keywords
rimcazole
pharmaceutically acceptable
disease
acceptable derivative
vessel
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PCT/GB2009/002700
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English (en)
Inventor
Lisa Patel
Samuel Cameron Williams
Ian Wilding
Martin Read
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Modern Biosciences Plc
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Publication of WO2010058166A1 publication Critical patent/WO2010058166A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a new therapy for diseases or conditions associated with vessel oedema and/or leakage.
  • the present invention concerns the use of Rimcazole for treating such diseases and conditions.
  • Vessel oedema and leakage is a symptom of a number of diseases and conditions and results from damage to endothelial barrier function which, in turn, leads to endothelial hyperpermeability and plasma leakage through gaps between endothelial cells.
  • endothelial barrier function Although several mechanisms have been implicated in the improvement of endothelial barrier function, current therapies based on these mechanisms, such as elevation of cyclic AMP by beta- 1 -adrenergic agents, or specific receptor blockers, often fail. In addition, to date therapies have focused on targeting the underlying cause rather than targeting the vessel oedema or leakage specifically.
  • AMD age related macular degeneration
  • Neovascularisation is the better characterised of the two mechanisms which contribute to AMD. The process involves a balance between a number of stimulating and inhibiting growth factors to regulate the growth of new vessels into areas of hypoxia.
  • VEGF vascular endothelial growth factor
  • endothelial specific mitogen are regarded as the most important ocular angiogenic factors (Ozaki et al., Am J Pathol 156, 697-707).
  • vessel oedema and/or leakage and vessel integrity in AMD The role of vessel oedema and/or leakage and vessel integrity in AMD is less well understood. However, the vessel oedma/leakage pathology is a key feature of this disease and leads to macular edema, bleeding, fibrinous deposits and scar formation.
  • CNV choroidal neovascularisation
  • the present inventors have surprisingly found that 9-[3-[3,5-dimethylpiperazin-l- yl]propyl]carbazole, i.e. Rimcazole, which has the structural formula I below, is effective when used to treat diseases or conditions associated with vessel oedema and/or vessel leakage.
  • Rimcazole has been found to be effective for treating AMD.
  • Rimcazole has been disclosed as having anti-aggressive and anti-psychotic properties (EP 0 012 208 A and US 5,955,459). However, clinical trials of the use of Rimcazole for these indications have not proved conclusive and Rimcazole has not been licensed or marketed for the treatment of aggression or psychoses in humans.
  • Rimcazole While investigating the effects of Rimcazole using the choroidal neovascularization model of vessel growth, formation and leakage, the inventors surprisingly found that Rimcazole is effective for treating vessel oedema and/or vessel leakage.
  • Rimcazole was found to be faster acting in the treatment of AMD than current commercially available therapies.
  • these advantageous results were obtained by intra-peritoneal administration, which is a surrogate for oral administration, of the Rimcazole, rather than needing to administer it directly at the target site. Previous studies have shown that Rimcazole is orally bioavailable. Through this model, it is expected that analogous results will be obtained for oral administration of Rimcazole. This is particularly advantageous where the disease or condition is AMD as it avoids the need for painful intra-vitreal administration.
  • the present invention provides Rimcazole or a pharmaceutically acceptable derivative thereof for use in treating a disease or condition associated with vessel oedema and/or leakage.
  • Rimcazole is used to treat such conditions, a rapid onset of action is observed.
  • the present invention further provides a method for the treatment of a disease or condition associated with vessel oedema and/or leakage, comprising the step of administering a therapeutically effective amount of Rimcazole or a pharmaceutically acceptable derivative thereof to a patient.
  • Rimcazole has been found to be particularly effective in treating age related macular degeneration (AMD), where a rapid reduction in disease, as compared to currently available therapies, is observed.
  • AMD age related macular degeneration
  • the disease is an ocular condition, such as AMD
  • the Rimcazole is administered orally (or via an intraperitoneal route). This is beneficial as it means that painful intra-vitreal injections can be avoided.
  • the invention provides Rimcazole or a pharmaceutically acceptable derivative thereof for use in treating AMD.
  • the Rimcazole or pharmaceutically acceptable derivative thereof is administered orally.
  • Rimcazole 9-[3-[3,5-dimethylpiperazin-l-yl]propyl]carbazole (BW 234U) is known as Rimcazole.
  • Methods of synthesising Rimcazole are known in the art, e.g. as described in EP 0 012 208, US 5,955,459 and WO01/74359.
  • Rimcazole includes Rimcazole and pharmaceutically acceptable derivatives thereof.
  • Derivatives include pharmaceutically acceptable salts, amides and solvates of Rimcazole.
  • Derivatives of Rimcazole may also include prodrugs.
  • Rimcazole has two stereogenic centres at the 3 and 5 positions of the piperazinyl ring and, as used herein, the term "Rimcazole” includes stereoisomers of Rimcazole.
  • the stereoisomer of Rimcazole is the (3S,5R) isomer, i.e. 9-[3-[(3S,5R)-3,5-dimethylpiperaz ⁇ n-l- yl]propyl]carbazole having the structural formula II:
  • Suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be 5 formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • the pharmaceutically acceptable salt is a hydrochloride salt of Rimcazol ⁇ , typically the dihydrochloride salt (Rimcazole dihydrochloride).
  • the salt is Rimcazole ) dihydrochloride, which is of structural formula III:
  • pharmaceutically acceptable solvate includes hydrates or solvates formed with common organic solvents.
  • the hydrate is Rimcazole dihydrochloride monohydrate.
  • the Rimcazole or a pharmaceutically acceptable derivative thereof may have one or more polymorph or amorphous crystalline forms and are also included in the invention.
  • pharmaceutically acceptable amide includes compounds formed by the reaction of Rimcazole with a carboxylic acid, e.g. a Ci- ⁇ carboxylic acid.
  • a carboxylic acid e.g. a Ci- ⁇ carboxylic acid.
  • the use of pharmaceutically acceptable amides as prodrugs is discussed, for example, in "The Theory and Practice of Industrial Pharmacy", 2nd Edition, Lachman, Lieberman & Kanig, 1976.
  • prodrug means a pharmaceutically acceptable form of a functional derivative of Rimcazole (or a salt thereof ⁇ , wherein the prodrug may be: 1) a relatively active precursor which converts in vivo to an active prodrug component; 2) a relatively inactive precursor which converts in vivo to an active prodrug component; or 3) a relatively less active component of the compound that contributes to therapeutic biological activity after becoming available in vivo.
  • the prodrug may be: 1) a relatively active precursor which converts in vivo to an active prodrug component; 2) a relatively inactive precursor which converts in vivo to an active prodrug component; or 3) a relatively less active component of the compound that contributes to therapeutic biological activity after becoming available in vivo.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, EP 0 012 208.
  • the present invention relates to the use of Rimcazole or a pharmaceutically active derivative thereof for treating diseases or conditions associated with vessel oedema and/or leakage.
  • Diseases or conditions associated with vessel oedema and/or leakage include those where vessel oedema and/or leakage is a symptom of the disease or condition and those where vessel oedema and/or leakage causes the disease or condition.
  • the Rimcazole or pharmaceutically active derivative thereof is used to treat diseases or conditions associated with vessel oedema.
  • the Rimcazole or pharmaceutically active derivative thereof is used to treat diseases or conditions associated with vessel leakage.
  • the Rimcazole or pharmaceutically active derivative thereof is used to treat diseases or conditions associated with vessel oedema and leakage.
  • the vessel is a blood vessel. In another embodiment, the vessel is a capillary or micro-capillary.
  • the disease or condition may be a disorder selected from the group consisting of ocular disorders and vasculitides.
  • the disease or disorder may be selected from the group consisting of disorders of the sclera, cornea, iris anatomy, iris and ciliary body; disorders of the lens, choroid and retina; glaucoma; disorders of the vitreous body and globe; disorders of the optic nerve and visual pathway; large vessel vasculitis; medium vessel vasculitis and small vessel vasculitis.
  • disorders of the sclera, and cornea include episcleritis and scleritis, keratitis, corneal neovascularization, Fuchs' dystrophy, keratoconjunctivitis sicca, ulceris and uveitis.
  • Disorders of the choroid and retina include hypertensive retinopathy, age-related macular degeneration, macular degeneration, retinitis pigmentosa, macular edema, retinopathy, including retinopathy of prematurity, hypertensive retinopathy, sickle-cell retinopathy, genetic retinopathy, solar retinopathy, drug-related retinopathy, retinal angiomatous proliferation, choroidal vasculitis, retinal vasculitis, Eales' disease and retinal vein/artery occlusion.
  • ocular disorders include neovascular glaucoma, river blindness, papillitis, optic nerve vasculitis, Sorsby's Fundus Dystrophy, blindness and Stargardt disease.
  • Large vessel vaculitis includes Takayasu arteritis or giant cell (temporal) arteritis.
  • Medium vessel vasculitis includes polyarteritis nodosa, Wegeners granulomatosis, Kawasaki disease or isolated CNS vasculitis.
  • Small vessel vasculitis includes Churg-Strauss arteritis, microscopic polyarteritis/polyangiitis, hypersensitivity/allergic vasculitis, Henoch-Schonlein purpura, essential cryoglobulinemic vasculitis, vasculitis secondary to connective tissue disorders, including systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis and Behcets disease or vasculitis secondary to viral infection, including Hepatitis B and C, HIV, cytomegalovirus, Epstein-Barr virus and parvo B 19 virus.
  • the disease or condition is a disorder of the choroid or retina.
  • the disease or condition is age related macular degeneration (AMD), in particular an exudative form of AMD.
  • AMD age related macular degeneration
  • treatment includes prophylactic treatment.
  • a “patient” means an animal, e.g. a mammal, typically a human, in need of treatment.
  • the amount of Rimcazole (or a pharmaceutically acceptable derivative thereof) administered should be a therapeutically effective amount where the Rimcazole is used for the treatment of a disease or condition, and a prophylactically effective amount where the compound or derivative is used for the prevention of a disease or condition.
  • terapéuticaally effective amount refers to the amount of Rimcazole (or a pharmaceutically acceptable derivative thereof) needed to treat or ameliorate a targeted disease or condition.
  • prophylactically effective amount used herein refers to the amount of compound needed to prevent a targeted disease or condition.
  • the exact dosage will generally be dependent on the patient's status at the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug combinations, reaction sensitivities and the patient's tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician. Administration & Formulation
  • the Rimcazole or pharmaceutically acceptable derivative thereof may be administered as a medicament by enteral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), oral, buccal, sublingual, intranasal, rectal, vaginal, and topical administration.
  • enteral or parenteral routes including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), oral, buccal, sublingual, intranasal, rectal, vaginal, and topical administration.
  • the Rimcazole or pharmaceutically acceptable derivative thereof should be assessed for its biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • the Rimcazole or pharmaceutically acceptable derivative thereof will be administered as a fo ⁇ nulation in association with one or more pharmaceutically acceptable excipients.
  • excipient includes any ingredient other than Rimcazole which may impart either a functional (e.g drug release rate controlling) and/or a non-functional (e.g. processing aid or diluent) characteristic to the formulations.
  • a functional e.g drug release rate controlling
  • a non-functional e.g. processing aid or diluent
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • Typical pharmaceutically acceptable excipients include:
  • diluents e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
  • lubricants e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;
  • binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;
  • disintegrants e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • the Rimcazole (or a pharmaceutically acceptable derivative thereof) may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids (e.g. aqueous solutions), emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • solid plugs solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids (e.g. aqueous solutions), emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Formulations suitable for oral administration may also be designed to deliver the Rimcazole or pharmaceutically acceptable derivative thereof in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
  • Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the Rimcazole to control its release.
  • rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
  • rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
  • Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the Rimcazole or pharmaceutically acceptable derivative thereof may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986.
  • the disease or condition is an ocular disorder, such as AMD
  • the Rimcazole or pharmaceutically acceptable derivative thereof is administered orally as this avoids the need for injection directly into the eye which can be painful to the patient.
  • the inventors have surprisingly found that, even when Rimcazole is administered orally, it is effective in treating the ocular disorder in question. This is surprising because it is necessary to administer current therapies via intra-vitreal injection.
  • Macugen® pegaptanib sodium
  • ranibizumab a VEGF-blocking antibody fragment. Both are administered via intra-vitreal injection.
  • VEGF blocking therapies are thought to be able to penetrate the retina ⁇ (Toxicol Path. 199; 27(50):536-544)).
  • the efficacy of both Lucentis and Avastin in treating AMD via the intra-vitreal route (Bashshur et al, American Journal of Ophthalmology 2006, 142(1), 1-9; Querques et al, Acta Ophthalmologica 2008, 86(6), 694 - 695) in spite of their differing molecular weights (48kDa and 149kDa respectively) indicates that factors such as delivery to the vitreous humour may be important, a feature which is supported by the low diffusion half-life of drugs out of the vitreous after administration (Bakri et al, Ophthalmology 2007, 114(12), 2179-2182).
  • Rimcazole is efficacious in treating diseases or conditions associated with vessel oedema and/or leakage when administered systemically, in particular via oral administration.
  • Systemic delivery, in particular oral administration, of Rimcazole results in greater efficacy than delivery of Avastin intra-vitreally. This is particularly surprising given that systemic delivery, in particular via oral administration, of Rimcazole is unlikely to result in significant drug accumulation in the vitreous humour.
  • the present invention provides Rimcazole or a pharmaceutically acceptable derivative thereof for use in the treatment of age-related macular degeneration by oral administration.
  • the age-related macular degeneration may be exudative age-related macular degeneration.
  • the Rimcazole may be administered orally as a single daily dose. In an alternative embodiment, the Rimcazole may be administered orally in multiple doses daily. In this regard, in one embodiment, the Rimcazole may be administered orally twice a day. In an alternative embodiment, the Rimcazole may be administered orally three times a day. Where administered in multiple oral doses daily, each of the doses may be the same or different.
  • the Rimcazole may be administered orally at a dose of at least about 20 mg/day, alternatively at least about 50 mg/day, alternatively at least about 100 mg/day.
  • the Rimcazole may be administered orally at a dose of about 600 mg/day or less, alternatively about 550 mg/day or less, alternatively about 500 mg/day or less.
  • the Rimcazole may be administered orally at a dose in the range from about 20 to about 600, alternatively from about 50 to about 500, alternatively from about 100 to about 450, alternatively from about 150 to about 400, alternatively from about 200 to about 350, alternatively from about 250 to about 300 mg/day.
  • the Rimcazole may be administered orally once a day at a dose in the range from about 50 to about 450, alternatively from about 100 to about 400, alternatively from about 150 to about 350 mg.
  • the Rimcazole may be administered orally twice a day, wherein each of the two doses is independently in the range from about 10 to about 300, alternatively from about 25 to about 250, alternatively from about 50 to about 225 mg. In such an embodiment, the two doses may be the same or different.
  • the Rimcazole (or a pharmaceutically acceptable derivative thereof) can be administered parenterally.
  • the Rimcazole (or a pharmaceutically acceptable derivative thereof) may be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ.
  • Suitable means for administration include intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but restricted to glucose, mannitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water (WFI).
  • excipients such as sugars (including but restricted to glucose, mannitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water (WFI).
  • WFI sterile, pyrogen
  • Parenteral formulations may include implants derived from degradable polymers such as polyesters ⁇ i.e. polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
  • degradable polymers such as polyesters ⁇ i.e. polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • Rimcazole or a pharmaceutically acceptable derivative thereof used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
  • the Rimcazole (or a pharmaceutically acceptable derivative thereof) can be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the Rimcazole (or a pharmaceutically acceptable derivative thereof) comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the Rimcazole comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable formulations for transdermal application include a therapeutically effective amount of a Rimcazole (or a pharmaceutically acceptable derivative thereof) with carrier.
  • Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the Rimcazole or pharmaceutically acceptable derivative thereof may be administered alone or in combination with one or more other drugs (or as any combination thereof).
  • composition comprising
  • X may consist exclusively of X or may include something additional e.g. X + Y.
  • the word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.
  • Figure 1 illustrates the grading procedure and assignment of disease index for the semi-quantitative assessment of late-phase fluorescein angiography
  • Figure 2(a) to (d) show SLO fluorescence angiography images of example retinal lesions seven days after laser photocoagulation and treatment with (a) intravitreal PBS, (b) intravitreal Avastin, (c) intraperitoneal water, and (d) intraperitoneal Rimcazole;
  • Figure 3 shows the individual disease index score of each retinal lesion imaged in Figures 2(a) to (d) at seven days following laser induced photocoagulation;
  • Figure 4(a) to (d) show SLO fluorescence angiography images of example retinal lesions fourteen days after laser photocoagulation and treatment with (a) intravitreal PBS, (b) intravitreal Avastin, (c) intraperitoneal water, and (d) intraperitoneal Rimcazole;
  • Figure 5 shows the individual disease index score of each retinal lesion imaged in Figures 4(a) to (d) at fourteen days following laser induced photocoagulation;
  • FIG. 6 illustrates that Rimcazole inhibits vessel leakage at 7 and 14 days after photocoagulation
  • Figure 7 shows SLO fluorescence angiography images 4 minutes after injection of FS at 7 and 14 days after photocoagulation.
  • Figure 8 shows Rimcazole plasma concentrations in rats on day 0 of treatment (the day of the laser burn, 4 days after Rimcazole dosing was started).
  • Rimcazole in treating a disease or condition associated with vessel oedema and/or vessel leakage was investigated using a choroidal neovascularisation (CNV) model.
  • CNV choroidal neovascularisation
  • Fluorescein angiography is a valuable tool for the evaluation and treatment of a number of retinal diseases and is considered to be the gold standard test for diagnosing neovascular AMD, as well as for the assessment of vessel leakage in preclinical models of CNV.
  • Fluoroscein angiography involves the injection of sodium fluorescein, which is a small water-soluble molecule, into the venous circulation, commonly through an antecubin vein.
  • the technique allows for the determination of the pattern (classic or occult), boundaries, composition and location of CNV with respect to the foveal centre.
  • Avastin which is one of the commercially available therapies for AMD, was administered as a positive control.
  • Avastin is a direct inhibitor of new vessel formation.
  • Dye laser PC was performed using a diode-pumped, 532 nm argon laser attached to a slit lamp funduscope, and a handheld planoconcave contact lens applied to the cornea to neutralize ocular power.
  • Eight lesions (532 nm, 150 mW, 0.2 second, 200 ⁇ m diameter) were made in a peripapillary distributed and standardized fashion centered on the optic nerve at 500 ⁇ m radius and avoiding major vessels in each eye.
  • the morphologic end point of the laser injury was identified as the temporary appearance of a cavitation bubble, a sign associated with the disruption of Bruch's membrane. Laser spots that did not result in the formation of a bubble were excluded from the studies.
  • Rimcazole Treatment with rimcazole dosed by intraperitoneal and intravitreal injection-Study Protocol Rimcazole was administered to animals via both the intra-vitreal route and the intra-peritoneal route as a surrogate for oral dosing and the results obtained are thus expected to mimic those which would be obtained following oral dosing.
  • Avastin (bevacizumab) was administered intra-vitreally as a positive control in the experiment.
  • Leakage was defined as the presence of a hyperfluorescent lesion that increased in size with time in the late-phase angiogram
  • Figure 1 illustrates the grading procedure and the assignment of disease index.
  • the intensity and area of staining in late-phase fluorescein angiography was graded by two examiners in a masked fashion. Angiograms were graded as follows: Score 0, no staining (leakage >100 ⁇ m diameter); score 1, slightly stained (>100 ⁇ m diameter); score 2, moderately stained (>300 ⁇ m diameter); score 3, strongly stained (>500 ⁇ m diameter) and the score was evaluated by a relevant statistical test, where each substance was compared against the relevant control group. When the two scores given for a particular lesion did not coincide, the higher score was used for the analysis. Such discrepant scoring was observed in ⁇ 10% of lesions analyzed, and the discrepancy was never by more than one grade. Values of P ⁇ 0.05 were considered statistically significant for all forms of statistical analysis used.
  • Figures 4(a) to (d) and 5 show the therapeutic benefit of early treatment with Rimcazole administered by intraperitoneal injection and Avastin administered by intravitreal injection directly compared to the comparative vehicle and route of administration controls.
  • treatment with Rimcazole leads to a pattern of diffuse fluorescence unaccompanied by intense major vessel staining which is seen very shortly after fluorescein administration. This reflects a generalised reduction in oedema from vessels of the choroid and the retina. This pattern is consistent with an inhibition of vessel leakage rather than an inhibition in new vessel formation as seen with Avastin.
  • Example 2 was carried out as detailed in Example 1 but with the exception that blood samples were taken from the animals 4 hours post dose on days 0 and 14 of treatment. Samples were processed for separation of plasma and plasma samples were analysed for the presence of Rimcazole using the following procedure.
  • Plasma samples were mixed 1 in 10 with a 5% v/v ammonia solution and extracted by the addition of 25 equivalents of extraction solvent (95 parts hexane and 5 parts isopropyl alcohol). Extraction was completed by vortexing for 10 minutes and centrifugation at 4000rpm for 10 minutes at 4 0 C. The resulting supernatant was freeze-dried and reconstituted into 90:10 methanol: 2mM ammonium acetate v/v prior to injection to liquid chromatography-mass spec (LC-MS/MS). Chromatographic separation was achieved using a Supelcosil LC-ABZ 4.6 X 50 mm, 5 ⁇ m column under isocratic conditions.
  • extraction solvent 95 parts hexane and 5 parts isopropyl alcohol
  • a dose of 10mg/kg/day was the lowest dose which showed a near maximal response. Analysis of the 7 day data also suggests that a dose between 10-15mg/kg/day was the minimally effective dose in controlling vascular leak associated with laser induced CNV and showed a near identical trend in the day 7 analysis.
  • SLO-FA images 4 mins after injection of FS are shown in Figure 7.
  • Scans of the vehicle animals show signs of choroidal neovascularisation as demonstrated by intense white areas of staining. These areas are reduced with Rimcazole treatment, with little or no evidence of vascular leakage seen in the 15, 20 and 25mg/kg/d treatment groups.

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Abstract

La présente invention concerne l’utilisation du rimcazole ou un dérivé pharmaceutiquement acceptable de celui-ci dans le traitement d’une maladie ou un trouble associé à un œdème et/ou une fuite vasculaire, par exemple la dégénérescence maculaire liée à l’âge. Dans un mode de réalisation, le rimcazole est administré par voie orale.
PCT/GB2009/002700 2008-11-18 2009-11-18 Utilisation du rimcazole pour le traitement de troubles oculaires WO2010058166A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074359A1 (fr) * 2000-03-31 2001-10-11 Barbara Spruce Ligands de recepteurs sigma et leurs utilisations medicales
WO2006021811A2 (fr) * 2004-08-27 2006-03-02 University Court Of The University Of Dundee Traitement de l'opacification de la capsule posterieure
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074359A1 (fr) * 2000-03-31 2001-10-11 Barbara Spruce Ligands de recepteurs sigma et leurs utilisations medicales
WO2006021811A2 (fr) * 2004-08-27 2006-03-02 University Court Of The University Of Dundee Traitement de l'opacification de la capsule posterieure
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAMEI J: "Possible role of sigma-receptors in the regulation of cough reflex, gastrointestinal and retinal function", NIPPON YAKURIGAKU ZASSHI. FOLIA PHARMACOLOGICA JAPONICA JUL 1999, vol. 114, no. 1, July 1999 (1999-07-01), pages 35 - 41, XP009129165, ISSN: 0015-5691 *
WANG L ET AL: "Sigma receptor antagonists inhibit human lens cell growth and induce pigmentation", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 46, no. 4, 1 April 2005 (2005-04-01), pages 1403 - 1408, XP002384041, ISSN: 0146-0404 *

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