Classifications

• • 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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

• the present invention involves the fields of ophthalmology, more precisely the treatment of eye disease or conditions, especially disease or condition affecting the posterior segment of the eye.
• the present invention relates to a method for in-vivo sustained release of an active agent through intraocular invasive delivery of a prodrug thereof.
• Treatment of diseases or conditions affecting the posterior segment of the eye are complicated by the inaccessibility of the posterior eye to topically applied medications.
• Treatments of posterior eye diseases require intravitreal or periocular injections or systemic drug administration.
• Local injections are usually preferred to systemic drug administration because the blood/retinal barrier impedes the passage of most drugs from the systemically circulating blood to the interior of the eye. Therefore large systemic doses are needed to treat eye posterior diseases, which often result in systemic toxicities.
• US20050244469 discloses a method for treating an ocular condition comprising the insertion of an implant into an ocular site of a patient with an ocular condition, more preferably in the vitreous body of the eye of a patient to treat a condition or disease of the posterior segment of the eye.
• a recognized advantage of providing a method for an extended treatment is to prevent recurrence of the inflammatory or other posterior ocular condition treated. It can also minimize the number of surgical interventions required by the patient over time to treat an ocular condition.
• the invention relates to the use of prodrug for the manufacture of a medicament or an ophthalmic composition useful for treating an ocular disease affecting the posterior segment of the eye, in a subject in need thereof, wherein the prodrug is a composition injected into the vitreous body, and the frequency of injections does not exceed one injection per month, preferably the frequency of injection is once every two months, more preferably once every six months or more.
• the invention also relates to the use of a prodrug for providing extended duration of treatment of an ocular disease affecting the posterior segment of the eye, in a subject in need thereof, said use comprising administering an amount of a prodrug enabling the sustained release of a therapeutically amount of said drug for a duration of at least one month, preferably at least 2 month, more preferably at least six months.
• no drug can be detected in the vitreous or the molar ratio of the prodrug to the drug, in the vitreous, two months after one single injection of said prodrug, is more than 60.
• the molar ratio of the prodrug to the drug, in the retina, two months after one single injection of said prodrug is less than 60.
• the molar ratio of the prodrug to the drug, in the choroid, two months after one single injection of said prodrug is less than 60.
• the molar ratio of the prodrug to the drug, in the vitreous, two months after one injection of said prodrug is more than 60 and the molar ratio of the prodrug to the drug, in the retina and/or in the choroid, two months after one injection of said prodrug, is less than 60.
• the prodrug is injected in the vitreous in an amount enabling the sustained release of a therapeutically amount of said drug for a duration of at least one month, preferably at least 2 months, more preferably at least 6 months.
• the prodrug is injected with a frequency of one injection every two months.
• the release of the prodrug and its transformation into the drug is such that a therapeutic amount of drug is present on the target site, for example retina or choroid, during two months, the prodrug being sustaineously released during this period of time.
• the prodrug is injected with a frequency of one injection every six months.
• the prodrug is within a composition, wherein said prodrug is in combination with any suitable excipient or carrier for ophthalmic use.
• the carrier is oily.
• suitable oily carrier are mineral oils such as silicone, paraffin or vegetal oils such as medium chain triglycerides, castor oil, olive oil, corn oil, palm oil or any other oil suitable for intraocular injection.
• the carrier is an emulsion, preferably an oil-in-water emulsion, more preferably an anionic emulsion.
• said emulsion comprises colloid particles having an oily core surrounded by interfacial film, the film comprising surface active agents, lipids or both, at least part or the surface active agents or lipids in the interfacial film having negatively charged polar groups, and the colloid particles have a negative zeta potential.
• the prodrug is comprised within the emulsion in an amount of about 0.01% to about 10% w/w of the composition.
• the prodrug is comprised in the amount of about 0.5% to about 3% w/w of the composition. In a preferred embodiment, the prodrug is comprised in an amount of about 2% w/w of the composition. In another preferred embodiment of the present invention, the prodrug is comprised in an amount of about 1% w/w of the composition.
• the Applicant performed a number of tests and noticed that the invention had the further advantage that he could not detect any release of drug in the plasma, which may mean that there is none or few passage of the drug released through the general system of the subject, and in any event, no related side effect is observed.
• injecting in the vitreous body means performing an intravitreal injection.
• the hydrolysis of the prodrug results in therapeutically amounts of drug at the targeted site of action, preferably at retina and/or choroid.
• the half-life of the prodrug in the target tissue is of at least 15 days, preferably of at least 30 days, preferably of at least 60 days, preferably of at least 6 months.
• the present invention intends to propose solutions for treating various ophthalmic or ocular conditions and diseases.
• the present invention is especially designed for the treatment of posterior ocular conditions, which means any disease, ailment or condition which primarily affects or involves a posterior ocular site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (including the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular site.
• a posterior ocular condition can include a disease, ailment or condition.
• Macular Disorders such as myopia, Non-Exudative Age Related Macular Degeneration (Dry), Exudative Age Related Macular Degeneration (Wet), Choroidal Neovascular Membranes (others than ARMD) and Cystoid Macular Edema
• Inflammatory Disorders such as Uveitic Retinal Disease, Endophthalmitis, Toxoplasmic Retinochoroiditis, Systemic General Disorders Associated with Retinal Uveitis or Retinochoroidal Syndromes (Syphilis, Tuberculosis, Lyme Diseases, Chung Strauss Disease, LED, etc), Neuroretinitis, Optic Neuritis
• Vascular Disorders such as Diabetic Retinopathy (all stages), Diabetic Macular Edema, Arterial Occlusion, Venous Occlusion; Heredo Retinal Dystrophies such as Stargardt's Disease, Fundus Flavimaculatus, other Heredomacular Dysropy; Trauma caused by
• an effective amount may be used interchangeably and refer to an amount of an ingredient which is sufficient to achieve an intended physiological effect.
• a “therapeutically effective amount” refers to a non-toxic, but sufficient amount of an active agent, to achieve therapeutic results in treating a condition for which the active agent is known to be effective. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine, in that it may depend on various biological factors or individual variation and response to treatments.
• subject refers to a mammal that may benefit from the administration of a composition or method as recited herein. Most often, the subject will be a human but can be of any animals.
• administering refers to the manner in which a prodrug is presented to a subject.
• invasive refers to a form of administration that ruptures or punctures a biological membrane or structure with a mechanical means across which a prodrug is being delivered.
• active agent or “drug” may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount.
• drugs useful in the present invention include without limitation: antivirals, chosen from the group comprising idoxuridine, trifluorothymidine, trifluorouridine, acyclovir, ganciclovir, cidofovir, interferon, DDI, AZT, foscamet, vidarabine, irbavirin; non-steroidal anti-inflammatories chosen from the group comprising amfenac, ketorolac, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam and other COX2 inhibitors; cytokines, interleukines and growth factors epidermal growth factor, fibroblast growth factor, pigment epithelium growth factor, platelet derived growth factor, transforming growth factor beta, cili
• the drug has an ophthalmic physiologic therapeutic activity, whereas the prodrug is inactive.
• the prodrug is a drug, or is prepared from a drug, which has or was grafted with functional groups such as haloformyl, hydroxyl, aldehyde, alkyl, alkenyl, alkynyl, carboxamide, primary amine, secondary amine, tertiary amine, quaternary ammonium ion, azo (Diimide), benzyl, carboxylate, carboxyl, cyanate, thiocyanate, ether, ester, halo, primary ketimine, secondary ketimine, primary aldimine, secondary aldimine, isocyanide, isocyanate, isothiocyanate, ketone, nitrile, nitro, nitroso, peroxy, phenyl, phosphino, phosphate, phosphono, phosphate, pyridyl, sulfonyl, sulfo, sulfinyl or
• prodrug refers to a drug precursors which following administration, release the drug in vivo via some chemical or physiological process.
• the prodrug is inactive.
• the prodrug releases the drug by a biological reaction, such as enzymatic cleavage.
• the prodrug is a composition including the pro-active ingredient, eventually in combination with any suitable excipient, especially any excipient injectable in the vitreous body of the eye.
• the term composition should not be construed as an implantable device.
• the enzyme involved in the transformation of the prodrug into the drug may be:
• Transferases transferring one carbon, alkyl, aryl, nitrogenous, aldehyde or ketone groups; transferases; acyltransferases; glycosyltransferases; transferases transferring phosphorus-, selenium- or sulfur-containing groups;
• Lyases such as carbon-carbon, carbon-oxygen, carbon-nitrogen, carbon-sulfur, carbon-halide or phosphorus-oxygen lyases
• Isomerases such as racemases and epimerases; intramolecular oxidoreductases; intramolecular transferases or intramolecular lyases;
• Preferred enzymes are hydrolases which act on ester or ether bonds; hydrolases acting on carbon-nitrogen, carbon-carbon, halide, phosphorus-nitrogen, sulfur-nitrogen, carbon-phosphorus, sulfur-sulfur or carbon-sulfur bonds; glycosylases; peptidases; hydrolases acting on acid anhydrides.
• Preferred prodrugs are esters of drugs, wherein the ester group is of formula —COOR, or ether of drugs wherein the ester group is of formula OR, wherein R is a long alkyl chain, preferably a C4-C16 alkyl chain, more preferably any suitable lipophilic chain.
• alkyl means straight chain saturated hydrocarbon or branched saturated hydrocarbon.
• Preferred alkyl groups are those comprising more than 4 carbon atoms, preferentially more than 8 atoms, more preferentially more than 12 atoms.
• a liquid chromatographic-mass spectrometric method for the simultaneous determination of dexamethasone and dexamethasone palmitate in ocular tissues was developed.
• Analytes and internal standard (roxithromycine) were extracted from the tissues using acetonitrile and separated by reverse phase liquid chromatography with a C8 column and a gradient mobile phase.
• the compounds were detected by mass spectrometric detection (atmospheric pressure ionization) with selected ion monitoring (SIM) (393.0 for dexamethasone and 631.5 for dexamethasone palmitate).
• SIM selected ion monitoring
• the method was selective for both compounds and the limits of quantification were 32.7 ng/g of retina and 71.6 ng/g choroid.
• the unweighed linear model was applied.
• dexamethasone therapeutic levels of about 1000 ng/g were maintained for at least 2 months in the target tissues. Moreover, considerable amounts of the prodrug dexapalmitate remained in both retina and choroid, indicating an even more long-lasting release.

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