WO2012047893A2 - Utilisation de rifalazil et d'analogues de celui-ci pour le traitement de troubles oculaires - Google Patents

Utilisation de rifalazil et d'analogues de celui-ci pour le traitement de troubles oculaires Download PDF

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WO2012047893A2
WO2012047893A2 PCT/US2011/054775 US2011054775W WO2012047893A2 WO 2012047893 A2 WO2012047893 A2 WO 2012047893A2 US 2011054775 W US2011054775 W US 2011054775W WO 2012047893 A2 WO2012047893 A2 WO 2012047893A2
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rifalazil
composition
eye
agent
infection
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WO2012047893A3 (fr
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Chalom Sayada
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Activbiotics Pharma, Llc
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Publication of WO2012047893A2 publication Critical patent/WO2012047893A2/fr
Publication of WO2012047893A3 publication Critical patent/WO2012047893A3/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0051—Ocular inserts, ocular implants
    • 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
    • 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

Definitions

  • the invention is generally in the area of treatment of ocular disorders, particularly infections of the eye, and ocular disorders caused by bacterial infections in the eye.
  • Eye Infections can be caused by bacterial, viral, or other microbiological agents. There are many different types of eye infections, some of which are more common than others.
  • Eye infections can affect any part of the eyes from the eye lids to the cornea and even to the optic nerves in the back of the eye.
  • Conjunctivitis is defined as an inflammation of the conjunctiva, which is the thin membrane that lines the inner surface of the eyelids and the whites of the eyes (called the sclera). Conjunctivitis can be caused by bacterial or viral infections, allergies, or non-specific conditions such as having a foreign object in the eye).
  • Bacterial conjunctivitis is commonly caused by Staphylococcus, Streptomonas, Haemophilus, Chlamydia, but also Gram negative bacteria such as Pseudomonas, Vibrio, Helicobacter, and Campylobacter.
  • the infection is highly contagious, and is spread by contact, usually with objects which have come into contact with the infected person's eye secretions.
  • the most common symptoms of bacterial conjunctivitis include redness and thick discharge, which may be yellow, white, or green, and it usually continues to drain throughout the day. The affected eye often is "stuck shut" in the morning.
  • Bacterial conjunctivitis is common, especially in young patients.
  • One current treatment involves a newer-generation fluoroquinolone.
  • Fluoroquinolone therapy in a rabbit model of post-LASIK methicillin-resistant Staphylococcus aureus keratitis., J Cataract Refract Surg., 34:295-301 (2008) moxifloxacin was shown to eradicate Streptococcus pneumoniae in vitro faster than other older antibiotics such as tobramycin, gentamicin, and polymyxin B- trimethoprim.
  • Mortality in the setting of bacterial conjunctivitis is related to the failure to recognize and treat the underlying disease.
  • Sepsis and meningitis caused by Neisseria gonorrhoeae can be life threatening.
  • Chlamydial infection in the newborn can lead to pneumonia and/or otitis media.
  • Chlamydial infections can be very persistent, and difficult to treat. When the occur in the eye, they can cause trachoma, which frequently leads to blindness.
  • Rifampin is highly active against chlamydiae, but resistance to it is easily developed. Because of resistance, rifampin is usually used in combination therapy. The effect of long term azithromycin, rifampin or azithromycin plus rifampin therapy has been evaluated on C. trachomatis infection in cell culture. Prolonged treatment with azithromycin failed to eliminate the chlamydial infection, leading to a state of persistent infection characterized by culture-negative, but viable, metabolically-active chlamydiae. In contrast, rifampin was highly active by in vitro susceptibility testing, but prolonged exposure lead to the emergence of resistance. In combination with azithromycin, no rifampin resistance emerged and the combined regime was more effective than azithromycin alone.
  • rifalazil (benzoxazinorifamycin), is a rifamycin which has a half life of around sixty hours, making it, like azithromycin, particularly suitable for single dose therapy of patients with genitourinary chlamydial infections, which, as discussed above, can be spread to newborns. It does not suffer from the same limitations as rifampin therapy. However, rifalazil has not been specifically disclosed for use in treating ocular infections, or in ocular formulations.
  • compositions and methods for treating ocular bacterial infections, and disorders associated with such infections It would be advantageous to provide new compositions and methods for treating ocular bacterial infections, and disorders associated with such infections.
  • the present invention provides such compositions and methods.
  • compositions and methods for treating or preventing ocular bacterial infections, or disorders associated with such infections are disclosed.
  • the compositions include rifalazil, or derivatives of rifalazil in which the sec -butyl group on the piperidine ring is replaced with methyl (i.e., 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin) or other alkyl groups, and optionally include other antimicrobial agents and/or anti-inflammatory agents.
  • the compositions can be used to treat bacterial infections and associated ocular disorders.
  • disorders that can be treated or prevented include bacterial infections in the eye, as well as ocular disorders resulting from a bacterial infection, such as trachoma, conjunctivitis, and the like.
  • Some of these disorders have an inflammatory component, such as wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, cataract, ocular allergy and dry eye.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma neovascular glaucoma
  • retinal vasculitis uveitis
  • Representative bacteria that cause ocular infections in the inner or external eye include Haemophilus, Neisseria, Staphylococcus, Streptococcus, and Chlamydia. As many of these bacteria are associated with a "cryptic" phase, it can be extremely difficult to treat these infections.
  • anti-inflammatory agents can be desirable.
  • Other active agents can also be added, including combinations of antibiotics, antivirals, antifungals, analgesics, and the like.
  • Representative formulations include oral dosage forms, eye drops, ointments, and other topically applied formulations, ocular inserts, formulations for injection, and formulations designed for iontophoretic administration.
  • oral dosage forms are used to treat trachoma.
  • a dosage of around 25 mg, ideally administered only once or twice, can be sufficient to treat trachoma in a patient.
  • the present invention further relates to stabilized aqueous rifalazil formulations.
  • the stabilized formulations do not require reconstitution with separately supplied sterile water, aqueous solutions, or aqueous suspensions.
  • Such stabilized formulations can be administered to a variety of tissues either prophylactically or to treat bacterial or parasitic infections of susceptible organisms. Routes of administration include topical, parenteral, and oral. Parenteral administration may be employed to treat a specific tissue, area of the body, or limb of a patient or parenteral administration may be employed for systemic treatment, for example by intravenous or intralymphatic administration.
  • the ophthalmic formulations include water and rifalazil; and preferably have a pH in the range of between about 5.0 and about 7.0, more preferably from a pH of about 6.0 to about 6.5.
  • the formulations can further include between about 0.4% and about 1.0% sodium chloride; between about 0.1% and about 2.0% citric acid; between about 0.1% and about 2.0% sodium citrate, between about 0.1% and about 10.0% rifalazil; and water.
  • compositions can also include a lightly crosslinked carboxyl-containing polymer, which causes the solution to undergo a rapid increase in viscosity upon a pH rise associated with administration to tissues, such as those of the eye and the surrounding region.
  • Such a formulation can be prepared, for example, by: (a) combining rifalazil with citric acid; (b) adding citrate to the solution formed in step (a); (c) adding water to the solution formed in step (b); and (d) adjusting the solution formed in step (c) to a pH of about 5.0 to about 7.0, or more preferably from a pH of about 6.0 to about 6.5.
  • the formulation can be administered topically to the eye, to treat eye infections and disorders resulting from such infections.
  • the formulations are topically applied to an eye in an amount effective to treat or prevent infection in the eye tissue.
  • a depot of rifalazil can be placed in contact with the eye for a sufficient length of time to allow a minimum inhibitory concentration (MIC) of the rifalazil to diffuse into the cells of the targeted eye tissue(s). Once the MIC threshold has been surpassed, a therapeutically effective concentration of the rifalazil will remain in the tissue(s) for a considerable period due to its long half-life. Accordingly, an advantage of certain preferred forms of the present invention is a simplified dosing regimen. For example, one or two topical applications may provide a sufficient tissue concentration that an inhibitory concentration remains resident in the infected tissue for several days, i.e. 4-12 days. Thus, a complete treatment regimen may involve only one or two topical applications.
  • a rifalazil-containing depot can be formed by several means.
  • One method of forming the depot involves including lightly crosslinked carboxyl containing polymers to the ophthalmic formulations, which causes the solutions to undergo a rapid increase in viscosity upon a pH rise associated with administration to tissues such as those of the eye and surrounding region.
  • a depot of the rifalazil can alternatively be formed by injecting a bolus of the antibiotic composition into a target tissue.
  • the injection is intended to form a depot of material within the sclera, to accommodate extended release of the material to the surrounding tissues.
  • Inserts placed under the eyelid have been used, for example, to deliver therapeutics to the ocular and periocular region.
  • Rifalazil can be administered alone or in combination with one or more additional antibiotics suitable for treating ocular infections, and/or anti-inflammatory agents suitable for treating inflammation in the eye.
  • an effective amount refers to the amount of rifalazil, alone or in combination with one or more additional antibiotics, needed to eradicate the ocular infection, and/or, in combination with an anti-inflammatory agent, to eradicate the bacterial cause and inflammatory symptoms associated with various ocular disorders.
  • administering is meant a method of giving one or more unit doses of an antibacterial pharmaceutical composition to an animal (e.g., topical, oral, intravenous, intraperitoneal, or intramuscular administration). The method of administration may vary depending on various factors, e.g., the components of the pharmaceutical composition, site of the potential or actual bacterial infection, bacteria involved, and severity of the actual bacterial infection.
  • bacteria a unicellular prokaryotic microorganism that usually multiplies by cell division.
  • bacteria capable of establishing a cryptic phase is meant any species whose life cycle includes a persistent, non-multiplying phase. These species include but are not limited to C. trachomatis, C. pneumoniae, C. psittaci, C. suis, C. pecorum, C. abortus, C. caviae, C. felis, C. muridarum, N. hartmannellae, W. chondrophila, S. negevensis, and P. acanthamoeba, as well as any other species described in Everett et al. (Int. J. Syst. Evol. Microbiol. 49:415-440, 1999).
  • ocular bacterial infection is meant the invasion of an eye in a host animal by pathogenic bacteria.
  • the infection may include the excessive growth of bacteria that are normally present in or on the body of an animal or growth of bacteria that are not normally present in or on the animal.
  • a bacterial infection can be any situation in which the presence of a bacterial population(s) is damaging to a host animal.
  • an animal is "suffering" from an ocular bacterial infection when an excessive amount of a bacterial population is present in or on the animal's eye, or when the presence of a bacterial population(s) is damaging the cells or other tissue in the eye of the animal.
  • cryptic phase is meant the latent or dormant intracellular phase of infection characterized by little or no metabolic activity.
  • the non-multiplying cryptic phase is often characteristic of persistent forms of intracellular bacterial infections.
  • EBs elementary bodies
  • EBs are small (300-400 nm), infectious, spore-like forms which are metabolically inactive, non-multiplying, and found most often in the acellular milieu.
  • EBs possess a rigid outer membrane which protects them from a variety of physical insults such as enzymatic degradation, sonication and osmotic pressure.
  • Intracytoplasmic inclusion is meant a multiplying reticulate body (RB) that has no cell wall.
  • RB reticulate body
  • Such inclusions may be detected, for example, through chlamydiae sample isolation and propagation on a mammalian cell lines, followed by fixing and staining using one of a variety of staining methods including Giemsa staining, iodine staining, and immunofluorescence. These inclusions have a typical round or oval appearance.
  • Persistent bacterial infection is meant an infection that is not completely eradicated through standard treatment regimens using antibiotics.
  • Persistent bacterial infections are caused by bacteria capable of establishing a cryptic phase or other non- multiplying form of a bacterium and may be classified as such by culturing bacteria from a patient and demonstrating bacterial survival in vitro in the presence of antibiotics or by determination of anti-bacterial treatment failure in a patient.
  • a persistent infection in a patient includes any recurrence of an infection, after receiving antibiotic treatment, from the same species more than two times over the period of two or more years or the detection of the cryptic phase of the infection in the patient.
  • RT-PCR reverse transcriptase polymerase chain reaction
  • chronic disease is meant a disease that is inveterate, of long continuance, or progresses slowly, in contrast to an acute disease, which rapidly terminates.
  • a chronic disease may begin with a rapid onset or in a slow, insidious manner but it tends to persist for several weeks, months or years, and has a vague and indefinite termination.
  • immunocompromised a person who exhibits an attenuated or reduced ability to mount a normal cellular or humoral defense to challenge by infectious agents, e.g., viruses, bacterial, fungi, and protozoa.
  • infectious agents e.g., viruses, bacterial, fungi, and protozoa.
  • Persons considered immunocompromised include malnourished patients, patients undergoing surgery and bone narrow transplants, patients undergoing chemotherapy or radiotherapy, neutropenic patients, HIV-infected patients, trauma patients, burn patients, patients with chronic or resistant infections such as those resulting from myelodysplastic syndrome, and the elderly, all of who may have weakened immune systems.
  • inflammatory disease is meant a disease state characterized by (1) alterations in vascular caliber that lead to an increase in blood flow, (2) structural changes in the microvasculature that permit the plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury.
  • the classic signs of acute inflammation are erythema, edema, tenderness (hyperalgesia), and pain.
  • Chronic inflammatory diseases are characterized by infiltration with mononuclear cells (e.g., macrophages, lymphocytes, and plasma cells), tissue destruction, and fibrosis.
  • Non-limiting examples of inflammatory ocular diseases include trachoma, wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, cataract, ocular allergy and dry eye.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma neovascular glaucoma
  • retinal vasculitis uveitis
  • uveitis such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma
  • episcleritis scleritis
  • treating is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • prevent disease refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease.
  • treat disease or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to improve the patient's condition.
  • treating is the administration to a mammal either for therapeutic or prophylactic purposes.
  • pharmaceutically acceptable salt is used throughout the specification to describe any pharmaceutically acceptable salt form or rifalazil or derivatives thereof.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Citric acid is a specific example of a suitable acid.
  • Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • the present invention satisfies an existing need for antibiotics that are effective in treating bacterial ocular infections, particularly bacterial ocular infections caused by bacteria capable of establishing a non-multiplying phase of infection, or diseases associated with these bacterial infections.
  • the invention described herein allows for a more complete treatment of a bacterial infection by targeting both the multiplying and non-multiplying phase of the bacteria responsible for the infection.
  • the treatment methods of the invention may improve compliance, reduce the emergence of resistance, and shorten the course of treatment.
  • Rifalazil refers to 3'-hydroxy-5'-(4-isobutyl-l-piperazinyl) benzoxazinorifamycin, also known as KRM-1648 or ABI1648. Methods of making rifalazil and microgranulated formulations thereof are described in U.S. Pat. Nos. 4,983,602 and 5,547,683, respectively. The invention as previously discussed contemplates the use of Rifalazil derivatives that are similar or superior in therapeutic effect to Rifalazil.
  • Rifalazil is a synthetic antibiotic designed to modify the parent compound, rifamycin. Compared to other antibiotics in the rifamycin class, it has extremely high antibacterial activity. However, while it has a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes, it is not an inducer of CYP450, like rifabutin and rifampicin. Accordingly, it can be used to treat ocular disorders in patients suffering from disorders that are treated by agents that are rendered less effective or ineffective by CYP450 inducers. Examples include patients suffering from HIV, HBV, HCV, and cancer, as well as patients on birth control, taking calcium channel blockers, a variety of anti-psychotic and antidepressant medications, and the like.
  • rifalazil analogs that can be used in addition to or in place of rifalazil. Principal among these is 3'-hydroxy-5'-(4- methylpiperazinyl)benzoxazinorifamycin.
  • Other rifalazil analogs include those described in U.S. Patent No. 7,078,399, U.S. Patent No. 7,342,011, U.S. Patent No. 7,220,738, U.S. Patent No. 7,271,165, U.S. Patent No. 7,488,726, U.S. Patent No. 7,547,692, and U.S. Patent No. 11/638,738, the contents of each of which are hereby incorporated by reference.
  • Rifalazil and the rifalazil derivatives described above is active against the following common bacterial eye pathogens: Staphylococcus aureus, Escherichia coli, Haemophilus influenzae, Klebsiella/Enterobacter species, Neisseria species, Pseudomonas aeruginosa, Serratia marcescens, C. trachomatus and C. pneumoniae, and Streptococci, including Streptococcus pneumoniae.
  • Various salt forms of rifalazil and rifalazil derivatives can be used in the broad practice of the present invention.
  • compositions described herein include rifalazil or a rifalazil derivative as described herein, and, optionally, one or more other antibiotic agents and/or anti-inflammatory agents.
  • rifalazil (or derivatives thereof or pharmaceutically acceptable salts thereof) used in the invention described herein can be in any suitable form that provides suitable bioavailability.
  • Drug delivery devices and formulations that locally deliver rifalazil to the eye are described in detail herein.
  • the disorders can be treated with an oral dosage form of rifalazil.
  • Rifalazil has a maximum stability over a pH interval of about 5.0 to about 7.0, preferably with a maximum at a pH of about 6.3.
  • the stabilized antibiotic formulations may advantageously contain one or more chelating agents or antioxidants.
  • Stabilized formulations of rifalazil can be prepared over this pH interval under strictly controlled Good Manufacturing Practice (GMP) conditions, ensuring both the quality and uniformity of the materials while avoiding the requirement for reconstitution by the pharmacist, physician, or patient. Moreover, sufficiently stable formulations are amendable to commercial transportation and can dispensed and administered without concern that the active component will be unacceptably degraded.
  • GMP Good Manufacturing Practice
  • suitably stable formulations can be dispensed for administration over an extended course of treatment, or packaged in single dose forms suitable for direct administration by a patient or physician without the effort or concern over reconstitution.
  • Stable aqueous formulations of rifalazil can be administered topically, parenterally, and orally.
  • the composition may be formulated for application as a liquid drop, ointment, a viscous solution or gel, a ribbon, or a solid.
  • the composition can be topically applied, for example, without limitation, to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac.
  • the stabilized formulation of rifalazil is formulated as a solid, semi-solid, powdered, or lyophilized composition, which upon addition of water or aqueous solutions produces a stabilized rifalazil formulation having a pH of about 5.0 to about 7.0, more preferably of about 5.8 to about 6.8, more preferably from about 6.0 to about 6.6, more preferably of about 6.2 to about 6.4, more preferably of about 6.25 to 6.35, and even more preferably about 6.3.
  • Topical administration eye drops or other suitable topical formulations for direct administration to the eye
  • subconjunctival injections periocular injections
  • intravitreal injections surgical implants, and systemic routes.
  • intravitreal injections can be used to achieve therapeutic levels of drugs in ocular tissues.
  • Eye drops are useful in treating conditions affecting either the exterior surface of the eye or tissues in the front of the eye, and some formulations can penetrate to the back of the eye for treatment of retinal diseases.
  • iontophoresis can be used to deliver the compounds described herein to the back of the eye.
  • the ocular iontophoresis system OcuPhorTM
  • Iontophoresis uses a small electrical current to transport ionized drugs into and through body tissues. Care must be taken not to use too high of a current density, which can damage eye tissues.
  • Iontophoresis typically involves using a drug applicator, a dispersive electrode, and an electronic iontophoresis dose controller.
  • the drug applicator can be a small silicone shell that contains a conductive element, such as silver-silver chloride.
  • a hydrogel pad can absorb the drug formulation.
  • a small, flexible wire can connect the conductive element to the dose controller.
  • the drug pad can be hydrated with a drug solution immediately before use, with the applicator is placed on the sclera of the eye under the lower eyelid. The eyelid holds the applicator in place during treatment.
  • the drug dose and rate of administration can be controlled by programming and setting the electronic controller.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose
  • the tablets may be uncoated or they may be coated by known techniques, preferably to delay disintegration and absorption in the gastrointestinal tract until the tablets reach the colon.
  • the coating can be adapted to not release the rifalazil until after passage through the stomach, for example, by using an enteric coating (e.g., a pH-sensitive enteric polymer).
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose.
  • a time delay material such as, for example, glyceryl monostearate or glyceryl distearate, may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical degradation prior to the release of the active drug substance).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin). Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin.
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. Additional examples include the formulations listed on the following websites: http://www.advancispharm.com/, http://www.intecpharma.com/, and www.depomedinc.com/
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, camauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl inethacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • Solid, semi-solid, powdered, or lyophilized composition may be prepared and packaged for single dose or multiple dose delivery.
  • the solid, semi-solid, powdered, or lyophilized compositions may also contain one or more additional medicaments or pharmaceutically acceptable excipients compatible with the intended route of administration.
  • the solid, semisolid, powdered, or lyophilized compositions may also contain polymeric suspending agents.
  • the reconstitutable formulations of stabilized rifalazil thus provide for compositions having the advantages of a shelf life comparable to that of, and additionally, the extended shelf life of the stablized aqueous formulations described herein.
  • rifalazil can reach many of the tissues and fluids of the eye by oral administration
  • rifalazil and the rifalazil analogs described herein are amenable to topical administration to eye and periocular tissues.
  • the rifalazil can be supplied to the eye surface in a variety of ways, including as an aqueous ophthalmic solution or suspension, as an ophthalmic ointment, and as an ocular insert, but application is not limited thereto.
  • any technique and ocular dosage form that supplies rifalazil to the external eye surface is included within the definition of "topically applying.”
  • the external surface of the eye is typically the outer layer of the conjunctiva, it is possible that the sclera, cornea, or other ocular tissue could be exposed such as by rotation of the eye or by surgical procedure, and thus be an external surface.
  • periocular tissues are defined as those tissues in contact with the lachrymal secretions, including the inner surface of the eye lid, the tissues of the orbit surrounding the eye, and the tissues and ducts of the lachrymal gland.
  • the amount of rifalazil topically supplied is effective to treat or prevent infection in a tissue of the eye. This means that the conditions of application result in a retarding or suppression of the infection.
  • at least about MIC 50 for the targeted bacteria or parasite is delivered to the ocular tissue by the topical application of an effective amount.
  • the concentration within the ocular tissue is desired to be at least about 0.25 ⁇ g/g, preferably at least about 1 ⁇ g/g, and more preferably at least about 10 ⁇ g/g.
  • the amount of rifalazil actually supplied to the external eye surface will almost always be higher than the tissue concentration.
  • formulations as a depot will advantageously maintain the concentration of the rifalazil in the affected tissues at or above the MIC 50 for a period of at least about 2 hours, or more preferably at least about 4 hours, more preferably at least about 8 hours, or more preferably at least about 12 hours.
  • a series of applications are typically employed in a topical administration dosing regimen, it is possible that one or more of the earlier applications will not achieve an effective concentration in the ocular tissue, but that a later application in the regimen will achieve an effective concentration. This is contemplated as being within the scope of topically applying rifalazil in an effective amount.
  • a single application such as consisting of one or two drops, provides a therapeutically effective concentration (e.g. one that retards or suppresses the infection) of the rifalazil within a tissue of the eye.
  • a single application will typically provide a therapeutically effective amount of the rifalazil within a tissue of the eye for at least about 2, more preferably about 4, more preferably about 8, more preferably about 12, and more preferably at least about 18 hours.
  • the stabilized rifalazil compositions of this invention may be topically administered to a variety of tissues, including the eye, to provide prophylaxis or treatment of infections.
  • rifalazil compositions of this invention can be administered parenterally by direct administration to muscle or affected tissues, intravenously or intralymphatically.
  • Formulations of this invention to be administered by injection will generally not include polymeric suspending agents.
  • Rifalazil compositions suitable for topical administration to the eye or periocular tissue can include one or more "ophthalmically acceptable carriers.”
  • rifalazil is administered to eye tissues by intrascleral injection, as disclosed in U.S. Pat. Nos. 6,397,849 and 6,378,526.
  • Administration by means of intrascleral injection can advantageously be employed to provide antibiotics to the tissues of the posterior segment of the eye.
  • the rifalazil will (1) form a depot within the scleral layer and diffuse into the underlying tissue layers such as the choroid and/or retina, (2) be propelled through the scleral layer and into the underlying layers, or (3) a combination of both (1) and (2).
  • a preferred form of the present invention for topical ophthalmic administration provides for achieving a sufficiently high tissue concentration of rifalazil with a minimum of doses so that a simple dosing regimen can be used to treat or prevent bacterial or parasitic infections.
  • a preferred technique involves forming or supplying a depot of rifalazil in contact with the external surface of the eye.
  • a depot refers to a source of rifalazil that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of rifalazil to be present in the fluid on the external surface of the eye by a single application.
  • a depot more easily facilitates loading of the ocular tissue in view of the typically slow and low penetration rate of the generally water- insoluble or poorly soluble rifalazil.
  • the depot which retains a bolus of concentrated drug, can effectively slowly "pump" the rifalazil into the ocular tissue.
  • the rifalazil penetrates the ocular tissue, it is accumulated therein and not readily removed due to its long half-life.
  • the tissue concentration increases and the minimum inhibitory concentration threshold is eventually reached or exceeded, thereby loading the ocular tissue with rifalazil antibiotic.
  • one or two applications may provide a complete dosing regimen. Indeed, such a simple dosing regimen may provide a 6 to 14 day treatment concentration within the ocular tissue.
  • a preferred dosing regimen involves one to two doses per day over a one to three day period, more preferably one or two doses in a single day, to provide in vivo at least a 6 day treatment and more typically a 6 to 14 day treatment.
  • a depot can take a variety of forms so long as the rifalazil can be provided in sufficient concentration levels therein and is releasable therefrom, and that the depot is not readily removed from the eye.
  • a depot generally remains for at least about 30 minutes after administration, preferably at least 2 hours, and more preferably at least 4 hours.
  • the term "remains" means that neither the depot composition nor the rifalazil is exhausted or cleared from the surface of the eye prior to the indicated time. In some embodiments, the depot can remain for up to eight hours or more.
  • Typical ophthalmic depot forms include aqueous polymeric suspensions, ointments, and solid inserts. Polymeric suspensions are the most preferred form for the present invention and will be discussed subsequently.
  • Ointments which are essentially an oil-based delivery vehicle, are a well known compositions for topical administration.
  • Common bases for the preparation of ointments include mineral oil, petrolatum and combinations thereof, but oil bases are not limited thereto.
  • ointments When used for ophthalmic administration, ointments are usually applied as a ribbon onto the lower eyelid. The disadvantage of ointments is that they can be difficult to administer, can be messy, and can be uncomfortable or inconvenient to the patient. Moreover, temporarily blurred vision is a common difficulty encountered when they are employed for ophthalmic administration.
  • Inserts are another well-known ophthalmic dosage form and comprise a matrix containing the active ingredient.
  • the matrix is typically a polymer, and the active ingredient is generally dispersed therein or bonded to the polymer matrix. The active ingredient is slowly released from the matrix through dissolution or hydrolysis of the covalent bond, etc.
  • the polymer is bioerodible (soluble) and the dissolution rate thereof can control the release rate of the active ingredient dispersed therein.
  • the polymer matrix is a biodegradable polymer that breaks down, such as by hydrolysis, to thereby release the active ingredient bonded thereto or dispersed therein.
  • the matrix and active ingredient can be surrounded with a polymeric coating, such as in the sandwich structure of matrix/matrix+active/matrix, to further control release, as is well known in the art.
  • a polymeric coating such as in the sandwich structure of matrix/matrix+active/matrix
  • the kinds of polymers suitable for use as a matrix are well known in the art.
  • the rifalazil can be dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization.
  • the amount of rifalazil is generally from about 0.1 to 50%, more typically about 2 to 20%.
  • the insert can be placed, depending on the location and the mechanism used to hold the insert in position, by either the patient or the doctor, and is generally located under the upper eye lid. A variety of shapes and anchoring configurations are recognized in the art.
  • a biodegradable or bioerodible polymer matrix is used so that the spent insert does not have to be removed. As the biodegradable or bioerodible polymer is degraded or dissolved, the trapped rifalazil is released.
  • inserts can provide long term release and hence only a single application of the insert may be necessary, they are generally difficult to insert and are uncomfortable to the patient.
  • a preferred form of the stabilized rifalazil composition for administration of rifalazil to the ocular and periocular tissues is an aqueous polymeric suspension.
  • at least one of the rifalazil or the polymeric suspending agent is suspended in an aqueous medium having the properties as described above.
  • the rifalazil may be in suspension, although in the preferred pH ranges the rifalazil will be in solution (water soluble), or both in solution and in suspension. It is possible for significant amounts of the rifalazil to be present in suspension.
  • the polymeric suspending agent is preferably in suspension (i.e.
  • suspending agent serves to provide stability to the suspension and to increase the residence time of the dosage form on the eye. It can also enhance the sustained release of the drug in terms of both longer release times and a more uniform release curve.
  • polymeric suspending agents examples include dextrans, polyethylene glycols, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosic polymers like hydroxypropyl methylcellulose, and carboxy-containing polymers such as polymers or copolymers of acrylic acid, as well as other polymeric demulcents.
  • a preferred polymeric suspending agent is a water swellable, water insoluble polymer, especially a crosslinked carboxy-containing polymer.
  • Crosslinked carboxy-containing polymers used in practicing this invention are, in general, well known in the art.
  • such polymers may be prepared from at least about 90%, and preferably from about 95% to about 99.9% by weight, based on the total weight of monomers present, of one or more carboxy- containing monoethylenically unsaturated monomers (also occasionally referred to herein as carboxy-vinyl polymers).
  • Acrylic acid is the preferred carboxy-containing monoethylenically unsaturated monomer, but other unsaturated, polymerizable carboxy-containing monomers, such as methacrylic acid, ethacrylic acid, .beta.- methylacrylic acid (crotonic acid), cis-.alpha.-methylcrotonic acid (angelic acid), trans-. alpha.-methylcrotonic acid (tiglic acid), .alpha.-butylcrotonic acid, .alpha.- phenylacrylic acid, . alpha.
  • Such polymers may be crosslinked by a polyfunctional crosslinking agent, preferably a difunctional crosslinking agent.
  • the amount of crosslinking should be sufficient to form insoluble polymer particles, but not so great as to unduly interfere with sustained release of the rifalazil antibiotic.
  • the polymers are only lightly crosslinked.
  • the crosslinking agent is contained in an amount of from about 0.01% to about 5%, preferably from about 0.1% to about 5.0%, and more preferably from about 0.2% to about 1%, based on the total weight of monomers present.
  • crosslinking agents include non-polyalkenyl polyether difunctional crosslinking monomers such as divinyl glycol; 2,3-dihydroxyhexa-l,5- diene; 2,5-dimethyl-l,5-hexadiene; divinylbenzene; ⁇ , ⁇ -diallylacrylamide; N,N- diallymethacrylamide and the like.
  • alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like; see, e.g., Brown U.S. Pat. No. 2,798,053, the entire contents of which are incorporated herein by reference.
  • Diolefinic non-hydrophilic macromeric crosslinking agents having molecular weights of from about 400 to about 8,000, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the crosslinking agents; see, e.g., Mueller et al. U.S. Pat. Nos. 4,192,827 and 4,136,250, the entire contents of each patent being incorporated herein by reference.
  • the crosslinked carboxy-vinyl polymers may be made from a carboxy-vinyl monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a crosslinking agent or agents.
  • the polymers are ones in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxy-containing monoethylenically unsaturated monomer or monomers has been replaced by one or more non-carboxyl-containing monoethylenically unsaturated monomer or monomers containing only physiologically and ophthalmically innocuous substituents, including acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N- vinylpyrrolidone, and the like; see Mueller
  • Particularly preferred polymers are lightly crosslinked acrylic acid polymers wherein the crosslinking monomer is 2,3-dihydroxyhexa-l,5-diene or 2,3- dimethylhexa-l,5-diene.
  • Preferred commercially available polymers include polycarbophil (Noveon AA-1) and Carbopol®.
  • the crosslinked carboxy-vinyl polymers used in practicing this invention are preferably prepared by suspension or emulsion polymerizing the monomers, using conventional free radical polymerization catalysts, to a dry particle size of not more than about 50 ⁇ in equivalent spherical diameter; e.g., to provide dry polymer particles ranging in size from about 1 to about 30 ⁇ , and preferably from about 3 to about 20 ⁇ , in equivalent spherical diameter.
  • polymer particles that were obtained by mechanically milling larger polymer particles to this size is preferably avoided.
  • such polymers will have a molecular weight which has been variously reported as being from about 250,000 to about 4,000,000, and from 3,000,000,000 to 4,000,000,000.
  • the particles of crosslinked carboxy-vinyl polymer are monodisperse, meaning that they have a particle size distribution such that at least 80% of the particles fall within a 10 ⁇ band of major particle size distribution. More preferably, at least 90% and most preferably at least 95%, of the particles fall within a 10 ⁇ band of major particle size distribution.
  • a monodisperse particle size means that there is no more than 20%, preferably no more than 10%, and most preferably no more than 5% particles of a size below 1 ⁇ . The use of a monodispersion of particles will give maximum viscosity and an increased eye residence time of the ophthalmic medicament delivery system for a given particle size.
  • the aqueous polymeric suspension normally contains rifalazil in an amount from about 0.05% to about 25%, preferably about 0.1% to about 20%, more preferably about 0.5% to about 15%, more preferably about 1% to about 12%, more preferably about 2% to about 10.0%, and polymeric suspending agent in an amount from about 0.05% to about 10%, preferably about 0.1% to about 5% and more preferably from about 0.2% to about 1.0% polymeric suspending agent.
  • another preferred amount of the polymeric suspending agent is an amount from about 0.5% to about 2.0%, preferably from about 0.5% to about 1.2%, and in certain embodiments from about 0.6% to about 0.9%, based on the weight of the composition.
  • the composition contains about 0.6% to about 0.8% of a polycarbophil such as NOVEON AA-1.
  • the amount of insoluble lightly crosslinked carboxy-vinyl polymer particles, the pH, and the osmotic pressure can be correlated with each other and with the degree of crosslinking to give a composition having a viscosity in the range of from about 500 to about 100,000 centipoise, and preferably from about 1,000 to about 30,000 or about 1,000 to about 10,000 centipoise, as measured at room temperature (about 25 °C) using a Brookfield Digital LVT Viscometer equipped with a number 25 spindle and a 13R small sample adapter at 12 rpm (Brookfield Engineering Laboratories Inc.; Middleboro, Mass.).
  • the viscosity is within the range of 500 to 3000 centipoise, it may be determined by a Brookfield Model DV-11+, choosing a number cp-52 spindle at 6 rpm.
  • the viscosity will typically be about 10 to about 400 centipoise, more typically about 10 to about 200 centipoises or about 10 to about 25 centipoise.
  • the stabilized rifalazil formulations of the instant invention containing aqueous polymeric suspensions may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye.
  • they may be formulated so that there is increased gelation upon contact with tear fluid.
  • a stabilized formulation containing DuraSite® or other similar polyacrylic acid- type polymer at a pH of about 5.8 to about 6.8, or more preferably about 6.0 to about 6.5, or more preferably at a pH of about 6.2 to about 6.4, or more preferably about 6.25 to about 6.35, or more preferably about 6.3 is administered to the eye
  • the polymer will swell upon contact with tear fluid which has a higher pH.
  • This gelation or increase in gelation leads to entrapment of the suspended rifalazil particles, thereby extending the residence time of the composition in the eye.
  • the rifalazil is released slowly as the suspended particles dissolve over time.
  • compositions advantageously combine stability and solubility characteristics of rifalazil, which display minimal degradation and relatively high solubility in aqueous compositions at the pre-administration pH, with the advantages of the gelling composition.
  • the viscous gels that result from fluid eye drops typically have residence times in the eye ranging from about 2 to about 12 hours, e.g., from about 3 to about 6 hours.
  • the agents contained in these drug delivery systems will be released from the gels at rates that depend on such factors as the drug itself and its physical form, the extent of drug loading and the pH of the system, as well as on any drug delivery adjuvants, such as ion exchange resins compatible with the ocular surface, which may also be present.
  • compositions can also contain one or more of the following: surfactants, adjuvants including additional medicaments, buffers, antioxidants, tonicity adjusters, preservatives, thickeners or viscosity modifiers, and the like.
  • Additives in the formulation may desirably include sodium chloride, EDTA (disodium edetate), and/or BAK (benzalkonium chloride), sorbic acid, methyl paraben, propyl paraben, and chlorhexidine.
  • BAK benzalkonium chloride
  • Other excipients compatible with various routes of adminsitration such as topical and parenteral administration are outlined in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18.sup.th edition (1990).
  • a further aspect of the present invention involves the above-mentioned use of additional medicaments in combination with the rifalazil antibiotic.
  • a composition comprising rifalazil, an additional medicament, and an ophthalmically acceptable carrier can advantageously simplify administration and allow for treating or preventing multiple conditions or symptoms simultaneously.
  • the "additional medicaments,” which can be present in any of the ophthalmic compositional forms described herein including fluid and solid forms, are pharmaceutically active compounds having efficacy in ocular application and which are compatible with rifalazil and with the eye.
  • the additional medicaments include antivirals, antifungals, anesthetics, anti-inflammatory agents including steroidal and non-steroidal antiinflammatories, and anti-allergic agents.
  • these other medicaments are generally present in a therapeutically effective amount. These amounts are generally within the range of from about 0.01 to 5%, more typically 0.1 to 2%, for fluid compositions and typically from 0.5 to 50% for solid dosage forms.
  • the aqueous compositions (solutions or suspensions) for use in the present invention preferably use water that has no physiologically or ophthalmically harmful constituents. Typically purified or deionized water is used.
  • the pH is adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases, or buffers to within the range of about 5.0 to about 7.0, more preferably from about 5.8 to about 6.8, more preferably about 6.0 to about 6.5, more preferably at a pH of about 6.2 to about 6.4, more preferably about 6.25 to about 6.35, or more preferably about 6.3.
  • the rifalazil compositions of the present invention can be adjusted to a pH in the range of 5.0 to about 6.0, or more preferably about 5.5 to about 5.95, or more preferably 5.6 to 5.9. Any of the aforementioned ranges can be used with any of the compositions of the present invention, including, without limitation, intravenous and topical embodiments.
  • acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
  • bases include potassium hydroxide, sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylamino-methane), and the like.
  • Salts and buffers include but are not limited to citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
  • the pH is preferably adjusted by adding sodium hydroxide.
  • rifalazil is administered in the form of a suspension, or in the form of eye drops, for topical application.
  • dexamethasone Another representative corticosteroid is loteprednol etabonate.
  • the combination therapy can be extremely useful in connection with steroid- responsive inflammatory ocular conditions for which a corticosteroid is indicated and where bacterial infection or a risk of bacterial ocular infection exists.
  • Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, where the inherent risk of steroid use in certain infective conjunctivitis is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.
  • Steroids are one of the most commonly used medications for decreasing ocular inflammation. By inhibiting the breakdown of phospholipids into arachidonic acid, these agents act early on the inflammatory pathway. The most common side effects of this class of medications are cataract formation and glaucoma. Drugs such as loteprednol etabonate (Lotemax; Bausch + Lomb, Rochester, NY) carry a lower risk of increased IOP.l Another new agent is difluprednate (Durezol; Sirion Therapeutics, Tampa, FL), which possesses even greater potency than the other available corticosteroids.
  • nonsteroidal anti-inflammatory drugs have been used to treat inflammatory conditions, physicians should exercise caution when prescribing this class of medications.
  • corneal melting Isawi and Dhaliwal, "Corneal melting and perforation in Stevens Johnson syndrome following topical bromfenac use," J Cataract Refract Surg.2007;33(9):1644-1646.
  • cyclosporine 0.05% Restasis; Allergan, Inc., Irvine, CA
  • rifalazil or rifalazil derivatives and cyclosporine particularly in the form of ocular formulations such as eye drops, are also within the scope of the invention.
  • autologous serum tears can be very effective. Because they contain several important components of natural tears such as epidermal growth factor, fibronectin, and vitamin A, autologous serum tears increase the health of the ocular surface (Kojima, et al., Autologous serum eye drops for the treatment of dry eye diseases, Cornea, 27(suppl l):S25-30 (2008)).
  • agents such as tacrolimus, Sirolimus, and the like, for example, in the form of a dermatologic ointment (Protopic; Astellas Pharma US, Inc., Deerfield, IL) (Wyrsch et al., "Safety of treatment with tacrolimus ointment for anterior segment inflammatory diseases,” Klin Monatsbl Augenheilkd, 226(4):234- 236 (2009)).
  • dermatologic ointment Protopic; Astellas Pharma US, Inc., Deerfield, IL
  • rsch et al. "Safety of treatment with tacrolimus ointment for anterior segment inflammatory diseases," Klin Monatsbl Augenheilkd, 226(4):234- 236 (2009).
  • combinations of these agents and rifalazil or rifalazil derivatives are also within the scope of the invention.
  • the rifalazil and/or rifalazil derivatives can be administered before, during, or after administration of another or more than one antibiotic, and another antibiotic can be included in the rifalazil-containing compositions.
  • antibiotics that are effective against multiplying bacteria and thus can be administered in the methods of the invention are beta-lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, and temocillin), cephalosporins (e.g., cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, lora
  • antibiotics can be used in the dose ranges currently known and used for these agents, particularly when such are prescribed for treating ocular disorders.
  • Different concentrations may be employed depending on the clinical condition of the patient, the goal of therapy (treatment or prophylaxis), the anticipated duration, and the severity of the infection for which the drug is being administered. Additional considerations in dose selection include the type of infection, age of the patient (e.g., pediatric, adult, or geriatric), general health, and co-morbidity. Determining what concentrations to employ are within the skills of the pharmacist, medicinal chemist, or medical practitioner. Typical dosages and frequencies are provided, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.).
  • Rifalazil, and the rifalazil derivatives described herein are suitable for use in treating bacterial infections in the eye, as well as ocular disorders resulting from a bacterial infection.
  • Some of these disorders have an inflammatory component, such as trachoma, wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, cataract, ocular allergy and dry eye.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma neovascular glaucoma
  • retinal vasculitis
  • Rifalazil formulations of this invention can be used to treat or prevent a variety of conditions associated with ocular infection.
  • conditions of the eyelids including blepharitis, blepharconjunctivies, meibomianitis, acute or chronic hordeolum, chalazion, dacryocystitis, dacryoadenities, and acne rosacea; conditions of the conjunctiva, including conjunctivitis, ophthalmia neonatorum, and trachoma; conditions of the cornea, including corneal ulcers, superficial and interstitial keratitis, keratoconjunctivitis, foreign bodies, and post operative infections; and conditions of the anterior chamber and uvea, including endophthalmitis, infectious uveitis, and post operative infections, are a few of the tissues and conditions that can be treated by topical application of rifalazil.
  • the prevention of infection includes pre-operative treatment prior to surgery as well as other suspected infectious conditions or contact.
  • prophylaxis situations include treatment prior to surgical procedures such as blepharoplasty, removal of chalazia, tarsorrhapy, procedures for the canualiculi and lacrimal drainage system and other operative procedures involving the lids and lacrimal apparatus; conjunctival surgery including removal of ptyregia, Pingueculae and tumors, conjunctival transplantation, traumatic lesions such as cuts, burns and abrasions, and conjunctival flaps; corneal surgery including removal of foreign bodies, keratotomy, and corneal transplants; refractive surgery including photorefractive procedures; glaucoma surgery including filtering blebs; paracentesis of the anterior chamber; iridectomy; cataract surgery; retinal surgery; and procedures involving the extraocular muscles.
  • the prevention of ophthalmia neonatorum is also included.
  • the rifalazil compositions can be used to treat or prevent infections, including ocular infections caused by a variety of bacteria or parasites, including but not limited to one or more of the following organisms: Staphylococcus including Staphylococcus aureus and Staphylococcus epidermidis; Streptococcus including Streptococcus pneumoniae and Streptococcus pyogenes as well as Streptococci of Groups C, F, and G and Viridans group of Streptococci; Haemophilus influenza including biotype III (H.
  • Aegyptius Haemophilus ducreyi; Moraxella catarrhalis; Neisseria including Neisseria gonorrhoeae and Neisseria meningitidis; Chlamydia including Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae; Mycobacterium including Mycobacterium tuberculosis and Mycobacterium av wm-intracellular complex as well as a typical mycobacterium including M. marinum, M. fortuitm, and M.
  • rifalazil is ideally suitable for treating such bacterial infections, as it has a long in vivo half-life, and can remain in the body long enough to treat bacteria when they emerge from the cryptic phase.
  • rifalazil-containing compositions include, but are not limited to, the following:
  • Trachomatis is an infectious eye disease, and the leading cause of the world's infectious blindness. Globally, 84 million people suffer from active infection and nearly 8 million people are visually impaired as a result of this disease.
  • Trachoma is caused by Chlamydia trachomatis and it is spread by direct contact with eye, nose, and throat secretions from affected individuals, or contact with fomites (inanimate objects), such as towels and/or washcloths, that have had similar contact with these secretions. Flies can also be a route of mechanical transmission. Untreated, repeated trachoma infections result in entropion— a painful form of permanent blindness when the eyelids turn inward, causing the eyelashes to scratch the cornea.
  • the bacterium has an incubation period of 5 to 12 days, after which the affected individual experiences symptoms of conjunctivitis, or irritation similar to "pink eye.” Blinding endemic trachoma results from multiple episodes of re-infection that maintains the intense inflammation in the conjunctiva. Without re-infection, the inflammation will gradually subside.
  • the conjunctival inflammation is called "active trachoma” and usually is seen in children, especially pre-school children. It is characterized by white lumps in the undersurface of the upper eye lid (conjunctival follicles or lymphoid germinal centers) and by non-specific inflammation and thickening often associated with papillae. Follicles may also appear at the junction of the cornea and the sclera (limbal follicles). Active trachoma will often be irritating and have a watery discharge. Bacterial secondary infection may occur and cause a purulent discharge.
  • trachoma The later structural changes of trachoma are referred to as "cicatricial trachoma". These include scarring in the eye lid (tarsal conjunctiva) that leads to distortion of the eye lid with buckling of the lid (tarsus) so the lashes rub on the eye (trichiasis). These lashes will lead to corneal opacities and scarring, and then to blindness.
  • compositions described herein can be used prophylactically to prevent the spread of infection, for example, in poor communities where infection has already occurred, and is likely to spread.
  • rifalazil is administered orally to a patient suffering from trachoma, typically in a dosage range of around 25 mg, and, ideally, administered in only one or two doses.
  • Bacterial conjunctivitis is a purulent infection of the conjunctiva by any of several species of gram-negative, gram-positive, or acid-fast organisms. Some of the more commonly found genera causing conjunctival infections are Haemophilus, Streptococcus, Neisseria, and Chlamydia.
  • Hordeolum is a purulent infection of one of the sebaceous glands of Zeis along the eyelid margin (external) or of the meibomian gland on the conjunctival side of the eyelid (internal).
  • Infectious keratoconjunctivitis is an infectious disease of cattle, sheep, and goats, characterized by blepharospasm, lacrimation, conjunctivitis, and varying degrees of corneal opacity and ulceration.
  • the causative agent is Moraxella bovis; in sheep, mycoplasma, rickettsia, Chlamydia, or acholeplasma, and in goats, rickettsia.
  • Ocular tuberculosis is an infection of the eye, primarily the iris, ciliary body, and choroid.
  • Uveitis is the inflammatory process that involves the uvea or middle layers of the eye.
  • the uvea includes the iris (the colored part of the eye), the choroid (the middle blood vessel layer) and the ciliary body - the part of the eye that joins both parts.
  • Uveitis is the eye's version of arthritis. The most common symptoms and signs are redness in the white part of the eye, sensitivity to light, blurry vision, floaters, and irregular pupil. Uveitis can present at any age, including during childhood.
  • Uveitis is easily confused with many eye inflammations, such as conjunctivitis (conjunctival inflammation) or pink eye; keratitis (corneal inflammation); episleritis or scleritis (blood vessel inflammation in the episclera or sclera respectively); or acute closed angle glaucoma.
  • Suppurative uveitis is an intraocular infection caused mainly by pus-producing bacteria, and rarely by fungi.
  • the infection may be caused by an injury or surgical wound (exogenous) or by endogenous septic emboli in such diseases as bacterial endocarditis or meningococcemia.
  • Nonspecific conjunctivitis has many potential causes, including fatigue and strain, environmental dryness and pollutants, wind and dust, temperature and radiation, poor vision correction, contact lens use, computer use and dry eye syndrome. Another cause relates to the body's innate reaction to dead cells, which can cause nonspecific conjunctivitis.
  • This type of infection can occur when a patient's lid disease causes mild conjunctivitis, and dead Staphylococcal bacteria from the lids fall onto the ocular surface.
  • the cells trigger an inflammatory hypersensitivity reaction on the already irritated eyes.
  • This inflammatory reaction against the dead cells can be treated using an anti-inflammatory agent to combat inflammation and the rifalazil or rifalazil derivatives described herein to address the potential for any living Staph bacteria.
  • the combined causes of inflammation and infection are probably the most common origins of conjunctivitis. In fact, this combination is more common than all types of infection combined.
  • the concentration of mast cells in the conjunctiva and the eyelids makes them prime targets for hypersensitivity reactions and inflammatory disease.
  • a compromised ocular surface cannot protect itself from bacteria with full efficacy.
  • NSC patients may not have full-blown bacterial infections, their eyes are susceptible to some bacterial disease components.
  • NSC patients can benefit from a combination treatment (rifalazil and an anti-inflammatory agent) to battle inflammatory NSC.
  • Corneal inflammation is one of the most common ocular diseases in both humans and animals and can lead to blindness or even cause lost of the eye itself.
  • keratitis is classified into infectious and non- infectious, while in veterinary medicine the tradition is to classify keratitis rather into ulcerative and non-ulcerative (Whitley and Gilger 1999).
  • Non-ulcerative keratitis in dogs is usually caused by mechanical irritation (pigmentary keratitis) or by immune-mediated process (pannus).
  • non-ulcerative infectious keratitis also exists (corneal abscess, mycotic, viral keratitis).
  • Ulcerative keratitis can be of non-infectious (recurrent erosions, traumatically induced superficial ulceration) or infectious (bacterial, viral, mycotic) origin. Even in the cases of originally non-infectious ulceration, after disruption in the epithelium secondary infection often occurs.
  • any and all of these disorders can be treated using rifalazil or rifalazil derivatives, alone or in combination with other antibiotics and/or anti-inflammatory agents, using appropriate compositions as described herein.
  • Hydroxypropylmethyl cellulose, sodium chloride, edetate sodium (EDTA), BAK and surfactant are dissolved in a beaker containing approximately 1/3 of the final weight of water and stirred for 10 minutes with an overhead stirring.
  • Rifalazil is added and stirred to disperse for 30 minutes.
  • the solution is sterilized by autoclaving at 121°C for 20 minutes.
  • the rifalazil may be dry heat sterilized and added by aseptic powder addition after sterilization.
  • Mannitol, Poloxamer 407, and boric acid are dissolved separately in approximately 1/2 of the final weight of water and added by sterile filtration (0.22 ⁇ filter) and stirred for 10 minutes to form a mixture.
  • the mixture is adjusted to the desired pH in the range of 5.8 to 7.0 with sterile sodium hydroxide (IN to 10N) while stirring, brought to a final weight with sterile water, and aseptically transferred to multi-dose containers.
  • Noveon AA-1 an acrylic acid polymer available from B. F. Goodrich, is slowly dispensed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs. with an overhead stirrer. Ethylene diamine tetra acetic acid (EDTA), benzalkonium chloride (BAK), sodium chloride, and surfactant are then added to the polymer solution and stirred for 10 minutes after each addition. The polymer suspension is at a pH of about 3.0-3.5. The rifalazil is added and stirred to disperse for 30 minutes. The pH of the mixture is titrated to the desired pH in the range of 5.8 to 6.8, and brought to final weight/volume with water.
  • EDTA Ethylene diamine tetra acetic acid
  • BAK benzalkonium chloride
  • sodium chloride sodium chloride
  • surfactant surfactant
  • the mixture is aliquoted into single or multiple dose containers, which are sterilized by autoclaving at 121 °C, for 20 minutes.
  • the rifalazil may be dry heat sterilized and added by aseptic powder addition after sterilization.
  • Noveon AA-1 is slowly dispensed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs., with overhead stirring, to form a Noveon suspension.
  • the Noveon suspension is sterilized by autoclaving at 121°C, for 20 minutes.
  • Solutions containing mannitol and boric acid, or solutions containing Dequest® (a brand of bisphosphonate), mannitol, and boric acid are dissolved separately in approximately 1/2 of the final weight of water, added to the sterilized Noveon polymer suspension by sterile filtration (0.22 ⁇ filter), and stirred for 10 minutes.
  • the dry heat sterilized rifalazil is then added by aseptic powder addition.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (IN to 10N) while stirring, brought to final weight with sterile water, and aseptically filled into multi-dose containers.
  • Noveon AA- 1 is slowly dispensed into a beaker containing approximately 1/2 of the final weight of water and stirred for 1.5 hrs., with overhead stirring.
  • Edetate sodium (EDTA) Poloxamer 407 (a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers, specifically, a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol, with approximate lengths of the two PEG blocks of 101 repeat units, and an approximate length of the propylene glycol block of 56 repeat units), and sodium chloride are then added to the polymer suspension and stirred for 10 minutes.
  • EDTA Edetate sodium
  • Poloxamer 407 a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers, specifically, a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flank
  • the polymer suspension is at a pH of about 3.0-3.5.
  • the rifalazil is added and stirred to disperse for 30 minutes.
  • the mixture is adjusted to desired pH with sodium hydroxide (IN to 10N) while stirring, and is sterilized by autoclaving at 121 °C for 20 minutes.
  • the rifalazil may be dry heat sterilized and added by aseptic powder addition after sterilization. Mannitol is dissolved in 1/10 of the final weight of water and sterile filtered (0.22 ⁇ filter) in to the polymer suspension and stirred for 10 minutes.
  • the mixture is adjusted to desired pH with sterile sodium hydroxide (IN to 10N) while stirring, brought to final weight with sterile water, and aseptically filled into unit-dose containers.
  • a rifalazil ointment is prepared by dissolving 0.3 grams of rifalazil and 0.5 grams of rifalazil in a mixture containing 3.0 grams mineral oil/96.2 grams white petrolatum by stirring in a 100 ml beaker while heating sufficiently to dissolve both compounds.
  • the mixture is sterile filtered through a 0.22 ⁇ filter at a sufficient temperature to be filtered and filled aseptically into sterile ophthalmic ointment tubes.
  • HPMC Hydroxypropylmethyl cellulose
  • sodium chloride sodium chloride
  • EDTA sodium sodium, and surfactant
  • HPMC Hydroxypropylmethyl cellulose
  • the mixture is sterilized by autoclaving at 121°C, for 20 minutes.
  • the rifalazil and steroid as indicated in table 2, are dry heat sterilized and added to the HPMC-containing solution by aseptic powder addition.
  • Mannitol, Poloxamer 407, BAK, and boric acid are dissolved separately in approximately 1/2 of the final weight of water and added by sterile filtration (0.22 um filter) and stirred for 10 minutes to form a mixture.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (IN to 10N) while stirring, brought to a final weight with sterile water, and aseptically dispensed into multi-dose containers.
  • Noveon AA- 1 is slowly dispersed into a beaker containing approximately 1/3 of the final weight of water and stirred for 1.5 hrs., with an overhead stirrer. EDTA, sodium chloride, and surfactant are then added to the polymer solution and stirred for 10 minutes after each addition.
  • the polymer suspension is at a pH of about 3.0-3.5.
  • the mixture is sterilized by autoclaving at 121°C for 20 minutes.
  • the rifalazil and steroid, as indicated in table 2 are dry heat sterilized and added to the polymer suspension by aseptic powder addition.
  • BAK, mannitol, and boric acid are dissolved separately in approximately 1/2 of the final weight of water, added to the polymer mixture by sterile filtration (0.22 um filter) and stirred for 10 minutes.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (IN to 10N) while stirring, brought to a final weight with sterile water, and aseptically dispensed into multi-dose containers.

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Abstract

L'invention porte sur des compositions et des procédés pour le traitement ou la prévention d'infections bactériennes oculaires ou de troubles associés à de telles infections. Les compositions comprennent du rifalazil ou des dérivés de rifalazil, et comprennent, de manière facultative, d'autres agents antimicrobiens et/ou d'autres agents anti-inflammatoires. Les compositions peuvent être utilisées pour traiter des infections bactériennes et des troubles oculaires associés. Le trachome et la conjonctivite bactérienne sont représentatifs de troubles bactériens qui peuvent être traités.
PCT/US2011/054775 2010-10-04 2011-10-04 Utilisation de rifalazil et d'analogues de celui-ci pour le traitement de troubles oculaires WO2012047893A2 (fr)

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BR112013008186A BR112013008186A2 (pt) 2010-10-04 2011-10-04 uso de ripazil e análogos para tratar problemas oculares
CA2813734A CA2813734A1 (fr) 2010-10-04 2011-10-04 Utilisation de rifalazil et d'analogues de celui-ci pour le traitement de troubles oculaires

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035408A2 (fr) * 1998-12-18 2000-06-22 Pathogenesis Corporation Procede de traitement des infections bacteriennes par administration hebdomadaire ou bi-hebdomadaire de rifalazil
WO2002100437A2 (fr) * 2001-06-08 2002-12-19 Novartis Ag Compositions pharmaceutiques
US20050143374A1 (en) * 2001-09-06 2005-06-30 Activbiotics, Inc. Antimicrobial agents and uses thereof
JP2009120572A (ja) * 2007-11-16 2009-06-04 Kaneka Corp リファマイシン誘導体を有効成分とする抗炎症剤または免疫調節剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035408A2 (fr) * 1998-12-18 2000-06-22 Pathogenesis Corporation Procede de traitement des infections bacteriennes par administration hebdomadaire ou bi-hebdomadaire de rifalazil
WO2002100437A2 (fr) * 2001-06-08 2002-12-19 Novartis Ag Compositions pharmaceutiques
US20050143374A1 (en) * 2001-09-06 2005-06-30 Activbiotics, Inc. Antimicrobial agents and uses thereof
JP2009120572A (ja) * 2007-11-16 2009-06-04 Kaneka Corp リファマイシン誘導体を有効成分とする抗炎症剤または免疫調節剤

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