WO2005051388A1 - Compositions et procedes utiles au traitement de conjonctivites - Google Patents

Compositions et procedes utiles au traitement de conjonctivites Download PDF

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Publication number
WO2005051388A1
WO2005051388A1 PCT/US2004/039382 US2004039382W WO2005051388A1 WO 2005051388 A1 WO2005051388 A1 WO 2005051388A1 US 2004039382 W US2004039382 W US 2004039382W WO 2005051388 A1 WO2005051388 A1 WO 2005051388A1
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group
pcl
total
cdv
chi
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PCT/US2004/039382
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English (en)
Inventor
Avinash N. Amin
Michael G. Douglas
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Novactyl Incorporated
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Publication of WO2005051388A1 publication Critical patent/WO2005051388A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • compositions comprising picolinic acid, or a derivative thereof, are effective in controlling or treating ocular inflammations.
  • Such compositions and methods are particularly useful in treating conjunctivitis.
  • Conjunctivitis commonly referred to as "pink eye" is an inflammation of the conjunctiva, the clear membrane that covers the white part of the eye and lines the inner surface of the eyelids.
  • Bacteria and viruses cause infectious conjunctivitis. Although many types of bacteria can cause conjunctivitis, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus are the most common cause of conjunctivitis. All types of conjunctivitis are contagious and can easily spread by contact, such as by touching, coughing, or sneezing.
  • Viral conjunctivitis commonly occurs with several viral infections. For example, during a common cold or the flu, adenoviruses or enteroviruses cause infections and conjunctivitis. A less common but more serious viral conjunctivitis is herpes simplex infection.
  • RT-PCR reverse transcription nested polymerase chain reaction
  • mumps virus have been found in tear samples from patients with conjunctivitis. Kalkan et al., Scand J. Infect. Dis. 36(9):697-700, 2004.
  • Adenovirus serotype 4c a new genome type of adenovirus serotype 4, causes nosocomial infections associated with epidemic conjunctivitis in Japan. Ariga er a/., J. Clin. Microbiol., 42(8):3644-3648, 2004. Parasites and fungal infections can also cause conjunctivitis, albeit rarely.
  • Organisms that cause the sexually transmitted diseases gonorrhea and chlamydia can also infect the eyes and cause conjunctivitis.
  • sexually transmitted bacteria Chlamydia trachomatis and Neisseria gonorrhoeae can pass from an infected mother's birth canal into her baby's eyes during delivery. These bacteria can cause symptoms of conjunctivitis in babies within the first two weeks of life and can lead to serious eye damage.
  • Allergic conjunctivitis occurs more frequently among children with allergic conditions such as hay fever. This type of conjunctivitis commonly occurs during the spring season when allergens, such as grass or ragweed pollen, permeate the environment.
  • Non-infective, or allergic conjunctivitis is characterized by ocular redness and itching and may involve mucus production in the eye. Other clinical manifestations are tearing (clear tears), crusting of the eyelids and photophobia. Animal dander or dust mites can also cause year-round symptoms of conjunctivitis.
  • allergic conjunctivitis is treated using an ophthalmic preparation that contains a topical decongestant, either with or without an antihistamine agent.
  • This condition may also respond to treatment for underlying allergies and may disappear when the causative allergen is removed.
  • the occurrence of allergic conjunctivitis in susceptible individuals can also be prevented by the topical application of sodium chromoglycate.
  • Topical ophthalmic preparation of 2-[4- (azolylbutyl)piperazinylmethyl] benzimidazole derivative have also been used in the treatment of allergic conjunctivitis.
  • the present invention provides a method for treating or preventing ocular inflammation comprising administering to a subject in need thereof, a composition comprising a therapeutically effective amount of a compound represented by the following structure:
  • R-i, R 2 , R 3 , and R 4 are selected from the group consisting of an oligopeptide, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group, neopentyl group, fluorine, chlorine, bromine, iodine and hydrogen.
  • the present invention further provides a method for treating or preventing conjunctivitis comprising administering to a subject in need thereof, a composition comprising a therapeutically effective amount of a compound represented by the following structure:
  • R ⁇ R 2 , R 3 , and R 4 are selected from the group consisting of an oligopeptide, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group, neopentyl group, fluorine, chlorine, bromine, iodine and hydrogen.
  • Figure 1 depicts the rate of positive Adenovirus-5 (Ad5) cultures using various concentrations and pH's of PCL-016 compared to a control and Cidofovir, a well known and potent antiviral. Note that increasing doses of PCL-016 tend to reduce the positive culture rate and that 0.8% and 1.5% PCL-016 perform similarly to cidofovir.
  • FIG. 2 depicts the change in the Adenovirus-5 (Ad5) positive culture rate during the early and late phases of conjunctivitis.for various concentrations of PCL-016 compared to control and Cidofovir. Note that both 0.8% and 1.5% PCL-016 are able to significantly reduce the positive culture rate similarly to Cidofovir.
  • FIG. 3 depicts the duration of Adenovirus-5 (Ad5) viral shedding for various doses of PCL-016 compared to a control and Cidofovir. Note that increasing amounts of PCL-016 are able to reduce the duration of viral shedding significantly. The effect of 0.8% and 1.5% PCL-016 is similar to that of Cidofovir.
  • Figure 4 depicts a series of Adenovirus-5 (Ad5) ocular titers for various concentrations of PCL-016 compared to a control and Cidofovir. Note that 0.8% and 1.5% PCL-016 are able to knock down the titer similarly to Cidofovir.
  • Figure 5 shows mean Adenovirus-5 (Ad5) ocular titers during the early and late phases of conjunctivitis for various doses of PCL-016 compared to a control and Cidofovir, a well known and potent antiviral. Note that during the late phase, 0.8% and 1.5% PCL-016 are able to knock down viral titers by approximately 1 log, similarly to Cidofovir.
  • the present invention provides a method for treating or preventing ocular inflammation comprising administering to a subject in need thereof, a composition comprising a therapeutically effective amount of a compound represented by the following structure:
  • R ⁇ R 2 , R 3 , and R 4 are selected from the group consisting of an oligopeptide, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group, neopentyl group, fluorine, chlorine, bromine, iodine and hydrogen.
  • R 3 is a hydrogen.
  • the compound is picolinic acid.
  • R 3 is a butyl group.
  • the compound is fusaric acid.
  • Picolinic acid and its derivatives are described in U.S. Patent Application Number 09/904,987, now U.S. patent no. 6,743,771 B1, which is hereby incorporated by reference.
  • Picolinic acid and many of its derivatives is represented by the following structure:
  • R 1 ; R 2 , R 3 and R 4 are selected from the group consisting of an oligopeptide, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group, neopentyl group, fluorine, chlorine, bromine, iodine and hydrogen.
  • compositions of picolinic acid and the above analogs may also be used, and are prepared from pharmaceutically acceptable non-toxic acids or bases including, but not limited to inorganic and organic acids.
  • Buffering agents for picolinic acid or its analogs or derivatives may also comprise non-toxic acids or bases including, but not limited to inorganic or organic acids. Examples of such inorganic acids include, but are not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric.
  • Organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids.
  • organic acids include, but are not limited to formic, acetic, propionic, succinic, glycolic, glucoronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic and galacturonic acids.
  • inorganic bases for potential salt formation with the sulfate or phosphate compounds of the invention include, but are not limited to monovalent, divalent, or other metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Appropriate organic bases may also be selected from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N- methylglucamine), procaine, ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, omithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide.
  • Carboxylic acids of picolinic acid and its derivatives are also contemplated as being within the scope of the invention.
  • a “pharmaceutical-acceptable carrier” refers to a carrier that is compatible with the other ingredients of the formulations and is not deleterious to the recipient thereof.
  • compositions according to the invention may also include a buffering agent.
  • a buffering agent Any suitable buffering agent may be used. Suitable buffering agents include, but are not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, formic, acetic, propionic, succinic, glycolic, glucoronic, maleic, furoic, citric, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic, pamoic, methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, galacturonic acid and mixtures thereof.
  • Buffering agents may comprise additional agents including, but not limited to pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose, calcium hydrogen phosphate, magnesium stearate, talc, silica, potato starch, sodium starch glycolate, sodium lauryl sulfate, sorbitol syrup, cellulose derivatives, hydrogenated edible fats, lecithin, acacia, almond oil, oily esters, ethyl alcohol, fractionated vegetable oils, methyl, propyl-p-hydroxybenzoates, sorbic acid and mixtures thereof.
  • the buffering agents may also comprise dichlorodifluoromethane, trichloro fluoromethane, dichlorotetra fluoroethane, carbondioxide, poly (N-vinyl pyrrolidone), poly (methylmethacrylate), polyactide, polyglycolide and mixtures thereof.
  • the compositions may be formulated as a medium selected from a group, including, but not limited to a suspension, solution, or emulsion.
  • the compositions may also comprise an agent selected from the group including, but not limited to a carrier, excipient, suspending agent, stabilizing agent and dispersing agent.
  • any effective concentration of the composition may be used. Methods of determining such concentrations are well known in the art, and are a matter of routine experimentation for the skilled artisan. The Examples provide guidance, utilizing the art accepted rabbit keratitis model, for determining the efficacy of various formulations. Some formulations may comprise within the range of about .001% to about 10% of the composition, although it is contemplated that higher concentrations may also be useful in certain formulations. Other formulations may comprise a concentration of the composition within the range of about .025% to about 5%. Still other formulations may comprise within about .369% to about 1.5% of the composition. Exemplary formulations are described herein.
  • compositions may be administered by any know means, including administration, directly to the eye, of an ophthalmic solution comprising the composition.
  • administration directly to the eye
  • an ophthalmic solution comprising the composition.
  • one common method of administering therapeutic agents to the eyes is by suspending such agents in a solution that mimics natural tears, and dropping the solution directly into the eyes.
  • Other methods include formulating the agent in an ophthalmic ointment, and applying the ointment directly to the eyes.
  • the invention is not limited to any particular method of administration, and may include any acceptable means.
  • topical application to affected areas other than the eyes are within the scope of the invention described, as the compositions and methods are believed to have broad applicability as treatments for viral and bacterial infections, based on the data presented in the examples.
  • the subject is a mammal.
  • the mammal is a human.
  • Treating or treatment refers to preventing a disease or symptom from occurring in an individual; inhibiting a disease or symptom from further development; or relieving the disease or symptom, resulting in regression or reversal of the disease or symptom.
  • the invention is not limited to treatment or prevention of a particular ocular inflammation.
  • inflammation includes conjunctivitis, such as allergic conjunctivitis, bacterial conjunctivitis, epidemic keratoconjunctivitis, viral conjunctivitis and hyperacute bacterial conjunctivitis.
  • the method treats or prevents conjunctivitis, wherein the method comprises administering to a subject in need thereof, a composition comprising a therapeutically effective amount of a compound represented by the following structure:
  • R ⁇ , R 2 , R 3 , and R 4 are selected from the group consisting of an oligopeptide, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group, neopentyl group, fluorine, chlorine, bromine, iodine and hydrogen.
  • R 3 is a hydrogen.
  • the compound is picolinic acid.
  • R 3 is a butyl group.
  • the compound is fusaric acid.
  • the subject is a mammal.
  • the mammal is a human.
  • the conjunctivitis is caused by a bacterium.
  • the bacterium is Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.
  • the conjunctivitis is caused by a virus.
  • the virus is an adenovirus or an enterovirus. More preferably, the virus is a herpes simplex virus.
  • the conjunctivitis is caused by an allergen.
  • the conjunctivitis may be seasonal or perennial allergic conjunctivitis.
  • Example 1 Preparation of compositions: picolinic acid ophthalmic formulations.
  • Polyvinyl alcohol USP Spectrum Chemicals 102310 Polyethylene glycol 300 NF PCCA C100508 Dextrose, anhydrous USP PCCA C100337 Disodium EDTA USP PCCA 92655 Methylparaben NF PCCA 82254 Propylparaben NF PCCA 62073 Sterile water for injection USP Abbott Laboratories 04-242-4B-1 Sodium hydroxide GFS Chemicals L133838
  • Polyethylene glycol 300 2 g 2 g 2 g 2 g 2 g
  • the pH was determined to be pH 4.86
  • the pH was adjusted to pH 7.05 and the product packaged.
  • the pH was determined to be pH 3.86.
  • the pH meter was determined and allowed to stabilize for one hour.
  • the pH meter was calibrated using pH 4 and pH 7 buffer solutions.
  • Drops were administered with at least a 1 hour interval between drops.
  • Ad5 titers were determined on A549 cell monolayers using a standard plaque assay.
  • the ocular cultures to be titered were thawed, diluted (1:10) and inoculated onto A549 monolayers.
  • the virus was adsorbed for 3 hours.
  • 1 ml of media plus 0.5% methylcellulose was added to each well, and the plates were incubated at 37°C in a 5% CO 2 -water vapor atmosphere. After 7 days incubation, the cells were stained with 0.5% gentian violet, and the number of plaques were counted under a dissecting microscope (25X).
  • the viral titers were then calculated, and expressed as plaque- forming units per milliliter (pfu/ml).
  • PCL-016 (Picolinic Acid) was supplied by Novactyl as prepared by Midwest Institute of Research & Technology, (Edmond, OK 73034) Lot 0828d. (Novactyl Lot #185.) The 1.5% PCL-016 was instilled using a Rainin EDP electronic pipet set in the multi-dispense mode. 37 :l drops were instilled.
  • PCL-016 (Picolinic Acid) was supplied by Novactyl as prepared by Midwest Institute of Research & Technology, (Edmond, OK 73034) Lot 0828c. (Novactyl Lot #184.) The 0.8% PCL-016 was instilled using a Rainin EDP electronic pipet set in the multi-dispense mode. 37 :l drops were instilled. 3. 0.369% PCL-016 (Picolinic Acid) pH 6.97
  • PCL-016 (Picolinic Acid) (pH 6.97) was supplied by Novactyl as prepared by Midwest Institute of Research & Technology, (Edmond, OK 73034) Lot 0828b. (Novactyl Lot #183.) The 0.369% PCL-016 (pH 6.97) was instilled using a Rainin EDP electronic pipet set in the multi-dispense mode. 37 :l drops were instilled.
  • PCL-016 (Picolinic Acid) (pH 3.86) was supplied by Novactyl as prepared by Midwest Institute of Research & Technology, (Edmond, OK 73034) Lot 0828b. (Novactyl Lot #181.) The 0.369% PCL-016 (pH 3.86) was instilled using a Rainin EDP electronic pipet set in the multi-dispense mode. 37 :l drops were instilled.
  • 450 :l (33.75 mg) of the 75 mg/ml Vistide (Cidofovir Injection, Gilead Sciences Inc., Foster City, CA Lot #A201A1 , Exp. 01/2005) was added to 6.3 ml of 0.9% Sodium Chloride Injection USP (Baxter Healthcare Corp. Deerfield, IL) to yield the 6.75 ml of 0.5% Cidofovir.
  • Vistide was purchased from the pharmacy at the University of Pittsburgh Medical Center.
  • the Cidofovir was instilled using a Rainin EDP electronic pipet set in the multi-dispense mode. 37 :l drops were instilled.
  • 0% PCL-016 (Control Vehicle) was supplied by Novactyl as prepared by Midwest Institute of Research & Technology, (Edmond, OK 73034) Lot0828a. (Novactyl Lot #182.) The 0% PCL- 016 (Control Vehicle) was instilled using a Rainin EDP electronic pipet set in the multi- dispense mode. 37 :l drops were instilled.
  • PCL-016 (pH 7.06) was much less irritating to eyes compared with what was demonstrated in the previous experiment (PCL-Ad-R1). The rabbits would not immediately run to the rear of their cages and wipe their eyes as in the previous experiment. There was no additional irritation in these eyes compared to the control eyes.
  • PCL-016 In general, 0.369% PCL-016 (pH 3.86) did not appear irritating to eyes compared with the control eyes, however the rabbits flinched after instillation for the first few days. * Concentration of PCL-016 may be 0.04%.
  • CDV 8 5.,750 .915 ( * )

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

L'invention porte sur des compositions et des procédés de traitement ou de prévention d'inflammation oculaire consistant à administrer de l'acide picolinique ou de l'acide fusarique ou un dérivé de ceux-ci. Cette invention porte aussi sur des compositions et des procédés de traitement ou de prévention de conjonctivite consistant à administrer de l'acide picolinique ou de l'acide fusarique ou un dérivé de ceux-ci.
PCT/US2004/039382 2003-11-21 2004-11-22 Compositions et procedes utiles au traitement de conjonctivites WO2005051388A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US52431603P 2003-11-21 2003-11-21
US60/524,316 2003-11-21
US57773004P 2004-06-07 2004-06-07
US60/577,730 2004-06-07

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WO2005051388A1 true WO2005051388A1 (fr) 2005-06-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407125B1 (en) * 1995-12-29 2002-06-18 Novactyl, Inc. Pharmacological agent and method of treatment
US6410570B1 (en) * 1995-12-29 2002-06-25 Novactyl, Inc. Methods of inactivating a virus and controlling viral replication
WO2003002117A2 (fr) * 2001-06-29 2003-01-09 Astion Development A/S Derives de pyridine carboxy et un sucre amine
WO2004071425A2 (fr) * 2003-02-06 2004-08-26 Bioresponse, Llc Utilisation combinee d'indoles cruciferes et de chelateurs pour le traitement d'etats lies au papillomavirus

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407125B1 (en) * 1995-12-29 2002-06-18 Novactyl, Inc. Pharmacological agent and method of treatment
US6410570B1 (en) * 1995-12-29 2002-06-25 Novactyl, Inc. Methods of inactivating a virus and controlling viral replication
WO2003002117A2 (fr) * 2001-06-29 2003-01-09 Astion Development A/S Derives de pyridine carboxy et un sucre amine
WO2004071425A2 (fr) * 2003-02-06 2004-08-26 Bioresponse, Llc Utilisation combinee d'indoles cruciferes et de chelateurs pour le traitement d'etats lies au papillomavirus

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