WO2013096512A1 - Pharmaceutical compositions and methods for treating gastrointestinal infections and disorders - Google Patents
Pharmaceutical compositions and methods for treating gastrointestinal infections and disorders Download PDFInfo
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- WO2013096512A1 WO2013096512A1 PCT/US2012/070730 US2012070730W WO2013096512A1 WO 2013096512 A1 WO2013096512 A1 WO 2013096512A1 US 2012070730 W US2012070730 W US 2012070730W WO 2013096512 A1 WO2013096512 A1 WO 2013096512A1
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- VFOKSTCIRGDTBR-UHFFFAOYSA-N CCCCOc(nc1N)nc(N(Cc2cc(CN3CCCC3)ccc2)C2)c1NC2=O Chemical compound CCCCOc(nc1N)nc(N(Cc2cc(CN3CCCC3)ccc2)C2)c1NC2=O VFOKSTCIRGDTBR-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- 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
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- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to the treatment of disorders of the digestive system, such disorders including allergies, treatment infectious agents and cancer. More particularly, the present invention provides methods and oral dosage forms for increasing interferon expression and interferon concentration that is locally increased in the digestive system, including the intestines, liver and pancreas, but remains systemically low in relation to the locally higher digestive system interferon concentration.
- Type 1 interferons such as IFN; ⁇ , ⁇ , ⁇ , and ⁇ , are secreted largely by plasmacytoid dendritic cells (pDCs), and play a critical role in the recruitment of cells involved in innate immune responses, as well as development of an adaptive immune response. Interferons directly activate macrophage and NK lymphocytes.
- pDCs plasmacytoid dendritic cells
- interferons initiate activation of signal transducer and activator of transcription (STAT) complexes leading to association with Janus Kinase (JAK) and interferon regulatory factor 9 (IRF9), forming an IFN-stimulated gene factor 3 complex, which is translocated to the cell nucleus, binding to specific nucleotide sequences known as IFN- stimulated response elements (ISREs) in the promoters of IFN stimulated genes (ISGs).
- ISREs IFN- stimulated response elements
- Interferons upregulate major histocompatibility complex types I and II (MHC class I and II) and increases the activity of immunoproteosomes in affected cells, for presentation to cytotoxic T cells (MHC class I) and helper T-cells (MHC class II).
- MHC class I and II major histocompatibility complex types I and II
- MHC class II helper T-cells
- interferons are capable of initiating pluripotent immune responses, such as facilitation of intercellular communication and inducing the transcription of interferon-stimulated genes (ISGs), the expression of which produces an antiviral state within the cell, they are sometimes given as a primary or adjunctive therapy for the treatment of viral infection or cancer.
- ISGs interferon-stimulated genes
- hepatitis B virus is a deoxyribonucleic acid (DNA) virus that is easily transmissible through perinatal, percutaneous and sexual exposure.
- CHB chronic HBV infection
- CHB hepatic decompensation and hepatocellular carcinoma
- the availability of a vaccine has reduced the incidence of new HBV infections in the U.S. since the mid 1980's; however, due to immigration from endemic areas in Asia and the Pacific islands, sub-Saharan Africa, the Amazon Basin, and Eastern Europe, the prevalence of CHB remains high, at 0.3-0.5% of the US population. Approximately 4,000 deaths per year result from HBV-related complications in the U.S. alone.
- HBV S Antigen is produced from HBV-infected cells via the replication intermediate: covalently closed circular DNA (cccDNA).
- cccDNA covalently closed circular DNA
- OAVs oral antivirals
- interferon preparations include, without limitation, pegylated rlFN-alpha 2b, pegylated rlFN- alpha 2a, rlFN-alpha 2b, rlFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta.
- IFN As exogenously administered IFN exerts similar effects, it is mechanistically consistent that IFN has demonstrated substantial therapeutic benefit in patients with chronic HCV and HBV infection.
- interferons are associated with a constellation of adverse events, including constitutional symptoms (i.e., flu-like symptoms), myelosuppression, elevated liver enzyme levels, and neurologic symptoms, which to some extent affect the majority of patients.
- TLR toll-like receptors
- PAMPs pathogen-associated molecular patterns
- TLR1 and TLR6 form heterodimers with TLR2, and act to stabilize TLR2.
- TLRs are present in pDCs, where they assist in the sentry role of these cells.
- TLRs can initiate an interferon response in patients, one treatment strategy has been to develop agonists of relevant TLRs to provide an alternative to IFN administration.
- the imiquimod, 3-(2-methylpropyl)-3,5,8- triazatricyclo[7.4.0.02,6]trideca-l(9),2(6),4,7,10,12-hexaen-7-amine is formulated for topical use on the skin. More recently, the compounds SM-324405 and AZ 12441970, both from
- AstraZeneca are formulated for aerosol inhalation for the treatment of asthma, were developed as antedrugs, having ester groups that are rapidly cleaved in plasma to reduce systemic exposure.
- TLR agonist for treating gastrointestinal disorders, including liver disorders.
- TLR agonist compound provides a presystemic oral dose of an orally available TLR agonist compound will lead to localized induction of IFN in the gastrointestinal system, particularly in the intestines, pancreas and liver, without inducing significant systemic IFN in a patient in need thereof.
- a method of treating a gastrointestinal disorder in a human patient in need thereof comprising administering to the patient an orally administered amount of a TLR modulator sufficient to provide -modified IFN expression in the gastrointestinal area, but in an amount less than sufficient to significantly alter systemic IFN.
- a method of treating a TLR modulator sufficient to provide -modified IFN expression in the gastrointestinal area, but in an amount less than sufficient to significantly alter systemic IFN.
- gastrointestinal disorder including a disorder of the liver or pancreas, comprising as a modality of treatment wherein a TLR-7 agonist compound having the formula:
- a TLR-7 agonist compound having the formula:
- a TLR-7 agonist compound having the formula:
- a TLR-7 agonist compound having the formula: 4-amino-2-butoxy-8-(3-(pyrrolidm
- viral diseases of the liver such as hepatitis A, hepatitis B, hepatitis C, or hepatitis D
- solid tumors such as hepatocellular carcinoma (HCC)
- Allergic and autoimmune disorders in the gastrointestinal system would be amenable to treatment, such as Crohns disease, graft vs. host disease, gastrointestinal organ transplant, including liver and pancreas transplant, and food allergies, including peanut allergies.
- Compound A is a TLR-7 agonist.
- Compound A, and methods to make it are disclosed in
- Compound B is also a TLR-7 agonist.
- Compound B, and methods to make it are disclosed in U.S. Published patent application US2010/0143301. Detailed Description of the Invention
- salts of the present invention are pharmaceutically acceptable salts.
- Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
- Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and ⁇ , ⁇ '-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt.
- inorganic acid addition salts such as
- the salts may be in some cases hydrates or ethanol solvates.
- a pharmaceutically acceptable salt, solvate, tautomer, or prodrug thereof is used, it is to be appreciated that each of these forms is independent of the others, and also includes combinations thereof.
- the term "a pharmaceutically acceptable salt, solvate, tautomer, or prodrug thereof includes, without limitation, a pharmaceutically acceptable salt alone, two or more pharmaceutically acceptable salts together, a pharmaceutically acceptable salt and prodrug, a pharmaceutically acceptable salt of a prodrug, and a pharmaceutically acceptable salt which is a solvate, for example.
- tautomers when tautomerization is possible in a compound, a given illustrative chemical structure, even when illustrating only one form, is to be interpreted as including its tautomeric structural form as well.
- the compounds of this invention are typically formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic.
- Excipients (1986), herein incorporated by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
- the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
- the formulations of the invention both for veterinary and for human use, comprise at least one active ingredient, together with one or more acceptable carriers and optionally other therapeutic ingredients.
- the carrier is
- the formulations include those suitable for the foregoing administration routes.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be administered as a bolus, electuary or paste.
- a tablet is made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.
- compositions according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
- Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic
- excipients which are suitable for manufacture of tablets are acceptable.
- excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
- inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
- granulating and disintegrating agents such as maize starch, or alginic acid
- binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia
- lubricating agents such as magnesium
- Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
- Tablets may be formed with Compound A or Compound B as an active ingredient, and may be dosed as 0.1 -mg, 0.5-mg, 1-mg, 2-mg, and 5-mg strength tablets.
- the tablets may contain commonly used excipients including lactose anhydrous, microcrystalline cellulose,
- croscarmellose sodium magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide
- Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example calcium phosphate or kaolin
- an oil medium such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include a suspending agent, such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl memylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,
- heptadecaethyleneoxycetanol a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
- the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
- Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation.
- These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
- a dispersing or wetting agent e.g., sodium tartrate
- suspending agent e.g., sodium EDTA
- preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
- Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
- the emulsion may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- sweetening agents such as glycerol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- a time-release formulation intended for oral administration to humans may contain approximately 0.5 to 12 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 1 to about 95% of the total compositions (weight: weight).
- the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
- an aqueous solution intended for intravenous infusion may contain from about 3 to 500 g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
- a suitable base comprising for example cocoa butter or a salicylate.
- Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
- the compounds of the present invention may be combined with one or more active agent.
- Combinations for the treatment of hepatitis B with compound A or compound B include nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors;
- protease inhibitors include cyclophilin inhibitors; immune modulators; and combinations thereof.
- Exemplary combination products for treatment of hepatitis B with compound A or compound B include: etbecavir, telbivudine, lamisvudine, adofovir dipivoxil, entecavir, tenofovir disoproxil fumarate, emtricitabine, tenofovir dipivoxil and its salts and co-crystals; and yeast- based therapeutic vaccinations, such as Tarmogens ®, from Globelmmune, inc.; and combinations thereof.
- Combinations for treatment of hepatitis C with compound A or compound B include:
- Nucleoside or nucleotide inliibitors of HCV NS5B polymerase comprising: non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors; HCV NS3 protease inhibitors; HCV NS4B protease cofactor inhibitors; cyclophilin inhibitors; HCV internal ribosome entry site (IRES) inhibitors; and combinations thereof.
- Exemplary combination active ingredients for treatment of hepatitis C with compound A or compound B include: ribavirin; sofosbuvir; declatasvir; tegobuvir; boceprevir; telaprevir; GS- 5885 (NS5A inhibitor); GS-9451 (protease inhibitor); GS-5816 (protease inhibitor); MK-5172 (protease inhibitor); filibuvir; GS-9857 (protease inhibitor); GS-9669 (non-nucleoside polymerase inhibitor); ABT-450 (protease inhibitor); ABT-450 with ritonavir; ABT-333 (polymerase inhibitor); ABT-267 (NS5A inhibitor); and combinations thereof.
- Combinations for the treatment of HIV with compound A or compound B include:
- Entry inhibitors capsid inhibitors; nucleoside reverse transcriptase inhibitors (NRTI); non- nucleoside reverse transcriptase inhibitors (NNRTI); protease inhibitors (PI); integrase inhibitors; maturation inhibitors; and combinations thereof.
- NRTI nucleoside reverse transcriptase inhibitors
- NRTI non- nucleoside reverse transcriptase inhibitors
- PI protease inhibitors
- maturation inhibitors and combinations thereof.
- Exemplary combination products for treatment of HIV with compound A or compound B include: Maraviroc (Selzentry ®); enfuvirtide (Fuzeon®); tenofovir disoproxil fumarate with emtricitabine (Truvada ®); tenofavir disoproxil fumarate with emtricitabine and efavirenz (Atripla ®); elvitegravir with emtricitabine, cobisistat and tenofavir disoproxil fumarate (Stribild ®); lamivudine with zidovudine (Combivir ®); abacavir with zidovudine and lamivudine (Trizivir ®); lopinavir with ritonovir (Kaletra ®); abacavir with lamivudine (Epzicom® - United States, Kivexa® - Europe), rilpivarine with tenofavir disoprox
- compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional active agent, and a pharmaceutically acceptable carrier or excipient.
- the present application provides a combination pharmaceutical agent with two or more therapeutic agents in a unitary dosage form.
- any compound of the invention with one or more other active agents in a unitary dosage form.
- the combination therapy may be administered as a simultaneous or sequential regimen.
- the combination may be administered in two or more administrations.
- Co-administration of a compound of the invention with one or more other active agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active agents, such that therapeutically effective amounts of the compound of the invention and one or more other active agents are both present in the body of the patient.
- Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active agents.
- a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active agents.
- a unit dose of one or more other active agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
- a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active agents. In other cases, it may be desirable to administer a unit dose of one or more other active agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
- the combination therapy may provide "synergy” and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
- an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
- kits comprising a course of treatment, with or without instructions for use, is provided.
- a kit comprising an oral dosage form
- kits typically provides a sequential series of solid dosage form tablets or capsules, provided in a structure adapted to provide a total daily , twice weekly or weekly dose of less than 12 mg. of compound A or compound B per day, over the course of a week or a month, for example.
- a kit is provided that contains multiple solid, oral dosage form tablets or capsules in a dispenser, said dispenser including a reminding device.
- the reminding device may be in the form of a calendar, or may provide an audible signal for reminding a patient that the oral dosage form composition should be taken at a predetermined interval, such as once or twice per week.
- a blister pack is provided with a single dose of less than 12 mg. of compound A or B in one section of the blister pack, with inactive ingredient tablets in the remaining sections of the blister pack.
- a weekly dosage pack may contain a tablet containing a single dose of less than 12 mg. of compound B in one blister section, with six additional blister sections containing tablets with no active ingredients.
- the blister pack may contain seven sections per week, with a single tablet containing both compound A or compound B together with the additional active ingredient or ingredients, and the remaining six sections of the weekly regimen blister pack containing tablets with only active ingredient or ingredients other than compound A or compound B.
- a four week regimen blister pack may contain a series of four, seven day sections, with a first section comprising a solid, orally available dosage form with a combination of compound B and one or more additional active ingredients, and the remaining six sections containing a solid, orally available dosage form with a combination of the active ingredients without compound B.
- plasmacytoid dendritic cells present in the gut and/or liver are activated by local exposure to an orally available TLR agonist compound to produce IFN-ct and stimulate ISG induction in lymphocytes and other cells as they circulate through the GALT and liver.
- ISG induction may occur in the liver by a similar effect (through either local IFN-a produced from stimulated pDCs residing in the liver or from a first pass effect on the liver from portal blood IFN-a produced from pDCs in the GALT).
- ISGs produced by IFN-a can mediate antiviral effects.
- TLR-7 As a consequence of the presystemic stimulation of TLR-7, local ISGs and other effectors of an interferon-mediated antiviral response may occur at reduced oral doses of an orally available TLR agonist compound that do not cause induction of serum/systemic IFN-a or clinical signs (increased body temperature and heart rate).
- the level of ISG induction in circulating blood cells reflects exposure of white blood cells trafficking through the GALT and the liver with exposure to an interferon-rich environment. Additionally, in subjects with viral hepatitis, increases in local interferon production may be detected by a reduction in serum viremia.
- Table 1 and Table 2 present the PK parameters of Compound B following the administration of a single dose of Compound B in the fasted cohorts and fed cohorts, respectively.
- Mean maximal plasma concentration values (Cmax) were higher with increasing dose in the fasted treatment groups.
- Mean maximal plasma concentration values were lower when Compound B (8 mg) was administered with moderate- or high-fat meal or following a high fat- meal than when Compound B was administered under fasting conditions.
- mean AUC values in the fed cohorts were 47% to 73% of those values in the fasted cohorts; the lowest exposures were observed when Compound B 8 mg was coadministered with a moderate-fat meal.
- Median terminal Compound B half-life values ranged from 14.65 to 26.92 hours except for the 0.3-mg group for which plasma concentrations were measured only to 24 hours postdose.
- Table 1 Compound B Pharmacokinetic Parameters
- Compound B signals through both the Toll-like receptor (TLR) 7 and 8 pathways, inducing cytokines including IFN-a, interleukin (IL)-12 and tumor necrosis factor alpha (TNF-a) from innate immune cells
- TLR Toll-like receptor
- cytokines including IFN-a, interleukin (IL)-12 and tumor necrosis factor alpha (TNF-a) from innate immune cells
- Compound B 0.01 mg/kg was tolerated; two 0.2 mg/kg subjects discontinued treatment. More subjects reported severe grade adverse events at 0.02 mg/kg; events were consistent with systemic cytokine induction, including fever, headache, shivering, and lymphopenia. Mean maximum serum Compound B concentrations were 3.82 ⁇ 1.47 and 7.55 ⁇ 4.17 ng/mL for 0.01 mg/kg and 0.02 mg/kg, respectively. At 0.02 mg/kg, two, three and one subjects had maximal reductions in viral levels of at least 1-, 2- and 3 -logs, respectively; reductions were generally transient.
- Interferon-alpha levels appeared correlated with decreases in viral titer and lymphocyte counts, as well as increase in neutrophil counts.
- Oral administration of Compound B 0.02 mg/kg transiently reduced viral levels but was associated with adverse effects similar to interferon-alpha.
- the maximum tolerated oral dose of Compound B was 0.03 mg/kg; in a placebo-controlled, multiple administration study in 25 healthy adults, the maximum administered regimen of 0.2 mg/kg two times per week for 2 weeks followed by 0.03 mg/kg two times per week for 2 weeks was adequately tolerated.
- autoimmune hepatitis ANA ⁇ 1 :640, ASMA > 1:320, ALKM antibody > 1 :320
- hepatocellular neoplasia anemia ( ⁇ 12 g/dL for men, ⁇ 1 1 for women), thrombocytopenia ( ⁇ 90,000/ ⁇ ), leukopenia ( ⁇ 2500 cells ⁇ L), neutropenia ( ⁇ 1500 cells/uL, U.S. study), ALT > 1000 U/L (French study) or aspartate aminotransferase (AST) or ALT > 500 U/L (U.S.
- bilirubin >1 mg/dL decompensated liver disease, other liver diseases, positive serology for HIV, positive HBsAg, prior organ transplantation, significant psychiatric disease, alcohol or drug abuse within 12 months, systemic immunomodulatory or investigational therapy within 3 months, and significant cardiac, pulmonary, systemic inflammatory or thyroid disease.
- Serum HCV RNA was measured by quantitative polymerase chain reaction (NGI). Subjects were categorized as responders (reduction from baseline of ⁇ 2 logs) or non-responders at the end-of-treatment visit (day 29), and at the last follow-up visit (day 1 13 U.S. study, and day 57 French study).
- Serum IL-6, IL- 1RA, TNF-a and IFN- ⁇ were measured by enzyme-linked immunosorbent assay
- Serum type I IFN levels were determined by bioassay [ 16].
- Serum 2',5' oligoadenylate synthetase (2'5' AS) was measured by radioimmunoassay (Eiken Chemical Co. Ltd., Tokyo, Japan).
- Serum IL-12 p40 was measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). Immunophenotyping of T lymphocytes in the U.S. study was performed at
- Placebo 0.01 mg kg 0.02 mg/kg Placebo 0.01 mg/kg 0.02 mg/kg studies Change in absolute neutrophil count Change in absolute lymphocyte count (cells/mm3) (cells/mm3)
- Tl/2,z terminal phase half-life. Ln2 divided by apparent terminal phase rate constant estimated by log linear regression of at least three data concentration-time points after Tmax. Results reported as means ⁇ standard deviation.CL/F: apparent clearance. Results reported as means ⁇ standard deviation. Vz/F: apparent volume of distribution. Results reported as means ⁇ standard deviation.
- Tmax time of maximum drug concentration, determined by direct inspection of the drug concentration versus time data point values. Results reported as median.
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CN106562970A (en) * | 2016-10-25 | 2017-04-19 | 中国医学科学院医学实验动物研究所 | Application of GS-9620 |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11744898B2 (en) | 2017-01-10 | 2023-09-05 | Nektar Therapeutics | Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods |
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US20080007955A1 (en) | 2006-07-05 | 2008-01-10 | Jia-Hao Li | Multiple-Set Heat-Dissipating Structure For LED Lamp |
WO2009005687A1 (en) * | 2007-06-29 | 2009-01-08 | Gilead Sciences, Inc. | Purine derivatives and their use as modulators of toll-like receptor 7 |
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US20080007955A1 (en) | 2006-07-05 | 2008-01-10 | Jia-Hao Li | Multiple-Set Heat-Dissipating Structure For LED Lamp |
WO2009005687A1 (en) * | 2007-06-29 | 2009-01-08 | Gilead Sciences, Inc. | Purine derivatives and their use as modulators of toll-like receptor 7 |
US20100143301A1 (en) | 2008-12-09 | 2010-06-10 | Gilead Sciences, Inc. | Modulators of toll-like receptors |
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Cited By (7)
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US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
CN106562970A (en) * | 2016-10-25 | 2017-04-19 | 中国医学科学院医学实验动物研究所 | Application of GS-9620 |
CN106562970B (en) * | 2016-10-25 | 2019-04-26 | 中国医学科学院医学实验动物研究所 | The purposes of GS-9620 |
US11744898B2 (en) | 2017-01-10 | 2023-09-05 | Nektar Therapeutics | Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11331331B2 (en) | 2017-12-07 | 2022-05-17 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11903959B2 (en) | 2017-12-07 | 2024-02-20 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
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