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WO2008115531A1 - Prévention et traitement de conditions infectieuses avec composés de vitamine d actifs ou substances mimétiques de ceux-ci - Google Patents

Prévention et traitement de conditions infectieuses avec composés de vitamine d actifs ou substances mimétiques de ceux-ci Download PDF

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Publication number
WO2008115531A1
WO2008115531A1 PCT/US2008/003630 US2008003630W WO2008115531A1 WO 2008115531 A1 WO2008115531 A1 WO 2008115531A1 US 2008003630 W US2008003630 W US 2008003630W WO 2008115531 A1 WO2008115531 A1 WO 2008115531A1
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Prior art keywords
vitamin
compound
active vitamin
calcitriol
mimic
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Alshad S. Lalani
John G. Curd
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Novacea Inc
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Novacea Inc
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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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

  • the present invention relates to a method for preventing, treating, or ameliorating infectious conditions in an animal by administering to the animal active vitamin D compounds or mimics thereof.
  • the invention further relates to a method for preventing, treating, or ameliorating infectious conditions in an animal by administering to the animal active vitamin D compounds or mimics thereof in combination with other therapeutic agents.
  • an infection is defined as the invasion of the body by pathogenic microorganisms that reproduce and multiply, causing disease by local cellular injury, or secretion of a toxin. While an infection can be symbiotic, in which the host and foreign species co-exist such that there is no detrimental effect to either, typically most infections are harmful to the host. The growth of the foreign species within the host often interferes with the normal homeostasis of the host thus causing the foreign species to become pathogenic.
  • Such an infection may be characterized by invasion and multiplication of a pathogen in a bodily part or tissue of the host animal. Subsequently, tissue injury and progression to an overt and identifiable disease state may occur. The pathogen continues to harm the host through a variety of cellular or toxic mechanisms as it persists and spreads throughout the host, thus interfering with the normal functioning of the host. This can lead to chronic wounds, progressing to gangrene, impaired functioning or loss of an infected tissue or limb and eventually death.
  • Pathogenic foreign species typically include microscopic organisms. Pathogens which cause disease include bacteria, parasites, fungi, protozoa, viruses, prions, and viroids.
  • An infectious disease is a clinically evident disease of an animal, in which the host animal is either damaged or injured by the pathogen such that there is impaired functioning of the host. The infectious disease may be transmitted between host animals or humans through several routes, including through direct contact with infected individuals, bodily fluid contact, by water, food, airborne inhalation, or through vectors.
  • pathogens and microorganisms which cause disease, however most normal or healthy animals do not become infected with these pathogens.
  • Host defenses such as inflammation and the immune response are effective defenses in reducing the spread of pathogens, preventing colonization within the host animal and/or minimizing and localizing the effect of the infection to a minimal area of the body. Only when the pathogen is able to subvert the inflammatory/immune response or the inflammatory/immune response is defective in some way does the pathogen cause an infectious disease state.
  • the classification of the infectious disease depends upon the ability of the pathogen to damage the host as well as the ability of the host to resist and defend against the pathogen. Pathogens are therefore classified as either primary pathogens or as opportunistic pathogens according to the effectiveness of the defense of the host.
  • Organisms which cause an infectious disease state within a host with depressed resistance are classified as opportunistic pathogens.
  • Opportunistic disease may be caused by organisms that are ordinarily in contact with the host, such as bacteria or fungi in the gastrointestinal or the upper respiratory tract or other otherwise innocuous organisms which are acquired by other hosts or the environment.
  • Opportunistic pathogens may also cause disease as a result of an injury, such as a mechanical piercing of the normal host environment, traumatic introduction by surgical wound, severe burns or open compound fractures.
  • An opportunistic disease requires impairment of host defenses, which may occur as a result of: (1) genetic defects such as severe combined immunodeficiency (SCID)-X linked, SCID-autosomal, adenosine deaminase deficiency (ADA deficiency), X-linked agammaglobulinemia (XLA), Bruton's disease, congenital agammaglobulinemia, X-linked infantile agammaglobulinemia, acquired agammaglobulinemia, adult onset agammaglobulinemia, late-onset agammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia, transient hypogammaglobulinemia of infancy, unspecified hypogammaglobul
  • Examples of organisms that cause opportunistic infections in humans include but are not limited to Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa, Staphylococcus sp., E.
  • coli Helicobacter pylori, Legionella pneumophila, Shigella sp., Bartonella bacilliformis, Streptococcus pyogenes, Streptococcus pneumoniae, Listeria monocytogenes, Nocardia asteroides, Actinetobacter baumannii, Corynebacterium amucolatum Salmonella sp., SV40, human papilloma virus (HPV), human herpes virus-8 (HHV-8/KSHV), herpes simplex virus (HSV), polyoma virus, Epstein Barr virus (EBV), hepatitis virus, cytomegalovirus (CMV), JC virus (JCV), - A -
  • Vitamin D is a fat-soluble vitamin essential as a positive regulator of calcium homeostasis. ⁇ See Harrison's Principles of Internal Medicine: Part Thirteen, "Disorders of Bone and Mineral Metabolism," Chapter 353, pp. 2214-2226, A.S. Fauci et al, (eds.), McGraw-Hill, New York (1998)).
  • the hormonally active form of vitamin D is l ⁇ ,25- dihydroxyvitamin D 3 , also known as calcitriol. Calcitriol is a steroid hormone synthesized from dietary precursors. Dietary 7-dehydrocholesterol is converted to vitamin D 3 by ultraviolet light absorbed through the skin.
  • Vitamin D 3 is hydroxylated at the 25 position by the liver and at the 1 position by the kidneys, converting it to the biologically active form, calcitriol.
  • l ⁇ -hydroxyvitamin D 3 also known as l ⁇ -calcidol
  • 25-hydroxyvitamin D 3 also known as calcifediol
  • l ⁇ -hydroxyvitamin D 3 is monohydroxylated vitamin D 3 and may be converted to calcitriol upon hydroxylation by the liver and kidney, respectively.
  • active vitamin D compounds have been discovered in cells from diverse organs not involved in calcium homeostasis. (Koyama et al., Blood 92:160 (1998)). Thus, in addition to influencing calcium homeostasis, active vitamin D compounds have been implicated in variety of biological processes including osteogenesis, modulation of immune response, modulation of the process of insulin secretion by the pancreatic B cell, muscle cell function, and the differentiation and growth of epidermal and hematopoietic tissues.
  • active vitamin D compounds may result in substantial therapeutic benefits, the treatment of infectious diseases in vivo with such compounds is expected to be limited by the effects these compounds have on calcium metabolism.
  • active vitamin D compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of calcitriol and other active vitamin D compounds as anti-infectious agents is severely limited by the risk of hypercalcemia.
  • HDPA high dose pulse administration
  • the active vitamin D compound may be administered no more than every three days, for example, once a week at a dose of at least 0.12 ⁇ g/kg per day (8.4 ⁇ g in a 70 kg person).
  • Pharmaceutical compositions used in the HDPA regimen of U.S. Patent No. 6,521,608 comprise 5-100 ⁇ g of active vitamin D compound and may be administered in the form for oral, intravenous, intramuscular, topical, transdermal, sublingual, intranasal, intratumoral, or other preparations.
  • One aspect of the present invention is a method for preventing, treating, or ameliorating an infectious condition in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof.
  • the active vitamin D compound, or a mimic thereof is administered by high dose pulse administration so that high doses of the active vitamin D compound or mimic can be administered to an animal without inducing severe symptomatic hypercalcemia.
  • the active vitamin D compound or a mimic thereof is administered at a dose of about 0.5 ⁇ g to about 300 ⁇ g, e.g., about 15 ⁇ g to about 260 ⁇ g, e.g., about 30 ⁇ g to about 240 ⁇ g, e.g., about 45 ⁇ g to about 220 ⁇ g, e.g., about 45 ⁇ g to about 200 ⁇ g.
  • the active vitamin D compound or a mimic thereof is administered at a dose sufficient to obtain a peak plasma concentration of the active vitamin D compound or a mimic thereof of at least 0.5 nM.
  • the active vitamin D compound is administered as a unit dosage form comprising about 10 ⁇ g to about 75 ⁇ g of calcitriol, about 50% MIGLYOL 812 and about 50% tocopherol PEG-1000 succinate (vitamin E TPGS). More preferably, the active vitamin D compound or the mimic thereof is administered as a unit dosage form comprising about 45 ⁇ g, e.g., about 45 ⁇ g of calcitriol, about 50% MIGLYOL 812, about 50% vitamin E TPGS, about 0.35% butylated hydroxyanisole (BHA), and about 0.10% butylated hydroxytoluene (BHT).
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • the active vitamin D compound or the mimic thereof may be administered orally, intravenously, parenterally, rectally, topically, nasally, sublingually, intramuscularly or transdermally.
  • Another aspect of the present invention is a method for preventing, treating, or ameliorating an infectious condition in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof in combination with one or more other therapeutic agents, including agents which themselves are anti-infectives.
  • the one or more therapeutic agents administered with the active vitamin D compound or a mimic thereof is a chemotherapeutic agent, an anti-infectious factor or a combination thereof.
  • the one or more therapeutic agents are selected from the group consisting of anti-infectious agents, cationic antimicrobial peptides, including cathelicidins, cathelicidin proforms, defensins, antimicrobial gene products such as hCAP18/LL37/FALL39, cationic antimicrobial peptides, and antineoplastic agents.
  • the one or more therapeutic agents administered with the active vitamin D compound or a mimic thereof may be selected from the group consisting of actinomycin D, irinotecan, vincristine, vinblastine, vinorelbine, SN-38, azacitidine, thalidomide, methotrexate, azathioprine, fluorouracil, doxorubicin, mitomycin, nitrates, calcium channel blockers, heparin, aspirin, coumarin, bishydroxycoumarin, warfarin, acid citrate dextrose, lepirudin, ticlopidine, clopidogrel, tirofiban, argatroban, eptifibatide, blockers of Ilb/IIIa receptors, hirudin, iloprost, sirolimus, everolimus, A24, tranilast, dexamethasone, tacrolimus, halofuginone, propyl hydroxylase, C-proteinas
  • administration of vitamin D or a mimic thereof can start prior to administration of the one or more therapeutic agents and/or continue during and beyond administration of the one or more therapeutic agents.
  • the method of administering an active vitamin D compound or a mimic thereof in combination with one or more therapeutic agents is repeated more than once.
  • the infectious condition may be a bacterial infection, a fungal infection, a viral infection, or a cancer-related infection, e.g., Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa, Staphylococcus sp., E.
  • a cancer-related infection e.g., Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa, Staphylococcus sp., E.
  • coli Helicobacter pylori, Legionella pneumophila, Shigella sp., Bartonella bacilliformis, Streptococcus pyogenes, Streptococcus pneumoniae, Listeria monocytogenes, Nocardia asteroides, Actinetobacter baumannii, Corynebacterium amucolatum, Salmonella sp., HIV, SV40, human papilloma virus (HPV), human herpes virus-8 (HHV-8/KSHV), herpes simplex virus (HSV), polyoma virus, Epstein Barr virus (EBV), hepatitis virus, cytomegalovirus (CMV), JC virus (JCV), adenovirus, Pneumocystis jiroveci, Pneumocystis carnii, Candida albicans, Aspergillus sp., Cryptococcus neoformans, or Toxoplasma gond
  • the combination of an active vitamin D compound, or a mimic thereof, with one or more therapeutic agents of the present invention can have additive potency or an additive therapeutic effect.
  • the invention also encompasses synergistic combinations where the therapeutic efficacy is expected to be greater than additive. Preferably, such combinations will also reduce or avoid unwanted or adverse effects.
  • the combination therapies encompassed by the invention are expected to provide an improved overall therapy relative to administration of an active vitamin D compound or a mimic thereof, or any therapeutic agent alone.
  • doses of existing or experimental therapeutic agents can be reduced or administered less frequently which increases patient compliance, thereby improving therapy and reducing unwanted or adverse effects.
  • the methods of the invention are useful not only with previously untreated patients but also useful in the treatment of patients partially or completely refractory to current standard and/or experimental therapies for prevention, treatment, or amelioration of infections.
  • the invention provides therapeutic methods for the prevention, treatment, or amelioration of infectious conditions that have been shown to be or may be refractory or non-responsive to other therapies.
  • the present invention is not limited to any particular mechanism, and an understanding of the mechanism is unnecessary to practice the present invention. Nonetheless, it is believed that ability of active vitamin D compounds to prevent, treat, or ameliorate an infectious condition in an animal may be at least partly due to the ability of active vitamin D compounds to increase the endogenous level of anti-infectious agents, including cationic antimicrobial peptides such as cathelicidins and defensins. In addition to anti-bacterial effects, some of these endogenous anti-infectious agents, such as the ⁇ - defensins, may also have anti-viral activity (e.g., against HIV, hepatitis C virus, and other viruses) and anti-fungal activity. Furthermore, the ability of active vitamin D compounds to stimulate the endogenous levels of anti-infectious agents may combine in an additive or synergistic fashion with the activities of additional therapeutic agents that are administered with the active vitamin D compounds.
  • the invention arose from the surprising discovery that late stage prostate cancer patients (i.e., patients with androgen independent prostate cancer) treated with Taxotere ® and intermittent high doses of calcitriol experienced fewer serious infections as compared to patients receiving placebo or Taxotere ® alone.
  • an active vitamin D compound or a mimic thereof is administered to an animal such that an infectious condition is prevented, treated or ameliorated.
  • the active vitamin D compound or a mimic thereof is administered to an animal having an active infection.
  • the active vitamin D compound or a mimic thereof is administered to an animal having a chemotherapy-related infection.
  • the active vitamin D compound or a mimic thereof has a reduced hypercalcemic effect, allowing higher doses of the compound to be administered to an animal without inducing severe symptomatic hypercalcemia.
  • a further aspect of the present invention relates to a method for preventing, treating, or ameliorating an infectious condition in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof by high dose pulse administration so that high doses of the active vitamin D compound or a mimic thereof can be administered to an animal without inducing severe symptomatic hypercalcemia.
  • the active vitamin D compound or a mimic thereof is administered to an animal to prevent, treat or ameliorate infections.
  • Infections or infectious diseases and disease states include bacterial, viral, and fungal infections and include, without limitation, bacterial infections in cancer, abscesses, urinary tract infections, cystic fibrosis, pneumonias, lung infections, cutaneous infections during dermatitis, wound infections in burn patients, TB, opportunistic infection in AIDS, chronic Helicobacter pylori infections during gastric cancers, Inflammatory Bowel Disease, Crohn's disease, Shigella infections, infections leading to Sepsis, and Mycobacterium, Pasteurella, or Cryptosporidium infections.
  • one aspect of the present invention is a method for preventing, treating, or ameliorating an infectious condition in an animal comprising administering to the animal an active vitamin D compound or a mimic thereof.
  • Another aspect of the invention is a method for preventing, treating, or ameliorating sepsis by administering to an animal in need of such treatment an active vitamin D compound or a mimic thereof.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to result in prevention of an infectious condition, amelioration of one or more symptoms of an infection, or prevention of advancement of an infection.
  • a therapeutically effective amount preferably refers to the amount of a therapeutic agent that reduces the extent of an active infection by at least 10%, preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%.
  • the extent of an infection can be determined by any method known in the art for quantitating infections, e.g., cell count and culture.
  • the principal tool in the diagnosis and quantitation of infectious disease is the microbiological culture.
  • a growth medium is provided for a particular agent.
  • Diagnosis may also initially be made by medical history and physical examination, as well as imaging (such as X-rays).
  • Certain infectious agents cannot be cultured, for example Treponema pallidum and many viruses.
  • serological markers were developed to diagnose such diseases, e.g., syphilis (the Wassermann test, later replaced by the VDRL and TPHA tests).
  • Serology involves detecting antibodies against an infectious agent in the patient's blood.
  • serology can be troublesome, because the antibody reaction is blunted.
  • DNA of pathogens in blood or bodily secretions utilizes PCR (polymerase chain reaction), and involves the amplification of DNA of a pathogen, which is subsequently detected using labeled DNA probes.
  • PCR polymerase chain reaction
  • the sensitivity (or, conversely, the antibiotic resistance) of the infectious agent can be then determined by exposing it to test doses of antibiotic.
  • This test called an antibiogram, determines how sensitive the target bacterium is to a certain antibiotic, and agents are usually reported as being: Sensitive, Intermediate or Resistant.
  • the antibiogram can then be used to determine optimal therapy for the patient. This can reduce the use of broad-spectrum antibiotics and lead to a decrease in antibiotic resistance in bacteria.
  • the terms "prevent, preventing, and prevention,” as used herein, are intended to refer to a decrease in the occurrence of an active infection.
  • the prevention may be complete, e.g., the total absence of any infections.
  • the prevention may also be partial, such that the amount of infection is less than that which would have occurred without the present invention.
  • the extent of an infection using the methods of the present invention may be at least 10%, preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% less than the amount of the infection that would have occurred without the present invention.
  • infection or "infectious condition,” as used herein, refers to any condition in which a microbe, bacteria or virus develops into or causes an infection or an infectious condition in the body.
  • active infection refers to an ongoing infectious condition in which the infectious organism is thriving, e.g., growing, expanding, or maintaining its numbers.
  • active vitamin D compounds or mimics thereof may be administered to animals having increased risk for infections in order to prevent, ameliorate or treat infections.
  • chemotherapy-related infection refers to an infectious condition acquired as a result of depressed resistance stemming from chemotherapy treatment.
  • the methods of preventing, treating or ameliorating an infectious condition in an animal by administering an active vitamin D compound or a mimic thereof further comprises administering one or more therapeutic agents.
  • the therapeutic agents may be agents that treat the infectious condition itself (e.g., antibiotics) or agents that treat an underlying cause of the infection or a condition that increases susceptibility of the animal to infection (e.g., cancer, immunosuppression, autoimmune disease).
  • Therapeutic agents useful as adjunctive therapy according to the invention include, but are not limited to, small organic molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA polynucleotides including, but not limited to, antisense nucleotide sequences, triple helices, and nucleotide sequences encoding biologically active proteins, polypeptides, or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules. Any agent which is known to be useful, or which has been used or is currently being used for the prevention, treatment, or amelioration of an infection can be used in combination with an active vitamin D compound or the mimic thereof in accordance with the invention described herein.
  • nucleic acids e.g., DNA and RNA polynucleotides including, but not limited to, antisense nucleotide sequences, triple helices, and nucleotide sequences encoding biologically active proteins, polypeptides,
  • Therapeutic agents useful in the methods and compositions of the invention include anti-infectious agents, cationic antimicrobial peptides, antimicrobial gene products, defensins, and antineoplastic agents.
  • examples include anti-angiogenic factors, vasodilators, anticoagulants, anti-platelet agents, anti-thrombins, immunosuppressants, collagen synthetase inhibitors, and antiinflammatories.
  • useful therapeutic agents include, without limitation, actinomycin D, irinotecan, vincristine, vinblastine, vinorelbine, SN-38, azacitidine, thalidomide, methotrexate, azathioprine, fluorouracil, doxorubicin, mitomycin, nitrates, calcium channel blockers, heparin, aspirin, coumarin, bishydroxycoumarin, warfarin, acid citrate dextrose, lepirudin, ticlopidine, clopidogrel, tirofiban, argatroban, eptifibatide, blockers of Ilb/IIIa receptors, hirudin, iloprost, sirolimus, everolimus, A24, tranilast, dexamethasone, tacrolimus, halofuginone, propyl hydroxylase, C-proteinase inhibitor, metalloproteinase inhibitor, corticosteroids, nonsteroidal anti-inflammatory drugs
  • therapeutic agents include cathelicidins, cathelicidin proforms, ⁇ -defensins, hCAP18/LL37/FALL39, and human defensin 2 (hBD2).
  • the therapeutic agent is a taxane, e.g., paclitaxel or docetaxel.
  • Administration of some antineoplastic and other therapeutic agents to patients in need of such treatment is known to cause serious adverse events which may be associated with infectious conditions or render a patient more susceptible to infectious conditions.
  • AVASTIN ® various serious adverse events were found to be associated with the administration of AVASTIN ® to patients, including gastrointestinal perforation, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure and slow or incomplete wound healing, in a trial in patients with untreated metastatic colorectal cancer. See AVASTIlSi Product Label, Genentech, Inc. [0041] To ameliorate, prevent or treat these infectious conditions and other side effects associated with the administration of therapeutic agents such as AVASTIN ® or TAXOTERE ® , the active vitamin D compound or a mimic thereof may be administered in combination with the therapeutic agent.
  • the vitamin D compound or mimic thereof may be administered prior to the administration of the therapeutic agent (e.g., 1-3 days prior to administration of the therapeutic agent), concurrent with the administration of the therapeutic agent, and/or after administration of the therapeutic agent.
  • the active vitamin D compound or a mimic thereof, TAXOTERE ® and one or more other therapeutic agents may be administered.
  • the one or more therapeutic agents may be chemotherapeutic agents such as alkylating agents, antimetabolites, anti-mitotic agents, epipodophyllotoxins, antibiotics, hormones and hormone antagonists, enzymes, platinum coordination complexes, anthracenediones, substituted ureas, methylhydrazine derivatives, imidazotetrazine derivatives, cytoprotective agents, DNA topoisomerase inhibitors, biological response modifiers, retinoids, therapeutic antibodies, differentiating agents, immunomodulatory agents, angiogenesis inhibitors and other anti-angiogenic agents.
  • chemotherapeutic agents such as alkylating agents, antimetabolites, anti-mitotic agents, epipodophyllotoxins, antibiotics, hormones and hormone antagonists, enzymes, platinum coordination complexes, anthracenediones, substituted ureas, methylhydrazine derivatives, imidazotetrazine derivatives, cytoprotective agents, DNA topoisomerase inhibitors, biological response modifiers,
  • Chemotherapeutic agents that may be combined with the active vitamin D compound or a mimic thereof and TAXOTERE ® include, but are not limited to, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, BCG live, bexarotene, bleomycin, bortezomib, busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin diftitox, dexraz
  • Anti-inflammatory drugs suitable for use as a therapeutic agent include salicylates
  • acetic acids such as indomethacin, sulindac, tolmetin, aceclofenac and diclofenac
  • 2-arylpropionic acids or profens such as ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiprofen and oxaprozin
  • N-arylanthranilic acids or fenamic acids such as mefenamic acid, fiufenamic acid, and meclofenamate
  • enolic acids or oxicams such as piroxicam and meloxicam
  • cox inhibitors such as celecoxib, rofecoxib (withdrawn from market), valdecoxib, parecoxib and etoricoxib
  • sulphonanilides such as nimesulide; naphthyl
  • an immunomodulatory agent refers to an agent that modulates a host's immune system.
  • an immunomodulatory agent is an agent that alters the ability of a subject's immune system to respond to one or more foreign antigens.
  • an immunomodulatory agent is an agent that shifts one aspect of a subject's immune response, e.g., the agent shifts the immune response from a ThI to a Th2 response.
  • an immunomodulatory agent is an agent that inhibits or reduces a subject's immune system (i.e., an immunosuppressant agent).
  • an immunomodulatory agent is an agent that activates or increases a subject's immune system (i.e., an imrnunostimulatory agent).
  • Immunomodulatory agents useful for the present invention include, but are not limited to, small molecules, peptides, polypeptides, proteins, nucleic acids (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices and nucleotide sequences encoding biologically active proteins, polypeptides or peptides), antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules.
  • a particularly useful immunomodulatory agent useful for the present invention is thalidomide.
  • Immunosuppressant agents are useful to counteract autoimmune diseases, such as rheumatoid arthritis or Crohn's disease, and to prevent the immune system from attacking healthy parts of the body.
  • immunosuppressive agents useful for the present invention include glucocorticoid receptor agonists (e.g., cortisone, dexamethasone, hydrocortisone, betamethasone), calcineurin inhibitors (e.g., macrolides such as tacrolimus and pimecrolimus), immunophilins (e.g., cyclosporin A) and mTOR inhibitors (e.g., sirolimus, marketed as RAPAMUNE ® by Wyeth).
  • glucocorticoid receptor agonists e.g., cortisone, dexamethasone, hydrocortisone, betamethasone
  • calcineurin inhibitors e.g., macrolides such as tacrolimus and pimecrolimus
  • immunomodulatory agents useful for the present invention further include antiproliferative agents (e.g., methotrexate, leflunomide, cisplatin, ifosfamide, paclitaxel, taxanes, topoisomerase I inhibitors (e.g., CPT-I l, topotecan, 9- AC, and GG-211), gemcitabine, vinorelbine, oxaliplatin, 5-fluorouracil (5-FU), leucovorin, vinorelbine, temodal, taxol, cytochalasin B, gramicidin D, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, melphalan, glucocor
  • an active vitamin D compound or a mimic thereof in combination with one or more therapeutic agents is intended to refer to the combined administration of an active vitamin D compound or a mimic thereof and one or more therapeutic agents, wherein the active vitamin D compound or the mimic thereof can be administered prior to, concurrently with, or after the administration of the therapeutic agents.
  • the active vitamin D compound or the mimic thereof can be administered up to three months prior to or after the therapeutic agents and still be considered to be a combination treatment.
  • active vitamin D compound is intended to refer to a vitamin D compound that is or becomes biologically active (e.g., binds to and stimulates the vitamin D receptor) when administered to a subject or contacted with cells.
  • Active vitamin D compounds include compounds that cause hypercalcemia and compounds that do not cause hypercalcemia upon administration.
  • the biological activity of a vitamin D compound can be assessed by assays well known to one of skill in the art such as, e.g., immunoassays that measure the expression of a specific gene regulated by vitamin D.
  • Vitamin D compounds exist in several forms with different levels of activity in the body.
  • a vitamin D compound may be partially activated by first undergoing hydroxylation in the liver at the carbon-25 position and then may be fully activated in the kidney by further hydroxylation at the carbon- 1 position.
  • the prototypical active vitamin D compound is l ⁇ ,25 -hydroxy vitamin D 3 , also known as calcitriol.
  • the active vitamin D compound of the present invention may also be a partially hydroxylated vitamin D such as l ⁇ -hydroxyvitamin D 3 , also known as l ⁇ -calcidol, and 25-hydroxyvitamin D 3> also known as calcifediol.
  • a large number of other active vitamin D compounds are known and can be used in the practice of the invention.
  • the active vitamin D compounds of the present invention include, but are not limited to, analogs, homologs mimics, and derivatives of vitamin D compounds such as those described in the following patents, each of which is incorporated by reference: U.S. Patent Nos. 4,391,802 (l ⁇ - hydroxyvitamin D derivatives); 4,717,721 (l ⁇ -hydroxy derivatives with a 17 side chain greater in length than the cholesterol or ergosterol side chains); 4,851,401 (cyclopentano- vitamin D analogs); 4,866,048 and 5,145,846 (vitamin D 3 analogues with alkynyl, alkenyl, and alkanyl side chains); 5,120,722 (trihydroxycalciferol); 5,547,947 (fluoro- cholecalciferol compounds); 5,446,035 (methyl substituted vitamin D); 5,411,949 (23- oxa-derivatives); 5,237,110 (19-nor- vitamin D compounds; 4,857,518 (hydroxylated
  • ROCALTROL Roche Laboratories
  • CALCIJEX injectable calcitriol investigational drugs from Leo Pharmaceuticals including EB 1089 (24a,26a,27a-trihomo-22,24-diene-l ⁇ ,25-(OH) 2 -D 3 , KH 1060 (20-epi-22-oxa-24a,26a,27a-trihomo-l ⁇ ,25-(OH) 2 -D 3 ), MC 1288 (1,25-(OH) 2 - 20-epi-D 3 ) and MC 903 (calcipotriol, l ⁇ ,24s-(OH) 2 -22-ene-26,27-dehydro-D 3 ); Roche Pharmaceutical drugs that include 1, 25-(OH) 2 - 16-ene-D 3 , l,25-(OH) 2 -16-ene-23-yne-D 3 , and 25-(OH) 2 - 16-ene-23-yne-D 3 ; Chugai
  • Additional examples include l ⁇ ,25- (OH) 2 -26,27-d 6 -D 3 ; l ⁇ ,25-(OH) 2 -22-ene-D 3 ; l ⁇ ,25-(OH) 2 -D 3; l ⁇ ,25 -(OH) 2 -D 2 ; l ⁇ ,25- (OH) 2 -D 4 ; l ⁇ ,24,25-(OH) 3 -D 3 ; l ⁇ ,24,25-(OH) 3 -D 2 ; l ⁇ ,24,25-(OH) 3 -D 4 ; l ⁇ -(OH)-25-FD 3 ; l ⁇ -(OH)-25-FD 4 ; l ⁇ -(OH)-25-FD 2 ; l ⁇ ,24-(OH) 2 -D 4 ; l ⁇ ,24-(OH) 2 -D 3 ; l ⁇ ,24-(OH) 2 -D 3 ; l ⁇ ,24-(OH) 2 -D 3 ;
  • U.S. Patent No. 6,521,608 See also, e.g., U.S. Patent Nos. 6,503,893, 6,482,812, 6,441,207, 6,410,523, 6,399,797, 6,392,071, 6,376,480, 6,372,926, 6,372,731, 6,359,152, 6,329,357, 6,326,503, 6,310,226, 6,288,249, 6,281,249, 6,277,837, 6,218,430, 6,207,656, 6,197,982, 6,127,559, 6,103,709, 6,080,878, 6,075,015, 6,072,062, 6,043,385, 6,017,908, 6,017,907, 6,013,814, 5,994,332, 5,976,784, 5,972,917, 5,945,410, 5,939,406, 5,936,105, 5,932,565, 5,929,056, 5,919,986, 5,905,074, 5,883,271, 5,880,113,
  • non-secosteroidal vitamin D mimic compounds are compounds that do not structurally fall within the class of compounds generally known as vitamin D compounds but which modulate the activity of vitamin D nuclear receptors.
  • vitamin D mimics include bis-aryl derivatives disclosed by U.S. Patent 6,218,430 and WO publication 2005/037755. Additional examples of non-secosteroidal vitamin D mimic compounds suitable for the present invention can be found in U.S. patents 6,831,106; 6,706,725; 6,689,922; 6,548,715; 6,288,249; 6,184,422, 6,017,907, 6,858,595 and 6,358,939.
  • the invention is drawn to methods employing non-secosteroidal vitamin D mimic compounds having Formula I:
  • R 1 and R 2 are each independently halo, haloalkyl, pseudohalo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; or
  • R 1 and R together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl consisting of:
  • k is an integer from 1 to 6;
  • R 1 and R together with the carbon atom to which they are attached, form an optionally substituted heterocyclyl selected from a group consisting of:
  • A is -O-, -NR X -, -S-, -S(O)- or -S(O) 2 - wherein R x is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -R 14 -C(J)R 15 , -R 1 ⁇ C(J)OR 15 , -R 14 - C(J)R 16 OR 15 , -R 14 -C(J)SR 16 , -R 14 -C(J)N(R 18 )R 19 , -R 14 -C(J)N(R 17 )N(R 18 )R 19 , -R 14 -C(J)N(R 17 )S(O) p R 20 , -R 14 -S(O)pN(R 18 )R 19 , or -R 14 -S(O) P R 20 ; and wherein B is -O-,
  • R 3 and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, pseudohalo, nitro, cyano, azido, -R 14 -OR 15 , -R 14 -N(R 18 )R 19 , -R 14 -SR 15 , -R 14 -OC(J)R 15 , -R 14 -NR 17 C(J)R 15 , -R 14 -OC(J)N(R 18 )R 19 , -R 14 -NR 17 C(J)N(R 18 )R 19 , -R 14 -NR 17 C(J)OR 15 , -R 14 -C(J)R 15 , -R 14 -C(J)OR 15 , -R 14 -C(J)SR 15 , -R 14 -C(J)N(R 18 )R 19 , or -R
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, halo, hydroxy, amino, pseudohalo, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy;
  • X is R 25 ;
  • Y is independently R 30 , -OR 31 , -SR 32 or -N(R 33 )(R 34 );
  • R 25 and R 30 are each independently selected from (i) or (ii) as follows:
  • optionally substituted alkyl that may be substituted with one to ten substituents each independently selected from a group consisting of halo, pseudohalo, nitro, cyano, thioxo, azido, amidino, guanidino, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR 15 , -OR 16 OR 15 , -N(R 18 )R 19 , -N(R 17 )N(R 18 )R 19 , -SR 15 , -SR 16 SR 15 , -N(R 17 )N(R 17 )S(O) P R 20 , -OC(J)R 15 , -NR 17 C(J)R 15 ,
  • optionally substituted alkenyl or optionally substituted alkynyl may be substituted with one to ten substituents each independently selected from a group consisting of oxo, thioxo, halo, pseudohalo, nitro, cyano, azido, amidino, guanidino, -OR 15 , -OR 16 OR 15 , -N(R 18 )R 19 , -N(R 17 )N(R 18 )R 19 , -SR 15 , -SR 16 SR 15 , -S(O) p R 20 , -N(R 17 )S(O) p R 20 , -N(R 17 )N(R 17 )S(O) p R 20 , -OC(J)R 15 , -NR 17 C(J)R 15 , -OC(J)N(R 18 )R 19 , -NR 17 C(J)N(R 18 )R 19 , -NR 17 C
  • R 31> R 32 , R 33 , and R 34 are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted cycloalkyl; all of which may be optionally substituted with one to ten substituents each independently selected from a group consisting of oxo, halo, pseudohalo, nitro cyano, azido, amidino, guanidino -OR 15 , -OR 16 OR 15 , -N(R 18 )R 19 , -N(R 17 )N(R 18 )R 19 , -SR 15 , -SR 16 SR 15 , -S(O)pR 20 , -N(R 17 )S(O)pR 20 , -N(R 17 )N(R 17 )S(O) P R 20 , -OC(J)R 15 , -NR 17 C(J)R 15 , -OC(J)N(
  • R 34 can additionally be hydrogen; where each R 14 is independently a direct bond or alkylene; where each R 15 and R 17 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, all of which, when substituted, are substituted with one to five substituents each independently selected from halo, cyano, hydroxy and amino; where each R 16 and R 20 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
  • R 22 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;
  • R and R 4 are each independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl or cycloalkyl; or R 23 and R 24 , together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; each J is independently O or S; as a single isomer, a mixture of isomers, or as a racemic mixture of isomers; as a solvate or polymorph; or as a prodrug or metabolite; or as a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 may form a substituted cyclohexyl, said cyclohexyl, when substituted at the 4-position relative to the gem-diaryl substituents, may be substituted with a substituent selected from the group consisting of halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl.
  • R 25 and R 30 are not -CH 2 COOH; -CH 2 -5-tetrazolyl; -
  • E and F are each independently selected from the group consisting of O, S, and
  • R 5 and R 3 are independently selected from the group consisting of alkyl groups, optionally fluorinated; or together R 35 and R 36 form a cycloalkylidene having 3 to 8 carbon atoms, optionally fluorinated;
  • R and R are independently selected from the group consisting of halogen; lower n-alkyl, optionally fluorinated; and lower alkoxy, optionally fluorinated;
  • R 39 is selected from the group consisting of H; optionally substituted alkyl groups; optionally substituted alkenyl groups; optionally substituted alkynyl groups; optionally substituted aryl groups; OR 45 ; NR 46 R 47 ; or together with R 42 , R 43 , or R 44 forms a 3- to 12- membered cyclic group wherein said cyclic group is selected from the group consisting of amidines, amines, ethers, lactams, lactones, ketals, hemiketals, aminals, hemiaminals, carbonates, carbamates, ureas, and combinations thereof;
  • R 40 is selected from the group consisting of H and alkyl groups, optionally substituted;
  • R 41 is selected from the group consisting of H and alkyl groups, optionally substituted;
  • R 4 is selected from the group consisting of H, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted aryl group, and optionally substituted acyl groups;
  • R 43 and R 44 are independently selected from the group consisting of H, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted aryl groups, and optionally substituted acyl groups;
  • R 45 is selected from the group consisting of H, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted aryl groups, and optionally substituted acyl groups;
  • R 4 and R 47 are independently selected from the group consisting of H, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted alkynyl groups, optionally substituted aryl groups, and optionally substituted acyl groups and pharmaceutically acceptable salts thereof.
  • R 45 , R 46 , and R 48 do not simultaneously comprise alkenyl ethers.
  • R 45 and R 46 do not both comprise glycidyl ethers.
  • HDPA high dose pulse administration
  • hypocalcemia refers to a medical condition in which the concentration of calcium ions in the plasma is greater than about 10.5 mg/dL in humans.
  • symptomatic hypercalcemia refers to symptoms associated with one of more of the signs or symptoms of hypercalcemia.
  • Early manifestations of hypercalcemia include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, or metallic taste.
  • Late manifestations include polydypsia, polyuria, weight loss, pancreatitis, photophobia, pruritis, renal dysfunction, aminotransferase elevation, hypertension, cardiac arrhythmias, psychosis, stupor, or coma.
  • Methods to determine the concentration of calcium ions in blood plasma are generally within the capability of a person of ordinary skill in the art.
  • a grade 4 toxic level of hypercalcemia as defined in U.S. Patent 6,521,608, which is incorporated by reference herein in its entirety.
  • a grade 4 toxicity is associated with reduced count for WBC, platelets, hemoglobin, neutrophils and lymphocytes; massive hemorrhage; gastrointestinal problems (such as vomiting more than 10 times a day, diarrhea (>10 times a day) and stomatitis which requires IV nutrition); hepatic failures (such as elevated bilirubin and hepatic coma), kidney/bladder dysfunction; cardiovascular events (such as refractory congestive heart failure, acute myocardial infraction, dyspnea at rest and cardiac tamponade); neuralgic disorders (such as paralysis, coma, seizures, cerebellar necrosis, severe headaches, blindness, uncorrectable deafness and suicidal mood) and metabolic problems (such as hyperglycemia (blood glucose >500 mg/dL) with ketoacidosis).
  • grade 3 toxicity is milder than grade 4 toxicity, it can be life threatening and is associated with reduced count for WBC, platelets, hemoglobin, neutrophils and lymphocytes; gross hemorrhage; gastrointestinal problems (such as vomiting 6-10 times a day, diarrhea (7-9 times a day) and painful ulcers (patient could not eat)); hepatic failures (such as precoma and elevated bilirubin); cardiovascular events (such as mild congestive heart failure responsive to treatment, angina without infraction and symptomatic effusion); neurologic disorders (such as severe loss or impairment of neuro-sensory, severe cortical contusion, unrelenting headache and correctable hearing loss) and weight change.
  • the active vitamin D compound or mimic thereof has a reduced hypercalcemic effect as compared to vitamin D so that sufficient doses of the compound can be administered without inducing hypercalcemia in the animal.
  • the reduced hypercalcemic effect may be due to the active vitamin D compound itself, the regimen by which the compound is administered, or both.
  • a reduced hypercalcemic effect is defined as an effect which is less than the hypercalcemic effect induced by administration of an equal dose of l ⁇ ,25-hydroxyvitamin D 3 (calcitriol).
  • EB 1089 has a hypercalcemic effect which is 50% of the hypercalcemic effect of calcitriol.
  • Additional active vitamin D compounds having a reduced hypercalcemic effect include Ro23-7553 and Ro24-5531 available from Hoffmann LaRoche.
  • Other examples of active vitamin D compounds having a reduced hypercalcemic effect can be found in U.S. Patent No. 4,717,721. Determining the hypercalcemic effect of an active vitamin D compound is routine in the art and can be carried out as disclosed in Hansen et al, Curr. Pharm. Des. (5:803-828 (2000).
  • one or more therapeutic agents are administered to an animal in addition to the active vitamin D compound or the mimic thereof.
  • the active vitamin D compound or the mimic thereof can be administered prior to ⁇ e.g., 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks or more), concurrently with, or after (e.g., 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks or more) the administration of one or more therapeutic agents.
  • the active vitamin D compound or a mimic thereof is administered before, during, and after the administration of one or more therapeutic agents.
  • the method of administering an active vitamin D compound or a mimic thereof in combination with one or more therapeutic agents may be repeated at least once.
  • the method may be repeated as many times as necessary to achieve or maintain a therapeutic response, e.g., from one to about ten times.
  • the active vitamin D compound or a mimic thereof and the one or more therapeutic agents may be the same or different from that used in the previous repetition.
  • the time period of administration of the active vitamin D compound and the manner in which it is administered i.e., daily or HDPA
  • the one or more therapeutic agents are administered in doses known to one of skill in the art to prevent, treat, or ameliorate an infectious condition or other disease, disorder, or condition.
  • the one or more therapeutic agents are administered in pharmaceutical compositions and by methods known to be effective.
  • the therapeutic agents may be administered systemically (e.g., intravenously, orally) or locally.
  • the doses of the vitamin D analogs and vitamin D mimics may be adjusted proportionate to the ratio of the efficacy index to the calcemic index according to the formula:
  • Dose is the analog or mimic dose
  • calcitriolDose is calcitriol dose
  • EI is the analog or mimic efficacy index
  • CI is the analog or mimic calcemic index
  • the term "efficacy index” is the ratio of the concentration of the vitamin D analog or mimic to the concentration of calcitriol at equivalent potency.
  • the efficacy index is a fraction less than one when the vitamin D analog or mimic is less potent than calcitriol.
  • EI is number greater than one when calcitriol is less potent than the vitamin D analog or mimic.
  • the "calcemic index" of a drug is a measure of the relative ability of the drug to generate a calcemic response as reported in Bouillon et al., Endocrine Reviews 16:200- 257, 1995.
  • a calcemic index of 1 corresponds to the relative calcemic activity of calcitriol.
  • a calcemic index of about 0.01 corresponds to the calcemic activity of a drug with approximately 100 times less calcemic activity than calcitriol.
  • a calcemic index of 0.5 would correspond to a drug having approximately half the calcemic activity of calcitriol.
  • the calcemic index of a drug can vary depending on the assay conducted, e.g.
  • the active vitamin D compound or a mimic thereof is preferably administered at a dose of about 3 ⁇ g to about 10 mg, more preferably from about 15 ⁇ g to about 1 mg.
  • an effective amount of an active vitamin D compound or a mimic thereof is 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000,
  • an effective dose of an active vitamin D compound or a mimic thereof is between about 3 ⁇ g to about 10 mg, e.g., between about 15 ⁇ g to about 1 mg, e.g., between about 30 ⁇ g to about 300 ⁇ g, e.g., between about 35 ⁇ g to about 200 ⁇ g, e.g., between about 40 ⁇ g to about 100 ⁇ g, or about 45 ⁇ g.
  • the methods of the invention comprise administering an active vitamin D compound or a mimic thereof in a dose of about 0.12 ⁇ g/kg bodyweight to about 200 ⁇ g/kg bodyweight.
  • the compound may be administered by any route, including oral, intramuscular, intravenous, parenteral, rectal, nasal, topical, or transdermal.
  • the dose may be kept low, for example about 0.5 ⁇ g to about 5 ⁇ g, in order to avoid or diminish the induction of hypercalcemia. If the active vitamin D compound or the mimic thereof has a reduced hypercalcemic effect a higher daily dose may be administered without resulting in hypercalcemia, for example about 10 ⁇ g to about 20 ⁇ g or higher (up to about 50 ⁇ g to about 100 ⁇ g).
  • the active vitamin D compound or a mimic thereof is administered by HDPA so that high doses of the active vitamin D compound or a mimic thereof can be administered without inducing hypercalcemia.
  • HDPA refers to intermittently administering an active vitamin D compound or a mimic thereof on either a continuous intermittent dosing schedule or a non-continuous intermittent dosing schedule.
  • High doses of active vitamin D compounds or a mimic thereof include doses greater than about 3 ⁇ g as discussed in the sections above. Therefore, in certain embodiments of the invention, the methods for the prevention, treatment, or amelioration of an infection encompass intermittently administering high doses of active vitamin D compounds or a mimic thereof.
  • the frequency of the HDPA can be limited by a number of factors including, but not limited to, the pharmacokinetic parameters of the compound or formulation and the pharmacodynamic effects of the active vitamin D compound or a mimic thereof on the animal. For example, animals having impaired renal function may require less frequent administration of the active vitamin D compound or a mimic thereof because of the decreased ability of those animals to excrete calcium.
  • HDPA can encompass any discontinuous administration regimen designed by a person of skill in the art.
  • the active vitamin D compound or the mimic thereof can be administered not more than once every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days, every ten days, every two weeks, every three weeks, or every four weeks.
  • the administration can continue for one, two, three, or four weeks or one, two, or three months, or longer.
  • the active vitamin D compound or the mimic thereof can be administered under the same or a different schedule.
  • the period of rest can be one, two, three, or four weeks, or longer, according to the pharmacodynamic effects of the active vitamin D compound or a mimic thereof on the animal.
  • the active vitamin D compound or a mimic thereof can be administered once per week for three months.
  • the vitamin D compound or a mimic thereof can be administered once per week for three weeks of a four week cycle. After a one week period of rest, the active vitamin D compound or a mimic thereof can be administered under the same or different schedule.
  • an effective dose of an active vitamin D compound or a mimic thereof is any dose of the compound effective to prevent, treat, or ameliorate an infection.
  • a high dose of an active vitamin D compound or a mimic thereof can be a dose from about 3 ⁇ g to about 10 mg or any dose within this range as discussed above.
  • the dose, dose frequency, duration, or any combination thereof may also vary according to age, body weight, response, and the past medical history of the animal as well as the route of administration, pharmacokinetics, and pharmacodynamic effects of the pharmaceutical agents. These factors are routinely considered by one of skill in the art.
  • the rate of absorption and clearance of vitamin D compounds or mimics thereof are affected by a variety of factors that are well known to persons of skill in the art. As discussed above, the pharmacokinetic properties of active vitamin D compounds limit the peak concentration of vitamin D compounds that can be obtained in the blood without inducing the onset of hypercalcemia. The rate and extent of absorption, distribution, binding or localization in tissues, biotransformation, and excretion of the active vitamin D compound can all affect the frequency at which the pharmaceutical agents can be administered.
  • an active vitamin D compound or a mimic thereof is administered at a dose sufficient to achieve peak plasma concentrations of the active vitamin D compound or a mimic thereof of about 0.1 nM to about 1000 nM, e.g., about 0.1 nM to about 25 nM.
  • the methods of the invention comprise administering the active vitamin D compound or a mimic thereof in a dose that achieves peak plasma concentrations of 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 12.5 nM, 15 nM, 17.5 nM, 20 nM, 22.5 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450
  • the active vitamin D compound or a mimic thereof is administered in a dose that achieves peak plasma concentrations of the active vitamin D compound or a mimic thereof exceeding about 0.5 nM, e.g., about 0.5 nM to about 1000 nM, about 0.5 nM to about 100 nM, about 0.5 nM to about 25 nM, about 5 nM to about 20 nM, or about 1O nM to about 15 nM.
  • 0.5 nM e.g., about 0.5 nM to about 1000 nM, about 0.5 nM to about 100 nM, about 0.5 nM to about 25 nM, about 5 nM to about 20 nM, or about 1O nM to about 15 nM.
  • the active vitamin D compound or a mimic thereof is administered at a dose of at least about 0.12 ⁇ g/kg bodyweight, more preferably at a dose of at least about 0.5 ⁇ g/kg bodyweight.
  • the methods of the invention further comprise administering a dose of an active vitamin D compound or a mimic thereof that achieves peak plasma concentrations rapidly, e.g., within four hours.
  • the methods of the invention comprise administering a dose of an active vitamin D compound, or a mimic thereof, that is eliminated quickly, e.g., with an elimination half- life of less than 12 hours.
  • the methods of the invention encompass HDPA of active vitamin D compounds or mimics thereof to an animal and monitoring the animal for symptoms associated with hypercalcemia. Such symptoms include calcification of soft tissues (e.g., cardiac tissue), increased bone density, and hypercalcemic nephropathy.
  • the methods of the invention encompass HDPA of an active vitamin D compound, or the mimic thereof, to an animal before, during, or after an infectious condition and monitoring the calcium plasma concentration of the animal to ensure that the calcium plasma concentration is less than about 11.5 mg/dL.
  • high blood levels of vitamin D compounds or mimics thereof can be safely obtained in conjunction with reducing the transport of calcium into the blood.
  • higher concentrations of active vitamin D compound or a mimic thereof are safely obtainable without the onset of hypercalcemia when administered in conjunction with a reduced calcium diet.
  • the calcium can be trapped by an adsorbent, absorbent, ligand, chelate, or other binding moiety that cannot be transported into the blood through the small intestine.
  • the rate of osteoclast activation can be inhibited by administering, for example, a bisphosphonate such as, e.g., zoledronate, pamidronate, or alendronate, or a corticosteroid such as, e.g., dexamethasone or prednisone, in conjunction with the active vitamin D compound or a mimic thereof.
  • a bisphosphonate such as, e.g., zoledronate, pamidronate, or alendronate
  • a corticosteroid such as, e.g., dexamethasone or prednisone
  • high blood levels of active vitamin D compounds or mimics thereof are safely obtained in conjunction with maximizing the rate of clearance of calcium.
  • calcium excretion can be increased by ensuring adequate hydration and salt intake.
  • diuretic therapy can be used to increase calcium excretion.
  • the active vitamin D compound or a mimic thereof is delivered locally, e.g., as a coating on a stent, blood levels of active vitamin D compound or calcium do not need to be monitored as the localized delivery is unlikely to result in systemically detectable levels of the active vitamin D compound or to affect systemic calcium levels.
  • the active vitamin D compound or a mimic thereof may be administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, wherein the active vitamin D compound or a mimic thereof is present in an amount which is effective to achieve its intended purpose, i.e., to have an anti-infective effect.
  • the pharmaceutical composition may further comprise one or more excipients, diluents or any other components known to persons of skill in the art and germane to the methods of formulation of the present invention.
  • the pharmaceutical composition may additionally comprise other compounds typically used as adjuncts during prevention, treatment, or amelioration of infections.
  • composition as used herein is to be understood as defining compositions of which the individual components or ingredients are themselves pharmaceutically acceptable, e.g., where oral administration is foreseen, acceptable for oral use and, where topical administration is foreseen, topically acceptable.
  • the pharmaceutical composition can be prepared in single unit dosage forms.
  • the dosage forms are suitable for oral, mucosal (nasal, sublingual, vaginal, buccal, rectal), parenteral (intravenous, intramuscular, intraarterial), or topical administration.
  • Preferred dosage forms of the present invention include oral dosage forms and intravenous dosage forms.
  • Intravenous forms include, but are not limited to, bolus and drip injections.
  • the intravenous dosage forms are sterile or capable of being sterilized prior to administration to a subject since they typically bypass the subject's natural defenses against contaminants.
  • intravenous dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles including, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles including, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.
  • aqueous vehicles including, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles including, but not limited to, ethyl alcohol, polyethylene glycol and polyprop
  • the pharmaceutical compositions comprising active vitamin D compounds, or mimics thereof are emulsion pre-concentrate formulations.
  • the compositions of the invention meet or substantially reduce the difficulties associated with active vitamin D compound therapy hitherto encountered in the art including, in particular, undesirable pharmacokinetic parameters of the compound upon administration to a patient.
  • a pharmaceutical composition comprising (a) a lipophilic phase component, (b) one or more surfactants, (c) an active vitamin D compound or a mimic thereof; wherein said composition is an emulsion pre-concentrate, which upon dilution with water, in a water to composition ratio of about 1 : 1 or more of said water, forms an emulsion having an absorbance of greater than 0.3 at 400 run.
  • the pharmaceutical composition of the invention may further comprise a hydrophilic phase component.
  • a pharmaceutical emulsion composition comprising water (or other aqueous solution) and an emulsion pre-concentrate.
  • emulsion pre-concentrate is intended to mean a system capable of providing an emulsion upon contacting with, e.g., water.
  • emulsion as used herein, is intended to mean a colloidal dispersion comprising water and organic components including hydrophobic (lipophilic) organic components.
  • emulsion is intended to encompass both conventional emulsions, as understood by those skilled in the art, as well as “sub-micron droplet emulsions,” as defined immediately below.
  • sub-micron droplet emulsion as used herein is intended to mean a dispersion comprising water and organic components including hydrophobic (lipophilic) organic components, wherein the droplets or particles formed from the organic components have an average maximum dimension of less than about 1000 run.
  • Sub-micron droplet emulsions are identifiable as possessing one or more of the following characteristics. They are formed spontaneously or substantially spontaneously when their components are brought into contact, that is without substantial energy supply, e.g., in the absence of heating or the use of high shear equipment or other substantial agitation. They exhibit thermodynamic stability and they are monophasic.
  • the particles of a sub-micron droplet emulsion may be spherical, though other structures are feasible, e.g. liquid crystals with lamellar, hexagonal or isotropic symmetries.
  • sub-micron droplet emulsions comprise droplets or particles having a maximum dimension (e.g. , average diameter) of between about 50 nm to about 1000 nm, and preferably between about 200 nm to about 300 nm.
  • the pharmaceutical compositions of the present invention will generally form an emulsion upon dilution with water.
  • the emulsion will form according to the present invention upon the dilution of an emulsion pre-concentrate with water in a water to composition ratio of about 1 : 1 or more of said water.
  • the ratio of water to composition can be, e.g., between 1 :1 and 5000:1.
  • the ratio of water to composition can be about 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 200:1, 300:1, 500:1, 1000:1, or 5000:1.
  • the skilled artisan will be able to readily ascertain the particular ratio of water to composition that is appropriate for any given situation or circumstance.
  • an emulsion upon dilution of said emulsion pre-concentrate with water, an emulsion will form having an absorbance of greater than 0.3 at 400 nm.
  • the absorbance at 400 nm of the emulsions formed upon 1 :100 dilution of the emulsion pre-concentrates of the present invention can be, e.g., between 0.3 and 4.0.
  • the absorbance at 400 nm can be about 0.4, 0.5, 0.6, 1.0, 1.2, 1.6, 2.0, 2.2, 2.4, 2.5, 3.0, or 4.0.
  • Methods for determining the absorbance of a liquid solution are well known by those in the art.
  • compositions of the present invention can be, e.g., in a solid, semi-solid, or liquid formulation.
  • Semi-solid formulations of the present invention can be any semi-solid formulation known by those of ordinary skill in the art, including, e.g., gels, pastes, creams and ointments.
  • compositions of the present invention comprise a lipophilic phase component.
  • Suitable components for use as lipophilic phase components include any pharmaceutically acceptable solvent which is non-miscible with water. Such solvents will appropriately be devoid or substantially devoid of surfactant function.
  • the lipophilic phase component may comprise mono-, di- or triglycerides.
  • Mono-, di- and triglycerides that may be used within the scope of the invention include those that are derived from C 6 , C 8 , C 1O , C 12 , C 14 , Cj 6 , Ci 8 , C 20 and C 22 fatty acids.
  • Exemplary diglycerides include, in particular, diolein, dipalmitolein, and mixed caprylin- caprin diglycerides.
  • Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, medium and long-chain triglycerides, structured triglycerides, and mixtures thereof.
  • preferred triglycerides include: almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; partially soy and cottonseed oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tri
  • a preferred triglyceride is the medium chain triglyceride available under the trade name LABRAFAC CC.
  • Other preferred triglycerides include neutral oils, e.g., neutral plant oils, in particular fractionated coconut oils such as known and commercially available under the trade name MIGLYOL, including the products: MIGLYOL 810; MIGLYOL 812; MIGLYOL 818; and CAPTEX 355.
  • caprylic-capric acid triglycerides such as known and commercially available under the trade name MYRITOL, including the product MYRITOL 813.
  • Further suitable products of this class are CAPMUL MCT, CAPTEX 200, CAPTEX 300, CAPTEX 800, NEOBEE M5 and MAZOL 1400.
  • Especially preferred as lipophilic phase component is the product MIGLYOL 812.
  • compositions of the present invention may further comprise a hydrophilic phase component.
  • the hydrophilic phase component may comprise, e.g., a pharmaceutically acceptable C 1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol.
  • Suitable hydrophilic phase components include, e.g., di- or partial-, especially partial-, -ethers of mono- or poly-, especially mono- or di-, -oxy-alkanediols comprising from 2 to 12, especially 4 carbon atoms.
  • the mono- or poly-oxy-alkanediol moiety is straight-chained.
  • Exemplary hydrophilic phase components for use in relation to the present invention are those known and commercially available under the trade names TRANS CUTOL and COLYCOFUROL. (See U.S. Patent No. 5,342,625).
  • the hydrophilic phase component comprises 1,2-propyleneglycol.
  • the hydrophilic phase component of the present invention may of course additionally include one or more additional ingredients.
  • any additional ingredients will comprise materials in which the active vitamin D compound or the mimic thereof is sufficiently soluble, such that the efficacy of the hydrophilic phase as a carrier medium for an active vitamin D compound or a mimic thereof is not materially impaired.
  • Examples of possible additional hydrophilic phase components include lower (e.g., C 1-5 ) alkanols, in particular ethanol.
  • compositions of the present invention also comprise one or more surfactants.
  • surfactants that can be used in conjunction with the present invention include hydrophilic or lipophilic surfactants, or mixtures thereof. Especially preferred are non- ionic hydrophilic and non-ionic lipophilic surfactants.
  • Suitable hydrophilic surfactants include reaction products of natural or hydrogenated vegetable oils and ethylene glycol, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example polyoxyethylene glycolated natural or hydrogenated castor oils.
  • Such products may be obtained in known manner, e.g., by reaction of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide, e.g., in a molar ratio of from about 1 :35 to about 1 :60, with optional removal of free polyethyleneglycol components from the product, e.g., in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819.
  • Suitable hydrophilic surfactants for use in the present pharmaceutical compounds also include polyoxyethylene-sorbitan-fatty acid esters, e.g., mono- and trilauryl, palmityl, stearyl and oleyl esters, e.g., of the type known and commercially available under the trade name TWEEN; including the products:
  • TWEEN 20 polyoxyethylene(20)sorbitanmonolaurate
  • TWEEN 40 polyoxyethylene(20)sorbitanmonopalmitate
  • TWEEN 60 polyoxyethylene(20)sorbitanmonostearate
  • TWEEN 80 polyoxyethylene(20)sorbitanmonooleate
  • TWEEN 65 polyoxyethylene(20)sorbitantristearate
  • TWEEN 85 polyoxyethylene(20)sorbitantrioleate
  • TWEEN 21 polyoxyethylene(4)sorbitanmonolaurate
  • TWEEN 61 polyoxyethylene(4)sorbitanmonostearate
  • TWEEN 81 polyoxyethylene(5)sorbitanmonooleate.
  • Especially preferred products of this class for use in the compositions of the invention are the above products TWEEN 40 and TWEEN 80. ⁇ See Hauer, et al., U.S. Patent No. 5,342,625).
  • hydrophilic surfactants for use in the present pharmaceutical compounds are polyoxyethylene alkylethers; polyoxyethylene glycol fatty acid esters, for example polyoxyethylene stearic acid esters; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and, e.g., fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; polyoxyethylene- polyoxypropylene co-polymers; polyoxyethylene-polyoxypropylene block co-polymers; dioctylsuccinate, dioctylsodiumsulfosuccinate, di-[2-ethylhexyl]-succinate or sodium lauryl sulfate; phospholipids, in particular lecithins such as, e.g., soya bean lecithins; propylene glycol mono- and di
  • Suitable lipophilic surfactants include alcohols; polyoxyethylene alkylethers; fatty acids; bile acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid esters of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene- polyoxypropylene block copolymers; trans-esterif ⁇ ed vegetable oils; sterols; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogen
  • Suitable lipophilic surfactants for use in the present pharmaceutical compounds also include trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols.
  • trans-esterification products are known in the art and may be obtained e.g., in accordance with the general procedures described in U.S. Patent No. 3,288,824. They include trans-esterification products of various natural (e.g., non- hydrogenated) vegetable oils for example, maize oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof with polyethylene glycols, in particular polyethylene glycols having an average molecular weight of from 200 to 800.
  • polyethylene glycol e.g., having an average molecular weight of from 200 to 800.
  • Additional lipophilic surfactants that are suitable for use with the present pharmaceutical compositions include oil-soluble vitamin derivatives, e.g., tocopherol PEG-1000 succinate ("vitamin E TPGS").
  • lipophilic surfactants for use in the present pharmaceutical compounds are mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol; sorbitan fatty acid esters; pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythrite- -dioleate, -distearate, - monolaurate, -polyglycol ether and -monostearate as well as pentaerythrite-fatty acid esters; monoglycerides, e.g., glycerol monooleate, glycerol monopalmitate and glycerol monostearate; glycerol triacetate or (l,2,3)-triacetin; and sterols and derivatives thereof, for example cholesterols and derivatives thereof, in particular phytosterols, e.g., products comprising sitosterols, e.g
  • surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a trans- esterification reaction.
  • the surfactants that are suitable for use in the present pharmaceutical compositions include those surfactants that contain a triglyceride.
  • Examples of commercial surfactant compositions containing triglycerides include some members of the surfactant families GELUCIRES, MAISINES, and IMWITORS.
  • GELUCIRE 44/14 saturated polyglycolized glycerides
  • GELUCIRE 50/13 saturated polyglycolized glycerides
  • GELUCIRE 53/10 saturated polyglycolized glycerides
  • GELUCIRE 33/01 saturated polyglycolized glycerides
  • GELUCIRE 39/01 saturated fatty acids
  • GELUCIRE 39/01 synthetic glycerides
  • other GELUCIRES such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, etc.
  • MAISINE 35-1 lainoleic glycerides
  • IMWITOR 742 caprylic/capric glycerides
  • compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the lipophilic phase component of the of the present invention, as well as all or part of the surfactants.
  • compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned.
  • the relative proportions will also vary depending on the particular function of ingredients in the composition.
  • the relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the product composition, e.g., in the case of a composition for topical use, whether this is to be a free flowing liquid or a paste. Determination of workable proportions in any particular instance will generally be within the capability of a person of ordinary skill in the art. All indicated proportions and relative weight ranges described below are accordingly to be understood as being indicative of preferred or individually inventive teachings only and not as limiting the invention in its broadest aspect.
  • the lipophilic phase component of the invention will suitably be present in an amount of from about 30% to about 90% by weight based upon the total weight of the composition.
  • the lipophilic phase component is present in an amount of from about 50% to about 85% by weight based upon the total weight of the composition.
  • the surfactant or surfactants of the invention will suitably be present in an amount of from about 1% to 50% by weight based upon the total weight of the composition.
  • the surfactant(s) is present in an amount of from about 5% to about 40% by weight based upon the total weight of the composition.
  • the amount of active vitamin D compound or mimic thereof in compositions of the invention will of course vary, e.g., depending on the intended route of administration and to what extent other components are present. In general, however, the active vitamin D compound, or the mimic thereof, of the invention will suitably be present in an amount of from about 0.005% to 20% by weight based upon the total weight of the composition. Preferably, the active vitamin D compound or the mimic thereof is present in an amount of from about 0.01% to 15% by weight based upon the total weight of the composition.
  • the hydrophilic phase component of the invention will suitably be present in an amount of from about 2% to about 20% by weight based upon the total weight of the composition.
  • the hydrophilic phase component is present in an amount of from about 5% to 15% by weight based upon the total weight of the composition.
  • the pharmaceutical composition of the invention may be in a semisolid formulation.
  • Semisolid formulations within the scope of the invention may comprise, e.g., a lipophilic phase component present in an amount of from about 60% to about 80% by weight based upon the total weight of the composition, a surfactant present in an amount of from about 5% to about 35% by weight based upon the total weight of the composition, and an active vitamin D compound or a mimic thereof present in an amount of from about 0.01% to about 15% by weight based upon the total weight of the composition.
  • compositions of the invention may be in a liquid formulation.
  • Liquid formulations within the scope of the invention may comprise, e.g., a lipophilic phase component present in an amount of from about 50% to about 60% by weight based upon the total weight of the composition, a surfactant present in an amount of from about 4% to about 25% by weight based upon the total weight of the composition, an active vitamin D compound, or a mimic thereof, present in an amount of from about 0.01% to about 15% by weight based upon the total weight of the composition, and a hydrophilic phase component present in an amount of from about 5% to about 10% by weight based upon the total weight of the composition.
  • a lipophilic phase component present in an amount of from about 50% to about 60% by weight based upon the total weight of the composition
  • a surfactant present in an amount of from about 4% to about 25% by weight based upon the total weight of the composition
  • an active vitamin D compound, or a mimic thereof present in an amount of from about 0.01% to about 15% by weight based upon the total weight of the composition
  • compositions that may be used include the following, wherein the percentage of each component is by weight based upon the total weight of the composition excluding the active vitamin D compound or the mimic thereof:
  • Gelucire 44/14 about 50% Vitamin E TPGS about 10% Miglyol 812 about 40%;
  • Vitamin E TPGS about 50% Miglyol 812 about 50%;
  • Gelucire 50/13 about 30% Vitamin E TPGS about 5% Miglyol 812 about 65%; k. Gelucire 50/13 about 50% Miglyol 812 about 50%;
  • Vitamin E TPGS about 20%
  • Vitamin E TPGS about 30%
  • Vitamin E TPGS about 20% Miglyol 812 about 40%
  • Vitamin E TPGS about 50% PEG 4000 about 50%;
  • Vitamin E TPGS about 50%
  • Vitamin E TPGS about 50%
  • Vitamin E TPGS about 5%
  • Vitamin E TPGS about 5%
  • Miglyol 812 about 65%
  • PEG 4000 about 30%
  • Vitamin E TPGS about 10% Miglyol 812 about 90%; ac. Vitamin E TPGS about 5% Miglyol 812 about 85% PEG 4000 about 10%; and
  • Vitamin E TPGS about 10% Miglyol 812 about 80%
  • PEG 4000 about 10%.
  • the pharmaceutical compositions comprise an active vitamin D compound or a mimic thereof, a lipophilic component, and a surfactant.
  • the lipophilic component may be present in any percentage from about 1% to about 100%.
  • the lipophilic component may be present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94
  • the surfactant may be present in any percentage from about 1% to about 100%.
  • the surfactant may be present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%.
  • the lipophilic component is MIGLYOL 812 and the surfactant is vitamin E TPGS.
  • the pharmaceutical compositions comprise about 50% MIGLYOL 812 and about 50% vitamin E TPGS, about 90% MIGLYOL 812 and about 10% vitamin E TPGS, or about 95% MIGLYOL 812 and about 5% vitamin E TPGS.
  • the pharmaceutical compositions comprise an active vitamin D compound, or a mimic thereof, and a lipophilic component, e.g., around 100% MIGLYOL 812.
  • compositions comprise about 50%
  • MIGLYOL 812 about 50% vitamin E TPGS, and small amounts of BHA and BHT.
  • This formulation has been shown to be unexpectedly stable, both chemically and physically (see Example 3).
  • the enhanced stability provides the compositions with a longer shelf life.
  • the stability also allows the compositions to be stored at room temperature, thereby avoiding the complication and cost of storage under refrigeration.
  • this composition is suitable for oral administration and has been shown to be capable of solubilizing high doses of active vitamin D compound or a mimic thereof, thereby enabling high dose pulse administration of active vitamin D compounds, or mimics thereof, for the treatment of hyperproliferative diseases and other disorders.
  • the pharmaceutical compositions comprise about 50%
  • the pharmaceutical compositions comprise about 50% MIGLYOL 812, about 50% vitamin E TPGS, and about 0.01% to about 0.50% each of BHA and BHT. In other embodiments, the pharmaceutical compositions comprise about 50% MIGLYOL 812, about 50% vitamin E TPGS, and about 0.05% to about 0.35% each of BHA and BHT. In certain embodiments, the pharmaceutical compositions comprise about 50% MIGLYOL 812, about 50% vitamin E TPGS, about 0.35% BHA, and about 0.10% BHT.
  • compositions that may be used include the following, wherein the percentage of each component is by weight based upon the total weight of the composition excluding the active vitamin D compound or a mimic thereof:
  • Vitamin E TPGS about 50%
  • Vitamin E TPGS about 50% BHT about 0.10%
  • Vitamin E TPGS about 50% BHA about 0.35%
  • Vitamin E TPGS about 50%
  • Vitamin E TPGS about 50%
  • formulations of the invention comprising a lipophilic component and a surfactant in amounts that total about 100% (e.g., about 50% lipophilic component and about 50% surfactant) provide adequate room for the active vitamin D compound and additives (e.g., antioxidants) which are present in the formulation in small amounts, each generally present at less than 1% by weight.
  • active vitamin D compound and additives e.g., antioxidants
  • compositions comprising the active vitamin D compound, or the mimic thereof, of the present invention may further comprise one or more additives.
  • Additives that are well known in the art include, e.g., detackifiers, anti-foaming agents, buffering agents, antioxidants (e.g., ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g., ⁇ -tocopherol (vitamin E)), preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • antioxidants e.g., ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g., ⁇ -tocopherol
  • antioxidants such as BHA and BHT may each be present in an amount of from about 0.01% to about 0.50% by weight based upon the total weight of the composition, e.g., about 0.05 to about 0.35% by weight, e.g., about 0.01, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50% by weight.
  • the additive may also comprise a thickening agent.
  • suitable thickening agents may be those known and employed in the art, including, e.g., pharmaceutically acceptable polymeric materials and inorganic thickening agents.
  • Exemplary thickening agents for use in the present pharmaceutical compositions include polyacrylate and polyacrylate copolymer resins, for example poly-acrylic acid and poly-acrylic acid/methacrylic acid resins; celluloses and cellulose derivatives including: alkyl celluloses, e.g., methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, e.g., hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses such as hydroxypropyl-methyl-celluloses; acylated celluloses, e.g., cellulose-acetates, cellulose-acetatephthallates, cellulose- acetatesuccinates and hydroxypropylmethyl-cellulose phthallates; and salts thereof such as
  • Such thickening agents as described above may be included, e.g., to provide a sustained release effect.
  • the use of thickening agents as aforesaid will generally not be required and is generally less preferred.
  • Use of thickening agents is, on the other hand, indicated, e.g., where topical application is foreseen.
  • compositions in accordance with the present invention may be employed for administration in any appropriate manner, e.g., orally, e.g., in unit dosage form, for example in a solution, in hard or soft encapsulated form including gelatin encapsulated form, parenterally or topically, e.g., for application to the skin, for example in the form of a cream, paste, lotion, gel, ointment, poultice, cataplasm, plaster, dermal patch or the like, as a coating for a medical device, e.g. , a stent, or for ophthalmic application, for example in the form of an eye-drop, -lotion or -gel formulation.
  • Readily flowable forms, for example solutions and emulsions may also be employed e.g., for intralesional injection, or may be administered rectally, e.g., as an enema.
  • the active vitamin D compound or the mimic thereof will preferably be present in an amount of between 1 and 1000 ⁇ g per unit dose. More preferably, the amount of active vitamin D compound or the mimic thereof per unit dose will be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 ⁇ g or any amount therein.
  • the amount of active vitamin D compound or the mimic thereof per unit dose will be about 5 ⁇ g to about 180 ⁇ g, more preferably about 10 ⁇ g to about 135 ⁇ g, more preferably about 45 ⁇ g.
  • the unit dosage form comprises 45, 90, 135, or 180 ⁇ g of calcitriol.
  • the total quantity of ingredients present in the capsule is preferably about 10-1000 ⁇ L. More preferably, the total quantity of ingredients present in the capsule is about 100-300 ⁇ L. In another embodiment, the total quantity of ingredients present in the capsule is preferably about 10-1500 mg, preferably about 100-1000 mg. In one embodiment, the total quantity is about 225, 450, 675, or 900 mg. In one embodiment, the unit dosage form is a capsule comprising 45, 90, 135, or 180 ⁇ g of calcitriol.
  • Animals which may be treated according to the present invention include all animals which may benefit from administration of the compounds of the present invention. Such animals include humans, pets such as dogs and cats, and veterinary animals such as cows, pigs, sheep, goats and the like.
  • C w /0.208 required weight of vehicle
  • C w weight of calcitriol, in mg
  • 0.208 final concentration of calcitriol (mg/g).
  • Amounts shown are percentages.
  • Vitamin E TPGS was warmed to approximately 50 0 C and mixed in the appropriate ratio with MIGLYOL 812. BHA and BHT were added to each formulation to achieve 0.35% w/w of each in the final preparations.
  • each formulation was prepared with 0.2 ⁇ g calcitriol/mg formulation and 0.35% w/w of both BHA and BHT.
  • the bulk formulation mixtures were filled into Size 3 hard gelatin capsules at a mass of 225 mg (45 ⁇ g calcitriol).
  • the capsules were then analyzed for stability at 5 0 C, 25°C/60% relative humidity (RH), 30°C/65% RH, and 40°C/75% RH.
  • the stability samples were analyzed for content of intact calcitriol and dissolution of the capsules.
  • the calcitriol content of the capsules was determined by dissolving three opened capsules in 5 mL of methanol and held at 5 0 C prior to analysis.
  • the dissolved samples were then analyzed by reversed phase HPLC.
  • a Phemonex Hypersil BDS Cl 8 column at 3O 0 C was used with a gradient of acetonitrile from 55% acetonitrile in water to 95% acetonitrile at a flow rate of 1.0 mL/min during elution. Peaks were detected at 265 run and a 25 ⁇ L sample was injected for each run. The peak area of the sample was compared to a reference standard to calculate the calcitriol content as reported in Table 5.
  • the dissolution test was performed by placing one capsule in each of six low volume dissolution containers with 50 mL of deionized water containing 0.5% sodium dodecyl sulfate.
  • Assay results indicate % of calcitriol relative to expected value based upon 45 ⁇ g content per capsule. Values include pre-calcitriol which is an active isomer of calcitriol.
  • Taxotere ® a drug in the taxoid class of chemotherapeutic agents. Taxotere ® is approved for use in prostate cancer and some other types of cancer. Oral dexamethasone is also given along with the Taxotere ® to minimize certain side effects (allergic reactions and fluid retention) associated with Taxotere ® .
  • infections and infestation events include [bronchopneumonia NOS, emphysema NOS, fungal sepsis, postoperative infection, psoas abscess, renal abscess NOS, serratia bacteremia, urethral infection, urosepsis] events where at least one patient treated with Taxotere ® alone had an infection while none of patients treated with Taxotere ® and calcitriol by HDPA suffered such an infection. Moreover, 8 patients who did not receive calcitriol developed mucosal inflammation NOS while 3 of the 125 patients treated with calcitriol by HDPA developed the condition. In addition, 1 of 125 patients treated with Taxotere ® alone developed upper respiratory tract infection while none of the 125 patients treated with Taxotere ® and calcitriol by HDPA did.
  • the active vitamin D compound or a mimic thereof will be tested in combination with AVASTIN as a first-line treatment of metastatic carcinoma of the colon or rectum.
  • Patients will be randomized to bolus-IFL (irinotecan 125 mg/m 2 IV, 5-fluorouracil 500 mg/m 2 IV and leucovorin 20 mg/m 2 IV given once weekly on day 2 for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus AVASTIN ® (5 mg/kg every two weeks on day 2) (Arm 2), 5-FU/LV (5-fluorouracil 500 mg/m 2 IV and leucovorin 20 mg/m 2 IV given once weekly on day 2 for 4 weeks every 6 weeks) plus AVASTIN (5 mg/kg every two weeks on day 2) (Arm 3), bolus-IFL plus AVASTEN (5 mg/kg every two weeks on day 2) plus calcitriol (45 ⁇ g once weekly on day 1) (Arm 4), and 5-FU/LV plus AVASTIN ® (5 mg//
  • calcitriol dosage will be varied from 5 ⁇ g to about 180 ⁇ g, administered once a week on the day prior to the administration of AVASTIN ® and the chemotherapeutic agents.
  • AVASTIN ® in combination with bolus-IFL or 5-FU/LV will be compared to those events exhibited by patients treated with AVASTIN ® in combination with bolus-IFL or 5- FU/LV.
  • Other chemotherapeutic agents will similarly be tested in combination with an active vitamin D compound or a mimic thereof and AV ASTEN .

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de prévention, de traitement ou d'amélioration de conditions infectieuses chez un animal comprenant l'administration à l'animal d'un composé de vitamine D actif ou d'une substance mimétique de celui-ci. Selon l'invention, le composé de vitamine D actif ou la substance mimétique de celui-ci peut être administré par administration à impulsion de dose élevée de sorte que les doses élevées du composé de vitamine D actif ou de la substance mimétique de celui-ci peuvent être administrées à un animal sans induire d'hypercalcémie symptomatique sévère. L'invention concerne également un procédé de prévention, de traitement ou d'amélioration de conditions infectieuses chez un animal comprenant l'administration à l'animal d'un composé de vitamine D actif ou d'une substance mimétique de celui-ci en combinaison avec un ou plusieurs autres agents thérapeutiques.
PCT/US2008/003630 2007-03-21 2008-03-20 Prévention et traitement de conditions infectieuses avec composés de vitamine d actifs ou substances mimétiques de ceux-ci Ceased WO2008115531A1 (fr)

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CN103784419A (zh) * 2012-10-31 2014-05-14 成都国弘医药有限公司 一种含有骨化三醇的软胶囊及其制备方法
WO2014126594A1 (fr) * 2013-02-15 2014-08-21 Guilford Frederick Timothy Traitement de maladies de résistance bactérienne évolutive comprenant klebsiella pneumoniae avec du glutathion formulé dans des liposomes
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WO2015123101A1 (fr) * 2014-02-12 2015-08-20 Albert Einstein College Of Medicine Of Yeshiva University Traitement d'infections dues à h pylori à l'aide d'inhibiteurs de la mtan
CN107811972A (zh) * 2017-11-03 2018-03-20 华中科技大学 一种阿霉素和基因药物共输送纳米载药系统及制备方法
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Cited By (16)

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US20150250803A1 (en) * 2009-12-23 2015-09-10 Jesse P. Goff Use of vitamin d glycosides and sulfates for treatment of disease
US20110152207A1 (en) * 2009-12-23 2011-06-23 Goff Jesse P Use of vitamin d glycosides and sulfates for treatment of disease
CN103784419A (zh) * 2012-10-31 2014-05-14 成都国弘医药有限公司 一种含有骨化三醇的软胶囊及其制备方法
WO2014126594A1 (fr) * 2013-02-15 2014-08-21 Guilford Frederick Timothy Traitement de maladies de résistance bactérienne évolutive comprenant klebsiella pneumoniae avec du glutathion formulé dans des liposomes
JP2017501203A (ja) * 2014-01-02 2017-01-12 ゼンサン （シャンハイ） サイエンス アンド テクノロジー，シーオー．，エルティーディー． 抗生作用のためのビタミンｄ及びその組成物の使用
CN104758300A (zh) * 2014-01-02 2015-07-08 上海泽生科技开发有限公司 维生素d及其组合物的抗菌用途
CN105916510A (zh) * 2014-01-02 2016-08-31 上海泽生科技开发股份有限公司 维生素d及其组合物的抗菌用途
EP3111939A4 (fr) * 2014-01-02 2017-11-08 Zensun (Shanghai) Science & Technology, Co., Ltd. Vitamine d et utilisations antibactériennes de composition associée
WO2015123101A1 (fr) * 2014-02-12 2015-08-20 Albert Einstein College Of Medicine Of Yeshiva University Traitement d'infections dues à h pylori à l'aide d'inhibiteurs de la mtan
US10118928B2 (en) 2014-02-12 2018-11-06 Albert Einstein College Of Medicine, Inc. Treatment of H. pylori infections using MTAN inhibitors
US10294233B2 (en) 2014-02-12 2019-05-21 Albert Einstein College Of Medicine Treatment of H. pylori infections using MTAN inhibitors
CN104688728A (zh) * 2015-02-05 2015-06-10 郑州点石生物技术有限公司 洛伐他汀在制备抗微小隐孢子虫药物中的应用
CN107811972A (zh) * 2017-11-03 2018-03-20 华中科技大学 一种阿霉素和基因药物共输送纳米载药系统及制备方法
WO2020052742A1 (fr) * 2018-09-11 2020-03-19 Parapharm Development Limited Capsule, comprimé ou pilule
US20210369741A1 (en) * 2020-05-27 2021-12-02 Northwestern University Vitamin d as an immune modulator to prevent immune-related complication from covid-19 infection
US11903952B2 (en) 2020-05-27 2024-02-20 Northwestern University Vitamin D as an immune modulator to prevent immune-related complication from COVID-19 infection

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