Classifications

• • 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
  • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

• This invention relates to pharmaceutical formulations of lipophilic therapeutic agents in which such agents are solubilized in largely aqueous vehicles, and uses for such formulations.
• the formulations are stable in aqueous-based vehicles, and have therapeutically and commercially useful concentrations of active ingredient.
• Lipophilic therapeutic agents span the entire range of biologically and/or pharmacologically active substances.
• they include certain analgesics and anti-inflammatory agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-neoplastic agents and immunosuppressants, ⁇ -blockers, corticosteroids, opioid analgesics, lipid regulating agents, anxiolytics, sedatives, hypnotics and neuroleptics.
• Efficacious aqueous-based formulations are particularly problematic for systemic administration, in particular parenteral administration (i.e., injectable solutions) and for certain liquid preparations for, e.g., topical gynecologic, dermatologic ophthalmic, etc. use, and for use on the oral mucous membranes.
• a number of approaches for obtaining aqueous compositions of sparingly water-soluble drugs are known. Such approaches seek to increase the solubility, and accordingly, increase the ease of formulation and the bioavailability of the sparingly soluble or lipophilic active agents.
• One such approach involves chemical modification of the lipophilic drug by introduction of a ionic or ionizable group or a group that lowers the melting point.
• the former generally depends upon the lipophilic drug having a hydroxyl or carboxy group which can be used to form various kinds of esters.
• the latter is based on the concept that, to be solubilized, the molecules have to leave the crystal lattice. Any modification of the molecule that lowers the melting point, and thus reduces the energy of the crystal lattice, tends to increase the solubility thereof in any solvent.
• Another method involves physico-chemical solubilization techniques such as micellar solubilization by means of surface-active agents, i.e., the use of surfactant micelles to solubilize and transport the therapeutic agent.
• Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds under certain conditions. Micelles, and pharmaceutical compositions containing micelles, have been extensively studied and are described in detail in the literature. In aqueous solution, micelles can incorporate lipophilic therapeutic agents in the hydrocarbon core of the micelle, or can entangle the agents at various positions within the micelle walls.
• micellar formulations can solubilize a variety of lipophilic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many lipophilic therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
• Complexing polymers employed in the pharmaceutical field include, e.g., polyethylene glycols, polypropylene glycols, cyclodextrins, carboxymethylcellulose, polyvinylpyrrolidone (PVP)
• Co-precipitation is yet another widespread method for the preparation of complexes with increased solubility.
• the substance and the polymer are dissolved in an organic solvent in which they are both soluble, and the solution is then evaporated at atmospheric pressure, under vacuum, by spray-drying or by lyophilization, to yield a dry product actually made of the complex of the treated drug.
• Such complexes can also be obtained by applying other methods, such as grinding and mixing the ingredients in a mill, or by extrusion of a paste containing the two products together with a minor amount of water, etc. In comparison with the starting drug, the complex typically shows an appreciably enhanced water-solubility.
• Still another method involves use of various co-solvent systems, i.e., compositions using a solvent mixture containing water and one or more organic solvents.
• One approach to solubilizing lipophilic drug agents in aqueous systems is to employ some combination of alcohols and glycols (PDA J. Pharm. Sci. Technol. 50(5) 1996; U.S. Patents 6,136,799; 6,361,758 and 5,858,999)
• Organic contents as high as 50% or more are often required to ensure solubility during manufacturing, storage and administration.
• organic levels while high will still be below the LD 5 o for a low volume parenteral dosage, the amounts are still typically undesirable.
• High levels of organic solvent can cause pain on injection and tissue necrosis.
• An exemplary and important class of lipophilic drug agents are the vitamin D compounds. Properly metabolized vitamin D compounds are necessary for the maintenance of healthy bones and have been found to display more other biological activities.
• the lipophilicity of the natural forms of vitamin D and of the many known synthetic analogs of vitamin D makes it difficult to manufacture an efficacious formulation, particularly, a parenteral formulation which is preferred for, e.g., renal dialysis patients.
• vitamin D compounds are known to be oxygen sensitive, being oxidized when exposed to air, and thus, losing integrity.
• One approach to circumventing this problem is to add an antioxidant directly to a formulation of the drug.
• certain antioxidants such as ascorbic acid and sodium ascorbate, which are highly water soluble, will discolor in the course of performing their intended function.
• Buffers and/or chelating agents have also been added to decrease oxygen sensitivity thus maintaining active drug potency (US patents 4,308,264; 4,948,788 and 5,182,274.)
• buffers and chelating agents are known to introduce undesirable levels of aluminum into the product.
• the present invention provides a pharmaceutical formulation that overcomes the problems associated with parenteral formulations of lipophilic drugs.
• the present invention provides a formulation that can be terminally sterilized, and contains little or no organic solvent such as alcohol. It has also been surprisingly discovered that the novel formulations of the present invention provide a synergistic solubilizing and antioxidative effect. Additionally, the present invention allows for the inclusion or occlusion of aseptic agents, depending on the intended use and/or handling.
• the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of (1) a lipophilic therapeutic agent, (4) a non-ionic solubilizer, (3) a lipophilic antioxidant, and (4) optionally, an agent that is an organic solvent, or a preservative (e.g., antimicrobial), or both, in an aqueous vehicle.
• Lipophilic therapeutic agents suitable for use in the formulations of the present invention are not particularly limited. Agents of particular interest include vitamin D compounds and analogs. By employing a lipophilic, i.e., fat-soluble, antioxidant, smaller amounts of antioxidant may be used compared to known formulations utilizing water soluble antioxidants.
• formulations of the present invention preclude the need for high organic solvent contents, which can cause irritations in some patients.
• formulations of the present invention omit buffers and chelating agents.
• the use of buffers and chelating agents in, e.g., some prior vitamin D formulations, has been linked to the introduction of undesirable aluminum levels into the product and eventually into the patient.
• the invention also relates to methods for the treatment and or prophylaxis of certain diseases and disorders comprising administering, e.g., parenterally, to a patient in need thereof a formulation in accordance with the present invention.
• these diseases include hyperparathyroidism, e.g., secondary hyperparathyroidsim, neoplastic diseases, such as cancers of the pancreas, breast, colon or prostate as well as other diseases of abnormal cell differentiation and/or cell proliferation such as psoriasis, and disorders of calcium metabolism such as osteomalacia.
• the present invention provides a stable, self-preserved pharmaceutical formulation of a lipophilic therapeutic agent in aqueous vehicle utilizing a non-ionic solubilizer and lipophilic antioxidant.
• the formulation is suitable for parenteral administration.
• lipophilic in reference to a therapeutic agent or drug is intended to mean a sparingly (or poorly, slightly, scarcely) soluble biologically active or pharmaceutically active substance or antigen-comprising material, which has a therapeutic or prophylactic effect, and has utility in the treatment or prevention of diseases or disorders affecting mammals, including humans, or in the regulation of an animal or human physiological condition.
• the water-solubility of lipophilic drugs, at room temperature, is typically too low to make commercially proposable, sufficiently active or advantageous any aqueous preparations containing the compound as an active ingredient.
• Lipophilic therapeutic agents include substances, typically compounds, with little or no water solubility.
• Intrinsic water solubilities for lipophilic therapeutic agents usable in the present invention include, for example, those with a solubility of less than about 1% by weight, and typically less than about 0.1% or 0.01% by weight, or, e.g., less than about 10 ⁇ g/mL.
• Lipophilic therapeutic agents suitable for use in the formulations of the present invention are not particularly limited, as the method of the present invention is surprisingly capable of solubilizing and delivering a wide variety of lipophilic therapeutic agents.
• Therapeutic agents that can be utilized with the formulations of the present invention may be selected from a wide range of biologically and/or pharmacologically active substances which lack adequate solubility in aqueous systems without a solubilizing agent.
• Such therapeutic agents include any agents having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, prodrugs (i.e., agents than transform into active substances), nutrients (nutraceuticals), and cosmetics (cosmeceuticals).
• Such therapeutic agents can be utilized in formulations in accordance with the present invention so as to yield an effective therapeutic dose, e.g., for parenteral administration.
• the precise biological and/or pharmacological activity of the substance is immaterial, so long as the substance can be solubilized in the present formulations.
• lipophilic therapeutic agents that can be used in the formulations of the present invention include the following representative compounds, as well as their pharmaceutically acceptable salts, isomers, esters, ethers and other derivatives. These include:
• analgesics and anti-inflammatory agents such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenaminc acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine;
• anthelmintics such as albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate and thiabendazole;
• anti-arrhythmic agents such as amiodarone HC1, disopyramide, flecainide acetate and quinidine sulfate;
• anti-asthma agents such as zileuton, zafirlukast, terbutaline sulfate, montelukast, and albuterol;
• an ti -bacterial agents such as alatrofloxacin, azithromycin, baclofen, benzathine penicillin, cinoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HC1, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphametho
• anti-coagulants such as cilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, and tirofiban;
• anti-depressants such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxine HCl;
• anti-diabetic agents such as acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide and troglitazone;
• anti-epileptic agents such as beclamide, carbamazepine, clonazepam, thotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, and vigabatrin;
• anti-epileptic agents such as beclamide, carbamazepine, clonazepam, thotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone,
• anti-fungal agents such as amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinaf ⁇ ne HCl, terconazole, tioconazole and undecenoic acid;
• anti-gout agents such as allopurinol, probenecid and sulphinpyrazone
• anti-hypertensive agents such as amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, and valsartan; [0041] anti-malarial agents, such as amodiaquine, chloroquine, and doxazos
• anti-migraine agents such as dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotifen maleate, rizatriptan benzoate, sumatriptan succinate, and zolmitriptan;
• anti-muscarinic agents such as atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl and tropicamide;
• anti-neoplastic agents and immunosuppressants such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene, busulfan, camptothecin, capecitabine, chlorambucil, cyclosporin, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl, and toremifene citrate;
• immunosuppressants such as aminoglutethimide, amsacrine, azathioprine, bical
• anti-protozoal agents such as atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole and tinidazole;
• anti-thyroid agents such as carbimazole and propylthiouracil
• anti-tussives such as benzonatate
• anxiolytics, sedatives, hypnotics and neuroleptics such as alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlo ⁇ rothixene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, triflupromazine, flupenthixol decanoate, fluphenthixol decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine,
• ⁇ -blockers such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol and propranolol;
• cardiac inotropic agents such as amrinone, digitoxin, digoxin, enoxi one, lanatoside C and medigoxin;
• corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
• diuretics such as acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone and triamterene;
• anti-parkinsonian agents such as bromocriptine mesylate, lysuride maleate, pramipexole, ropinirole HCl, and tolcapone;
• gastrointestinal agents such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lanosprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL, rabeprazole sodium, ranitidine HCl and sulphasalazine;
• histamine Hi and H 2 -receptor antagonists such as acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlo ⁇ heniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide, and terfenadine;
• acrivastine such astemizole, chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlo ⁇ heniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide, and terfen
• keratolytics such as acetretin, calciprotriene, calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin, and tazarotene;
• lipid regulating agents such as atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol, and simvastatin;
• muscle relaxants such as dantrolene sodium and tizanidine HCl
• nitrates and other anti-anginal agents such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate and pentaerythritol tetranitrate;
• nutritional agents and fat-soluble vitamins such as calcitriol, carotenes, dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonadiol, vitamin A, vitamin B 2 , vitamin D, vitamin E and vitamin K;
• opioid analgesics such as codeine, dextropropoxyphene, diamo ⁇ hine, dihydrocodeine, fentanyl, meptazinol, methadone, mo ⁇ hine, nalbuphine and pentazocine;
• sex hormones such as clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone and tibolone;
• sex hormones such as clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol,
• stimulants such as amphetamine, dexamphetamine, dexfenfluramine, fenfluramine and mazindol;
• erectile dysfunction improvement agents such as becaplermin, donepezil HCl, L- thryroxine, methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene HCl, sibutramine HCl, sildenafil citrate, tacrine, tamsulosin HCl, and tolterodine.
• lipophilic therapeutic agents and their therapeutic classes are merely illustrative. Indeed, a particular feature, and su ⁇ rising advantage, of the formulations of the present invention is the ability of the present formulations to solubilize and deliver a broad range of lipophilic therapeutic agents, regardless of functional class. Of course, mixtures of lipophilic therapeutic agents may also be used where desired.
• lipophilic agents of particular interest include active vitamin
• activated vitamin D or “active vitamin D” is intended to include any biologically active vitamin D compound, including a pro-drug (or pro-hormone), a precursor, a metabolite or an analog, in any stage of its metabolism. It is known that vitamin D compounds display a variety of biological activities, e.g., in calcium and phosphate metabolism (see, e.g., U.S. Patent 5,104,864), as an antineoplastic agent (see, e.g., U.S. Patent 5,763,429), and as an anti-hype ⁇ arthyroid agent (see, e.g., U.S.
• an active vitamin D compound or analog is hydroxylated in at least the C-1, C-24 or C-25 position of the molecule, and either the compound itself or its metabolite binds to the vitamin D receptor (VDR).
• VDR vitamin D receptor
• Pro-drugs include vitamin D compounds that are hydroxylated in the C-1. Such compounds undergo further hydroxylation in vivo and their metabolites bind the VDR.
• Precursors include previtamins, such as l ⁇ -hydroxyprevitamin D , l ⁇ ,24- dihydroxyprevitamin D 2 , l ⁇ ,25-dihydroxyprevitamin D 2 , 24-hydroxyprevitamin D 2 , l ⁇ - hydroxyprevitamin D and l ⁇ ,25-dihydroxyprevitamin D 3 , which are thermal isomeric forms of the vitamin forms.
• Metabolites generally include compounds or analogs that have undergone further metabolic processing, e.g., hydroxylation.
• vitamin D compounds suitable for formulations of the present invention include, without limitation, l ⁇ ,24-dihydroxyvitamin D 2 , l ⁇ ,2- dihydroxy vitamin D 4 , l ⁇ ,24-dihydroxyvitamin D 2 , l ⁇ ,25-dihydroxy vitamin D 3 (calcitriol), l ⁇ hydroxy vitamin D 3 ( ⁇ -calcidol) l ⁇ ,25-dihydroxyvitamin D 2 , l ⁇ ,25- dihydroxyvitamin D 4 , and l ⁇ ,24,25-dihydroxyvitamin D 2 , seocalcitol (EB-1089), calcipotriol, 22-oxacalcitriol (maxacalcitol), fluorinated compounds such as falecalcitriol, and 19-nor compounds such as paricalcitol.
• any numerical value recited herein includes all values from the lower value to the upper value. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.
• the amount of selected therapeutic is not critical to the present invention and may be varied to achieve the desired therapeutic response for a particular patient.
• the amount of active therapeutic agent in the formulations of the invention will be dependent, in part, on the solubility of the specific surfactant used and its intended use. Those skilled in the arts can adjust the ratios without undue experimentation.
• the selected dosage also will depend on the activity of the specific therapeutic, the route of administration, the severity of the condition being treated and the condition and history of the specific patient. For example, a therapeutic dose for vitamin D-type compounds may range between about 2 ⁇ g and about 100 ⁇ g/dose.
• Suitable solubilizing agents for the formulations of the present invention include nonionic solubilizers.
• a non-ionic solubilizer is one where the hydrophilic part of the solubilizer carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene groups.
• Some surfactants known for use in the pharmaceutical field also have a solubilizing function.
• Solubilizers generally include, but are not limited to, the polyoxyalkylenes dextrans, fatty acid esters of saccharose, fatty alcohol ethers of oligoglucosides (e.g., the akylpolyglucosides such as TRITONTM), fatty acid esters of glycerol (e.g., glycerol mono/distearate or glycerol monolaurate), and polyoxyethylene type compounds (e.g., POE, PEG, PEO, SOLUTOLTM CREOMOPHORTMS, MACROGOL, CARBOWAX, POLYOXYL).
• polyoxyalkylenes dextrans e.g., the fatty acid esters of saccharose, fatty alcohol ethers of oligoglucosides (e.g., the akylpolyglucosides such as TRITONTM), fatty acid esters of glycerol (e.g., glycerol mono/
• the latter also include polyethoxylated fatty acid esters of sorbitan (e.g., polysorbates, such as TWEENTMs, SPANTMs), fatty acid esters of poly(ethylene oxide) (e.g., polyoxyethylene stearates), fatty alcohol ethers of poly(ethylene oxide) (e.g., polyoxyethylated lauryl ether), alkylphenol ethers of poty(ethylene oxide) (e.g., polyethoxylated octylphenol), polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers, such as "Pluronic"), and ethoxylated fats and oils (e.g., ethoxylated castor oil, or polyoxyethylated castor oil, also known as polyethylene glycol- glyceryl triricinoleate).
• polyethoxylated fatty acid esters of sorbitan e.g., polysorbates,
• Solubilizers of particular interest include polysorbates, e.g. TWEENTM. Amounts of such solubilizer present in the formulations of the present invention include from about 0.05% to about 5% w/w.
• Suitable lipophilic antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), lipoic acid, lycopene, lutein, lycophyll, xanthophyll, carotene, zeaxanthin or vitamin E and/or esters thereof.
• BHT butylated hydroxytoluene
• the lipophilic antioxidants are present in very small but effective amounts, e.g., about 20 to about 2000 ppm.
• formulations of the present invention can optionally include additional agents to enhance the solubility of the lipophilic therapeutic agent in the carrier system.
• optional agents include organics solvents, preservatives or both.
• agents include alcohols and polyols, such as ethanol, benzyl alcohol, chlorobutanol, isopropanol, butanol, ethylene glycol, propylene glycol, butanediols, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives.
• Amounts of optional agents include 0% to about 30% w/w, e.g., organic solvent.
• a useful range is 0% to about 10% w/w, and a particularly useful
• a formulation in accordance with the present invention includes a lipophilic drug agent (e.g., a drug agent with a solubility in water of ⁇ 10 ⁇ g/mL), about 0.05% to about 5% w/w of a non-ionic solubilizer, about 20 to about 2000 ppm lipophilic antioxidant, and 0% to about 30% w/w optional agent.
• a particular formulation for treating secondary hype ⁇ arathyroidism includes 2 - 6 ⁇ g/mL l ⁇ - hydroxyvitamin D 2 (doxercalciferol), 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w TWEENTM-20, and 20 ppm BHT.
• the amount of optional agent e.g., benzyl alcohol or ethanol, may range from 0 to 30% w/w; a highly useful range comprises 1% to 3% w/w.
• a vitamin D formulation e.g., a doxercalciferol formulation
• a most useful amount of optional agent comprises 2.5% w/w.
• a pharmaceutical formulation in accordance with the present invention comprises an aqueous vehicle.
• the aqueous vehicle contains, of course, water, but it may furthermore also contain pH adjusting agents, stabilizing agents, solubilizing agent (see, hereinabove), isotonic adjusting agents, and solvents (e.g. organic solvents; as discussed above).
• a formulation in accordance with the present invention precludes the need for high organic solvent which can cause irritation in some patients. In some cases, however, it may be appropriate to include an organic solvent or co-solvents.
• the amount of water in a formulation in accordance with the present invention is normally at least about from about 50% to about 99% w/w.
• the intended route of administration is suitably parenteral, i.e., for use by injection into, e.g., an animal or human body.
• parenteral i.e., for use by injection into, e.g., an animal or human body.
• Such route includes intravenous, intramuscular and subcutaneous administration, the intravenous route being especially suitable for the formulations of the present invention for use in connection with, e.g., secondary hype ⁇ arathyroidism or neoplastic disorders.
• formulations in accordance with the present invention may also be suitable for use by other administration routes such as, e.g., the oral route, the topical route or the nasal route.
• other administration routes such as, e.g., the oral route, the topical route or the nasal route.
• a person skilled in the art can make any necessary adjustments with respect to the concentration of the active substance and with respect to the other ingredients included in the formulation.
• a formulation in accordance with the present invention is normally presented as an aqueous solution.
• a formulation in accordance with the present invention may include a liquid composition which may be presented in the form of a solution or a gel.
• compositions may be readily prepared by using pharmacopoeia grade reagents in which the reagents are made up in stock solutions from which the resulting solutions at the appropriate concentrations can be made. Once the appropriate amounts of stock solution and combined, it is often desirable to stir the reagents for several minutes under nitrogen gas gently blown over the top of the mixture, i.e., a nitrogen gas overlay. Degassed Water for Injection is then added to bring the desired final volume, and stirring under nitrogen gas continued for another several minutes.
• a pharmaceutical formulation in accordance with the present invention containing a vitamin D compound or a vitamin D analogue like those substances described above, is suitable for use in the treatment and/or prophylaxis of (i) diseases or conditions characterized by abnormal cell differentiation and/or cell hype ⁇ roliferation such as, e.g., psoriasis and other disturbances of keratinisation, neoplastic diseases and cancers, such as pancreas, breast, colon and prostate cancers as well as skin cancer; (ii) diseases of, or imbalance in, the immune system, such as host-versus-graft and graft- versus-host reaction and transplant rejection, and auto-immune diseases such as discoid and systemic lupus erythematosus, diabetes mellitus and chronic dermatoses of autoimmune type, e.g., scleroderma and pemphigus vulgaris; (iii) inflammatory diseases such as rheumatoid arthritis as well as in
• vitamin D formulations in accordance with the present invention are especially suited for treatment of cell hype ⁇ roliferative disorders; disorders of the calcium metabolism, such as osteomalacia; or neoplastic diseases, such as cancers of the pancreas, breast, colon or prostate.
• the method of treatment comprises treating the cells and/or administering to a patient in need thereof a formulation in accordance with the present invention in an amount that is effective to amelariate or prevent the disease or disorder.
• an effective amount is, e.g., a growth-inhibiting amount.
• vitamin D compounds in accordance with the present invention include prodrugs, i.e., drugs that require further metabolic processing in vivo, e.g., additional hydroxlation.
• prodrugs of vitamin D compounds that have been found to be effective therapeutic agents are generally less reactive than, e.g., the dihydroxy natural hormone, l ⁇ ,25-dihydroxyvitamin D 3 .
• These compounds may offer further advantage for use in formulations.
• formulations of the current invention may be terminally sterilized by means of e.g., autoclaving.
• TWEENTM-20KR 100 g TWEENTM-20KR was transferred to a 1-L volumetric flask and diluted to volume with degassed Water for Injection. A magnetic stir bar was added and the mixture stirred to mix.
• ESRD End Stage Renal Disease
• patients undergoing chronic hemodialysis are studied in a multicenter, double-blind, placebo-controlled study based in two major U.S. metropolitan areas.
• the selected patients reside in two major metropolitan areas within the continental U.S., have ages between 20 and 75 years and have a history of secondary hype ⁇ arathyroidism. They have been on hemodialysis for at least four months, have a normal (or near normal) serum albumin, and have controlled serum phosphorus (often by using oral calcium phosphate binders).
• each patient is assigned at random to one of two treatment groups.
• One of these groups receives two consecutive 12- week courses of therapy with l ⁇ -OH-vitamin D 2 (doxercalciferol); the other receives a 12-week course of therapy with l ⁇ -OH-vitamin D 2 followed, without interruption, by a 12- week course of placebo therapy.
• Each patient discontinues any l ⁇ ,25-(OH) 2 - vitamin D 3 therapy for eight weeks prior to initiating l ⁇ -OH-vitamin D 2 therapy (daily dose of 4 ⁇ g doxercalciferol, formulated with 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w TWEEN TM -20, an d 20 ppm BHT).
• doxercalciferol formulated with 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w/w TWEEN TM -20, an d 20 ppm BHT.
• serum calcium and phosphorus Serum intact PTH is monitored weekly or biweekly, and bone-specific serum markers, serum vitamin D metabolites, serum albumin, blood chemistries, hemoglobin and hematocrit are monitored at selected intervals.
• mean serum level of PTH increases progressively and significantly.
• mean serum PTH decreases significantly to less than 50% of pretreatment levels. Due to this drop in serum PTH, some patients need to reduce their dosage of l ⁇ -OH-vitamin D 2 to 4 ⁇ g three times per week (or to even lower levels) to prevent excessive suppression of serum PTH. In such patients, exhibiting excessive suppression of serum PTH, transient mild hypercalcemia is observed, which is corrected by appropriate reductions in l ⁇ -OH- vitamin D 2 dosages.
• mean serum PTH is in the desired range of 130 to 240 pg/mL and serum levels of calcium and phosphorus are normal or near normal for end stage renal disease patients.
• mean serum PTH values markedly increase, reaching pretreatment levels.
• Subjects are requested to keep a diet providing approximately 500 mg calcium per day without the use of calcium supplements.
• subjects self-administer orally 2.5 ⁇ g/day l ⁇ -OH-vitamin D 2 .(i.e., 2.5 ⁇ g doxercalciferol, 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w TWEENTM-20, and 20 ppm BHT)
• subjects are monitored for serum PTH levels, serum calcium and phosphorus, and urine calcium and phosphorus levels.
• Efficacy is evaluated by pre- and post-treatment comparisons of serum PTH levels.
• Safety is evaluated by serum and urine calcium and phosphorus values.
• Example 7 Clinical studies of l ⁇ ,24-(OH) 2 D 2 in treatment of prostate cancer
• the patients are monitored at regular intervals for: (1) hypercalcemia, hype ⁇ hosphatemia, hypercalciuria, hype ⁇ hosphaturia and other toxicity; (2) evidence of changes in the progression of metastatic disease; and (3) compliance with the prescribed test drug dosage.
• the maximal tolerated dosage (MTD) of daily l ⁇ ,24-(OH) 2 D 2 is determined by administering progressively higher dosages to successive groups of patients. All doses are administered in the morning before breakfast.
• the first group of patients is treated with 25.0 ⁇ g of l ⁇ ,24-(OH) 2 D 2 (formulated with 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w TWEENTM-20, and 20 ppm BHT).
• Subsequent groups of patients are treated with 50.0, 75.0 and 100.0 ⁇ g/day.
• Dosing is continued uninterrupted for the duration of the study unless serum calcium exceeds 11.6 mg/dL, or other toxicity of grade 3 or 4 is observed, in which case dosing is held in abeyance until resolution of the observed toxic effect(s) and then resumed at a level which has been decreased by 10.0 ⁇ g.
• (OH) 2 D 2 is above 20.0 ⁇ g/day, a level which is 10- to 40-fold higher than can be achieved with 1 ⁇ ,25-(OH) 2 D 2 .
• Analysis of blood samples collected at regular intervals from the participating patients reveal that the levels of circulating l ⁇ ,24-(OH) 2 D 2 increase proportionately with the dosage administered, rising to maximum levels well above 100 pg/mL at the highest dosages, and that circulating levels of l ⁇ ,25-(OH) 2 D 2 are suppressed, often to undetectable levels.
• Serum and urine calcium are elevated in a dose responsive manner.
• Patients treated with the MTD of l ⁇ ,24-(OH) 2 D 2 for at least six months report that bone pain associated with metastatic disease is significantly diminished.
• Example 7 The study of Example 7 is repeated for the active vitamin D compound, l ⁇ -(OH)D 2 (formulated with 2.5% w/w benzyl alcohol, 0.5% - 2.5% w/w TWEENTM-20, and 20 ppm BHT).
• the results of the phase one study indicate that patients treated with the MTD of l ⁇ -(OH)D 2 for at least six months report that bone pain associated with metastatic disease is significantly diminished.
• the results of the phase two study indicate that after two years, CAT scans, X-rays and bone scans used for evaluating the progression of metastatic disease show stable disease or partial remission in many patients treated at the lower dosage, and stable disease and partial or complete remission in many patients treated at the higher dosage.
• the present invention provides an improved formulation for lipophilic drug agents that are only slightly soluble in an aqueous vehicle.
• the formulation in addition to the lipophilic drug agent includes a lipophilic antioxidant, a non-ionic solubilizer or surfactant, and optionally, an agent which is an organic solvent/ preservative.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Neurosurgery (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Diabetes (AREA)
• Dermatology (AREA)
• Endocrinology (AREA)
• Pain & Pain Management (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Hematology (AREA)
• Psychiatry (AREA)
• Reproductive Health (AREA)
• Rheumatology (AREA)
• Urology & Nephrology (AREA)
• Obesity (AREA)
• Anesthesiology (AREA)
• Nutrition Science (AREA)
• Virology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (8)

Applications Claiming Priority (2)

Publications (2)

Family

ID=31992558

Family Applications (1)

Country Status (11)

Cited By (3)

Families Citing this family (83)

Family Cites Families (143)

• 2002
  • 2002-09-18 US US10/247,765 patent/US7148211B2/en not_active Expired - Lifetime
• 2003
  • 2003-09-10 KR KR1020057004755A patent/KR101089049B1/ko not_active Expired - Fee Related
  • 2003-09-10 BR BR0314354-6A patent/BR0314354A/pt not_active IP Right Cessation
  • 2003-09-10 CA CA002498331A patent/CA2498331A1/en not_active Abandoned
  • 2003-09-10 CN CNB038222035A patent/CN100349573C/zh not_active Expired - Fee Related
  • 2003-09-10 JP JP2004537767A patent/JP5137293B2/ja not_active Expired - Fee Related
  • 2003-09-10 MX MXPA05002814A patent/MXPA05002814A/es active IP Right Grant
  • 2003-09-10 EP EP03749606A patent/EP1553956A4/en not_active Withdrawn
  • 2003-09-10 AU AU2003267131A patent/AU2003267131B2/en not_active Ceased
  • 2003-09-10 WO PCT/US2003/028499 patent/WO2004026231A2/en not_active Ceased
• 2005
  • 2005-03-08 IL IL167309A patent/IL167309A/en unknown
• 2006
  • 2006-04-20 US US11/379,423 patent/US20060183722A1/en not_active Abandoned
• 2009
  • 2009-09-03 US US12/553,547 patent/US20100197641A1/en not_active Abandoned
• 2011
  • 2011-08-22 US US13/214,461 patent/US20120214773A1/en not_active Abandoned

Also Published As

Similar Documents

Legal Events