Classifications

• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to conjugates of fatty acids and anticancer agents useful in treating cancer, and compositions and formulations thereof. Methods for using the conjugates also are provided.
• Taxol paclitaxel
• Taxol ® paclitaxel was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the US Food and Drug Administration for treatment of metastatic ovarian cancer and later for breast cancer.
• Taxol induces expression of cytokines, affects the activity of kinases and blocks processes essential for metastasis, in as yet uncharacterized mechanisms of action.
• Taxol has attracted unusually strong scientific attention, not only because of its unique antiproliferative mechanism of action, but also because it is active against nearly all cancers against which it has been tested and because it has been discovered to be an analog of numerous closely related compounds occurring naturally. These compounds, taxanes, are now recognized as a new class of anticancer compounds.
• Taxol's strength against cancers of diverse tissue origin also represents a significant drawback.
• An ideal anticancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells. Taxol analogs with tissue specificity therefore are desired.
• Another drawback of Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including Cremophor ® EL (polyoxyethylated castor oil), which combination can provoke severe hypersensitive immune responses.
• Cremophor ® EL polyoxyethylated castor oil
• Taxol analogs In general with Taxol analogs, the solubility problems remain, and/or potency is sharply reduced, and/or selectivity is not improved, and/or the ratio of the median toxic dose to the median effective dose ("therapeutic index") is unacceptably reduced.
• Taxol has the following formula:
• Taxanes have the basic three ring structure (A, B and C), substituted or unsubstituted. Taxol' s carbons are numbered conventionally as follows:
• Taxol affects microtubule formation inside a cell, but a change in structure that increases intracellular activity may adversely affect the ability of Taxol to gain entry into a cell. Taxol also is known to bind to proteins, and the effect on activity that results from a change in Taxol's binding to protein (in terms of conformation, cellular absorption and solubility) is unknown.
• Taxol does not get into the brain, apparently excluded by the blood brain barrier. It is not known why this is so, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier.
• Taxotere ® docetaxel
• Taxotere differs from Taxol at sites which typically do not have a strong influence on activity, and one would not predict the improvements in Taxotere from these differences, even in hindsight.
• Taxotere has the following formula:
• DHA docosahexaenoic acid
• DHA is a 22 carbon naturally-occurring, unbranched fatty acid that previously has been shown to be unusually effective, when conjugated to a drug, in crossing the blood brain barrier.
• DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic).
• DHA is an important constituent of the brain and recently has been approved as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
• pipotiazine is a drug that acts within the central nervous system.
• the purpose of conjugating pipotiazine to the fatty acids was to create an oily solution of the drug as a liquid implant for slow release of the drug when injected intramuscularly. The release of the drug appeared to depend on the particular fatty acid selected, and the drug was tested for its activity in the central nervous system.
• Lipidic molecules including the fatty acids, also have been conjugated with drugs to render the conjugates more lipophilic than the drug.
• increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver.
• the type of lipidic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 4 carbon atoms to more than 30 carbon atoms.
• enhanced receptor binding activity was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with molecule interacted with the phospholipid membrane to act as a distal anchor for the receptor ligand in the membrane micro environment of the receptor.
• This increase in potency was not observed when the same lipid derivatives of adenosine receptor antagonists were used, and generalizations thus were not made possible by those studies.
• a fatty acid-anticancer compound conjugate appears to be confined, unexpectedly, to the plasma space of a subject receiving such treatment, and that the conjugate has, suprisingly, (i) a smaller volume of distribution as compared to the unconjugated anticancer compound alone (in many instances -100 fold less), and (ii) a smaller clearance as compared to the unconjugated anticancer compound alone (in many instances -100 fold less).
• the fatty acid-anticancer compound conjugate was present at a higher concentration in tumor cells as compared to the unconjugated anticancer compound.
• a fatty acid-anticancer compound conjugate composition for administration to a subject includes at least one fatty acid-anticancer compound conjugate in a container for administration to a subject.
• the amount of the fatty acid-anticancer compound in the container is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anti-cancer compound (based on the weight of the anticancer compound in the conjugate versus the weight of the anti- cancer compound itself, or calculated on a molar basis of the conjugate versus the unconjugated anti-cancer compound).
• MTD maximum tolerated dose
• the amount of the fatty acid-anticancer compound in the container is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300% greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anticancer compound.
• the container is a container for intravenous administration.
• the anticancer compound is a taxane, preferably paclitaxei or docetaxel.
• the conjugate is not encapsulated in a liposome.
• methods for treating a subject having an abnormal mammalian cell proliferative disorder include administering a composition including at least one fatty acid-anticancer compound conjugate to the subject in an amount which is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anticancer compound.
• MTD maximum tolerated dose
• the amount of the at least one fatty acid-anticancer compound administered is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300% greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anticancer compound.
• the anticancer compound is a taxane, preferably paclitaxei or docetaxel.
• the conjugate is not encapsulated in a liposome.
• kits for administration of a fatty acid-anticancer compound conjugate composition to a subject include a container containing a composition which includes at least one fatty acid-anticancer compound conjugate, and instructions for administering the at least one fatty acid-anticancer compound conjugate to subject in need of such treatment in an amount which is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anticancer compound.
• MTD maximum tolerated dose
• the subject has an abnormal mammalian cell proliferative disorder.
• the amount of the at least one fatty acid-anticancer compound conjugate to be administered is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300% greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anticancer compound.
• the container is a container for intravenous administration.
• the anticancer compound is a taxane, particularly paclitaxei or docetaxel.
• the conjugate is not encapsulated in a liposome.
• a method for increasing the therapeutic index of anticancer compounds in a subject includes conjugating a fatty acid to an anticancer compound to form a fatty acid-anticancer compound conjugate; and administering the fatty acid-anticancer compound conjugate to the subject.
• the therapeutic index of the anticancer compound thus administered is improved relative to non-conjugated formulations of the anticancer compound.
• the subject has an abnormal mammalian cell proliferative disorder, and the subject preferably is human.
• the anticancer compound is a taxane, preferably paclitaxei or docetaxel.
• the conjugate is not encapsulated in a liposome.
• methods for administering a fatty acid- anticancer compound conjugate to a subject in need of such treatment include infusing the conjugate in fewer than 3 hours.
• the conjugate is infused in 2 hours or less.
• the subject has an abnormal mammalian cell proliferative disorder, and the subject preferably is human.
• the anticancer compound is a taxane, preferably paclitaxei or docetaxel.
• the conjugate is not encapsulated in a liposome.
• it is preferred that a dose of a fatty acid-conjugated anticancer compound is administered which exceeds the maximum tolerated dose of the unconjugated anticancer compound.
• an injectable preparation of at least one fatty acid-taxane conjugate composition includes greater than about 6 mg/ml of the at least one fatty acid-taxane conjugate composition. Preferably, the preparation includes greater than about 7 mg/ml, 8 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml, 80 mg/ml, or 100 mg/ml of the at least one fatty acid-taxane conjugate composition.
• Preferred taxanes include paclitaxei and docetaxel.
• the invention also provides an injectable composition of at least one fatty acid-taxane conjugate which includes less than about 0J mg/ml of the at least one fatty acid-taxane conjugate.
• the composition includes less than about 0J75, 0J5, 0J25, 0.2, 0J5, or 0J mg/ml of the at least one fatty acid-taxane conjugate.
• Preferred taxanes include paclitaxei and docetaxel.
• fatty acid-taxane conjugate compositions include an amount of at least one fatty acid-taxane conjugate greater than about 6 mg/ml.
• the compositions also include a surfactant.
• the compositions include greater than about 7 mg/ml, 8 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml, 80 mg/ml, or 100 mg/ml of the at least one fatty acid-taxane conjugate.
• Preferred taxanes include paclitaxei and docetaxel.
• the surfactant in the fatty acid-taxane conjugate compositions is
• Cremophor EL or EL-P Preferably the concentration of Cremophor is between about 9.6% and about 49.7% (vol/vol).
• other fatty acid-taxane conjugate compositions are provided.
• the compositions include at least about 37 mg/ml of at least one fatty acid-taxane conjugate.
• the compositions include at least about 40 mg/ml, 50 mg/ml. 60 mg/ml, 80 mg/ml, or 100 mg/ml of the at least one fatty acid-taxane conjugate.
• the taxane is paclitaxei or docetaxel.
• fatty acid-taxane conjugate compositions which have certain ratios between the amount of the fatty acid-taxane conjugates and volume of surfactant.
• the compositions include at least one fatty acid-taxane conjugate and a surfactant; the ratio of the weight of the at least one fatty acid-taxane conjugate and volume of the surfactant is at least about 50 mg/ml.
• the ratio of the weight of the at least one fatty acid-taxane conjugate and volume of the surfactant is at least about 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, or 100 mg/ml.
• the preferred surfactants include Cremophor EL and EL-P, and the preferred taxanes include paclitaxei or docetaxel.
• the compositions include a solvent, preferably ethanol; the preferred ratio of surfactant to solvent is about 1 : 1.
• fatty acid-taxane conjugate compositions are provided which have certain ratios between the amount of the fatty acid-taxane conjugate and volume of solvent.
• the compositions include at least one fatty acid-taxane conjugate and a solvent; the ratio of the weight of the at least one fatty acid-taxane conjugate and volume of the solvent is at least about 42 mg/ml.
• the ratio of the weight of the at least one fatty acid- taxane conjugate and volume of the solvent is at least about 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, or 100 mg/ml.
• the preferred solvents include ethanol, and the preferred taxanes include paclitaxei or docetaxel.
• the compositions include a surfactant, preferably Cremophor EL of EL-P; the preferred ratio of surfactant to solvent is about 1 :1.
• compositions of fatty acid-taxane conjugates which include solvent and surfactant are provided.
• the compositions include between about 7 and about 120 milligrams of a fatty acid-taxane conjugate, between about 40% and 100%) of solvent, and between about 1% and about 60% surfactant.
• the compositions include between about 20 mg and about 120 mg of a fatty acid-taxane conjugate, between about 40% and 100% of solvent, and between about 1 % and about 60% surfactant. More preferably, compositions include between about 35 mg and about 45 milligrams of a fatty acid-taxane conjugate, between about 45% and about 55% of solvent, and between about 45% and about 55%) surfactant.
• the compositions include between about 6 mg and about 20 milligrams of a fatty acid-taxane conjugate, between about 5% and about 15% of solvent, and between about 5% and about 15% surfactant, or between about 6 mg and about 12 milligrams of a fatty acid-taxane conjugate, between about 8% and about 12% of solvent, and between about 8% and about 12% surfactant, or between about 1 mg and about 5 milligrams of a fatty acid-taxane conjugate, between about 1 % and about 10% of solvent, and between about 0.5% and about 4% surfactant.
• the solvent is ethanol and the surfactant is Cremophor EL or EL-P.
• the fatty acid is preferably a C8-C26 fatty acid. More preferably, the fatty acid is a C8-C26 unbranched, naturally occurring fatty acid. More preferably, the fatty acid is selected from the group consisting of C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 (palmitic acid). C16J (palmitoleic acid), C16J, C18:0 (stearic acid). C18J (oleic acid).
• C18J -7 (vaccenic), C18J-6 (linoleic acid), C18J-3 ( ⁇ -linolenic acid), C18J-5 (eleostearic), C18J-6 ( ⁇ - ⁇ nolenic acid), C18:4-3, C20J (gondoic acid).
• C20J-6 (vaccenic), C18J-6 (linoleic acid), C18J-3 ( ⁇ -linolenic acid), C18J-5 (eleostearic), C18J-6 ( ⁇ - ⁇ nolenic acid), C18:4-3, C20J (gondoic acid).
• C20J-6 (dihomo-y-hnolenic acid), C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (eicosapentaenoic acid), C22J (docosenoic acid), C22:4-6 (docosatetraenoic acid), C22:5-6 (docosapentaenoic acid), C22:5-3 (docosapentaenoic ), C22:6-3 (docosahexaenoic acid) and C24J-9 (nervonic). Particularly preferred is docosahexaenoic acid.
• ranges of doses, ratios, and amounts have been given.
• the ranges include the numbers specifically set forth as well as each and every number therebetween.
• an amount of a fatty acid-taxane conjugate is specified as "greater than about 6 mg/ml, 7 mg/ml, 8 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 40 mg/ml, 60 mg/ml, 80 mg/ml, 100 mg/ml”
• the range includes conjugates in the amounts of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, and so on including each number throughout the range.
• a method for treating a subject having an abnormal mammalian proliferative disorder involves administering to the subject a fatty acid-taxane conjugate in an amount of the conjugate which is at least 250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1 100, 1 150, 1200, 1250, 1300, 1350 or 1400 mg/meter 2 of body surface area (BSA).
• the amount is administered to the subject over a period of 24 hours or less, 6 hours or less, 3 hours or less, or 2 hours or less.
• the fatty acid is a C8-C26 fatty acid. In important embodiments, the fatty acid is a C16-C22 unbranched, naturally occurring fatty acid. In certain particularly preferred embodiments, the fatty acid can be linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, 2-octanoate, 2-hexanoate. CH hexanoate, CH butanoate, or oleic acid.
• the fatty acid is linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid.
• the taxane is paclitaxei. In important embodiments, when the taxane is paclitaxei. the fatty acid is conjugated at the 2' OH position of paclitaxei. In the most preferred embodiment, the fatty acid is docosahexaenoic acid.
• the Maximum Tolerated Dose can be determined according to procedures known to those of ordinary skill in the art.
• the Maximum Tolerated Doses of many compounds are already known. Some for known anti-cancer agents are listed below.
• a composition of matter comprises a crystal of a conjugate of a polyunsaturated C 16-26 fatty acid and a drug.
• the fatty acid is a C16-C22 fatty acid.
• the fatty acid is a naturally-occurring, unbranched fatty acid.
• the fatty acid can be linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, 2- octanoate, 2-hexanoate, CH 3 -hexanoate, CH,-butanoate, or oleic acid.
• the fatty acid is linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid.
• the polymorph of the crystal of docosahexaenoic acid-paclitaxel is described in the examples.
• the drug can be among those listed below.
• the drug must contain a site (reactive group) amenable for conjugation to a fatty acid.
• Chemists of ordinary skill in the art can make such determinations.
• Preferred catagories of drugs are anti-cancer agents, anti-viral agents and anti-psychotic agents.
• the anti-cancer compound can be a taxane.
• the taxane is paclitaxei.
• the fatty acid is conjugated at the 2' OH position of paclitaxei.
• the fatty acid is docosahexaenoic acid.
• a method for isolating a conjugate of a polyunsaturated C16-C22 fatty acid and a drug is provided.
• the method involves covalently conjugating the fatty acid and the drug to form the conjugate, forming a crystal of the conjugate, and isolating the crystal.
• the fatty acid is an oil at room temperature.
• the preferred fatty acids, drugs, anticancer compounds, and conjugates are as described above.
• a kit is provided.
• the kit comprises a package containing a first container housing a solution of a conjugate of a fatty acid and a taxane dissolved in a first solvent, a second container causing a mixture of a second solvent and a surfactant, the second solvent miscible with the first solvent, and instructions for combining the solution and the mixture.
• the first solvent is ethanol.
• the surfactant is cremophor.
• the second solvent is ethanol.
• the cremophor is present in a ratio to the second solvent of at least 1 : 1 , 2: 1 , 3 : 1 , or
• the preferred fatty acids, anticancer compounds, and conjugates are as described above.
• the concentration of the conjugate in the solvent is about 100 mg/ml.
• a pharmaceutical preparation comprises an intravenous solution of a conjugate of a C8-C26 fatty acid and a taxane, wherein the solution is substantially free of liposomes.
• Preferred fatty acids, anticancer compounds, and conjugates are as described above.
• a method for preparing an intravenous solution for administration to a subject having a mammalian cell proliferative disorder is provided.
• the method involves combining (a) a solution of a conjugate of a fatty acid and a taxane dissolved in a first solvent, and (b) a mixture of a second solvent and a surfactant, the second solvent miscible with the first solvent, and said combining resulting in a pre-mix, and adding the pre-mix to an intravenous solution.
• the first solvent is an alcohol, preferably ethanol.
• the surfactant is cremophor.
• the second solvent is an alcohol, preferably ethanol.
• the cremophor is present in a ratio to the second solvent of at least 1 :1, 2:1, 3:1, or 4:1.
• the preferred fatty acids, anticancer compounds, and conjugates are as described above. In particularly preferred embodiments, the concentration of the conjugate in the solvent is about 100 mg/ml.
• Figure 1 depicts a kit 11 comprising packaging 15, a first agent of the invention 17 (e.g., a container that contains TAXOPREXIN ® CONCENTRATE [ “Concentrate” ⁇ , a second agent of the invention 19 (e.g., a container that contains DILUENT FOR Taxoprexin ® Concentrate ["Diluent”]), and instructions 21, for utilizing such agents in therapeutic applications.
• a first agent of the invention 17 e.g., a container that contains TAXOPREXIN ® CONCENTRATE [ “Concentrate” ⁇
• a second agent of the invention 19 e.g., a container that contains DILUENT FOR Taxoprexin ® Concentrate ["Diluent”]
• instructions 21 for utilizing such agents in therapeutic applications.
• DHA docosahexaenoic acid
• DHA can be isolated, for example, from fish oil or can be chemically synthesized. These methods, however, can generate trans isomers. which are difficult and expensive to separate and which may present safety problems in humans.
• the preferred method of production is biological synthesis to produce the all cis isomer.
• the preferred source of DHA is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented system for manufacturing DHA using microalgae which synthesize only a single isomer of DHA, the all cis isomer. Martek's patents include U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397,591.
• DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DHA as a nutritional supplement for infant formula.
• DHA can be unstable in the presence of oxygen.
• vehicle 100 g propylene glycol. 70 mg ⁇ -tocopherol, 5 mg dialaurylthiodipropionic acid, 50 mg ascorbic acid
• anti-oxidants may also be employed: ascorbic acid, ascorbyl palmitate, dilauryl ascorbate, hydroquinone, butyated hydroxyanisole, sodium meta bisulfite, t-B carotene and ⁇ -tocopherol.
• a heavy metal chelator such as ethylenediamine tetra-acetic acid (EDTA) may also be used.
• Paclitaxei was first isolated from the bark of Taxus brevifolia (Wani et al, J. Am. Chem. Soc, 93, 2325, 1971). Its isolation and synthesis have been reported extensively in the literature. Applicants obtained paclitaxei from a commercial source, Hauser Laboratories, of Boulder, Colorado.
• the preferred compound of the invention, "TaxoprexinTM” is a covalent conjugate of DHA and paclitaxei. Its chemical structure, synthesis, purification and in vitro action are described in
• the MTD for any particular therapeutic compound may vary according to its formulation (e.g., injectable formulation, implantable bioerodible polymer formulation, oral formulation), route of delivery (e.g., intravenous, oral, intratumoral), manner of delivery (e.g., infusion, bolus injection), dosing schedule (e.g., hourly, daily, weekly) and the like.
• the MTD frequently is defined as the highest dose level at which 50% of subjects administered with the drug develop a dose limiting toxicity.
• the doses for anti- neoplastic pharmaceutical agents found in the Physicians Desk Reference (PDR) are defined as the MTD for those agents.
• the MTD is further defined to include only doses for drugs (including anti-neoplasties) used as single agents and without additional cellular, genetic, pharmaceutical, or other agents added to alter the MTD.
• drugs including anti-neoplasties
• Other definitions which are clinically relevant and generally accepted will be known to one of ordinary skill in the art.
• Measurement of maximum tolerated dose may be expressed as weight of drug per weight of subject, weight of drug per body surface area, etc.
• the MTD of anticancer compounds is frequently expressed as weight per square meters (mg/m 2 ) of body surface area.
• MTD for paclitaxei infusion in humans is 225 mg/m 2 .
• the most often used clinical tolerated dose is 175 mg/m 2 .
• MTD also may be expressed as a dose relative to a time component, such as weight of drug per body surface area per day.
• MTD For therapeutics which have not yet been subjected to human clinical trails, or subjected to any determination of the MTD in humans (e.g., experimental or highly toxic compounds), one of skill in the art can estimate the MTD by using animal models. Calculation of MTD in animals may be based on a number of physiological parameters, such as death, particular toxicities, drug induced weight loss. Using death as an endpoint, the MTD may be the dose given test animals in which each member of the test group survived. Using toxicity as an endpoint, the MTD may be the dose at which moderate but not severe toxicity is observed. Using weight loss as an endpoint, the MTD may be the dose above which a certain percent change in body weight is induced. Other methods for determining MTDs using animal models and various endpoints are known to one of ordinary skill in the art. Correlation of animal MTDs to human MTDs for a therapeutic compound is an accepted practice in the pharmaceutical arts.
• a conjugate of DHA and paclitaxei has a maximum tolerated dose in animals (mice, rats and dogs) which is about 4-5 times greater (by weight) than paclitaxei alone or about 3-4 times greater (by molarity) than paclitaxei alone.
• compositions and formulations for administration to a subject preferably a human subject, containing amounts of a fatty acid-anticancer compound conjugate which exceeds the maximum tolerated dose for the unconjugated anticancer compound.
• the fatty acid-anticancer compound conjugate preferably is in a container for administration to a subject.
• the container is a container for intravenous administration, such as an IV bag.
• the amount of the fatty acid-anticancer compound in the container is at least about 10% greater than the MTD for the unconjugated compound.
• the amount of the fatty acid- anticancer compound in the container is at least about 20%, 30%, 40%, 50%, 75%, 100%, 200%, 300% or 400%) greater than the MTD for the unconjugated at least one anticancer compound.
• the anticancer compound is preferably a taxane, particularly paclitaxei or docetaxel.
• compositions having an abnormal mammalian cell proliferative disorder are provided.
• Kits containing fatty acid-anticancer compounds in amounts also are provided.
• the kits contain one or more containers with the conjugated anticancer compound along with instructions for mixing, diluting and/or administering the anticancer compound in amounts greater than the MTD for the unconjugated anticancer compound.
• the kits also can include other containers with one or more solvents, surfactants, preservatives and/or diluents (e.g. normal saline (0.9% NaCl), or 5% dextrose (D5W)), as well as containers for mixing, diluting, and/or administering the conjugates to a subject in need of such treatment.
• a kit embodying features of the present invention, generally designated by the numeral 1 1, is illustrated in Figure 1.
• Kit 11 is comprised of the following major elements: packaging 15, a first agent of the invention 17 (e.g., a container that contains TAXOPREXIN ® CONCENTRATE [ “Concentrate” ⁇ ), a second agent of the invention 19 (e.g., a container that contains DILUENT FOR Taxoprexin ⁇ Concentrate [".Dt/wewt”]), and instructions 21 for utilizing such agents in therapeutic applications.
• a first agent of the invention 17 e.g., a container that contains TAXOPREXIN ® CONCENTRATE [ "Concentrate” ⁇
• a second agent of the invention 19 e.g., a container that contains DILUENT FOR Taxoprexin ⁇ Concentrate [".Dt/wewt”]
• instructions 21 for utilizing such agents in therapeutic applications.
• Individuals skilled in the art can readily modify packaging 15 to suit individual needs.
• the anticancer compounds in the kit may be provided as liquid solutions, or as dried powders.
• the powder When the compound provided is a dry powder, the powder may be reconstituted by the addition of a suitable solvent, which also may be provided.
• Liquid forms of the conjugates may be concentrated (for dilution prior to administration) or ready to administer to a subject.
• the solvent will depend on the drug and the mode of administration. Suitable solvents are well known for known drug compounds and are available in the literature.
• the therapeutic index is the ratio of the median toxic dose to the median effective dose. Conjugation of fatty acids to anticancer compounds to form a fatty acid-anticancer compound conjugate reduces toxicity of the anticancer compounds, and increases effectiveness as compared to the unconjugated anticancer compounds.
• the invention also provides methods for increasing the therapeutic index of anticancer compounds in a subject.
• the methods include conjugating a fatty acid to an anticancer compound to form a fatty acid-anticancer compound conjugate and administering the fatty acid-anticancer compound conjugate to the subject.
• the therapeutic index of the anticancer compound conjugate is improved relative to unconjugated formulations of the anticancer compound.
• the anticancer compound is a taxane, particularly paclitaxei or docetaxel.
• the conjugate may be encapsulated in a liposome, it is preferred that the conjugate is not encapsulated by a liposome.
• the preferred subjects for the method are humans.
• the conjugated anticancer compounds described herein are less toxic and more effective than the corresponding unconjugated anticancer compounds. Therefore the fatty acid-anticancer compound conjugates can be administered in amounts which are equally toxic but more effective, or in doses which are equally effective and less toxic than the corresponding unconjugated anticancer compounds. In general, conjugation of fatty acids to anticancer compounds permits an increase in the maximum tolerated dose relative to unconjugated anticancer compounds.
• the invention provides injectable preparations of at least one fatty acid-taxane conjugate composition.
• the injectable preparations are prepared for administration to a subject in need of treatment with a taxane, e.g., a subject having cancer.
• the injectable preparations contain higher concentrations of taxane derivatives than was previously thought possible.
• present infusion formulations of paclitaxei contain 0J mg/ml - 1J mg/ml diluted in aqueous solution. It has been found, su risingly, that taxane derivatives having a conjugated fatty acid, as disclosed herein, can be administered at much higher concentrations to subjects without the dose limiting toxicities observed with other taxane formulations.
• the injectable preparations have greater than about 6 mg/ml of the fatty acid-taxane conjugates described herein.
• the preparations contain greater than about 7 mg/ml, greater than about 8 mg/ml, greater than about 9 mg/ml, greater than about 10 mg/ml, greater than about 12 mg/ml, and so on.
• low-dose injectable preparations of taxanes having lower amounts of taxanes than the formulations presently used clinically are also provided.
• the surprisingly increased activity of fatty acid-taxane conjugates relative to unconjugated taxanes permits administration of lesser amounts while obtaining the same anticancer activity.
• injectable preparations having less than 0.3 mg/ml are provided, which formulations have anticancer acitivity when administered to a subject with cancer.
• the low-dose injectable preparations contain less than about 0J5 mg/ml, less than about 0J mg/ml, less than about 0J5 mg/ml. less than about 0J mg/ml, and so on.
• compositions which have still higher amounts of fatty acid-taxane conjugates.
• the compositions contain greater than about 6 mg/ml of at least one fatty acid-taxane conjugate and a surfactant.
• the compositions contain greater that about 7 mg/ml, greater that about 8 mg/ml, greater that about 9 mg/ml, greater that about 10 mg/ml, greater that about 12 mg/ml, and so on.
• the compositions include at least about 37 mg/ml of at least one fatty acid-taxane conjugate.
• compositions contain at least about 40 mg/ml, at least about 50 mg/ml, at least about 60 mg/ml, at least about 80 mg/ml, and at least about 100 mg/ml of at least one fatty acid-taxane conjugate.
• compositions may be encapsulated by liposomes, according to standard procedures for preparation of liposomes, but preferably are not. All of the compositions herein which contain taxanes or other anticancer compounds optionally can contain additional anticancer compounds.
• the compositions also can contain other components useful in formulating anticancer compounds for administration to humans, including surfactants, solvents, preservatives, diluents, and the like, all of which are standard in the pharmaceutical arts.
• Suitable surfactants for use with the present invention include nonionic agents, such as long-chain fatty acids and their water-insoluble derivatives.
• fatty alcohols such as lauryl cetyl and stearyl alcohol, glyceryl esters such as the naturally occurring mono-, di- and triglycerides, and fatty acid esters of fatty alcohols, such as propylene glycol.
• polyethylene glycol, sorbitan, sucrose and cholesterol Also useful are compounds that are those that have polyoxyethylene groups added through an ether linkage with an alcohol group.
• Compounds that are particularly useful in the present invention include the polyoxyethylene sorbitan fatty acid esters and polyoxyethylene glycerol and steroidal esters.
• Particularly preferred surfactants are
• Cremophor ® EL and Cremophor ® EL-P which are polyoxyethylated castor oil surfactants.
• surfactants may be used to solubilize the compositions described herein.
• polysorbate 80, polysorbate 20, sodium laurate, sodium oleate, and sorbitan monooleate may be useful in context of the present invention.
• Anionic surfactants may also be useful in the practice of the present invention. Examples of these include, but are not limited to, sodium cholate, sodium lauryl sulfate. sodium deoxycholate, sodium laurate, sodium oleate, and potassium laurate.
• dehydrated ethanol is used as a solvent for the compositions described herein.
• glycols such as propylene glycol or polyethylene glycol are within the scope of the invention.
• Simple complex polyols may also be suitable solvents.
• non-dehydrated alcohols may also be suitable within the scope of the present invention. It is recognized that the determination of a solvent and its proper concentration to fully solubilize the fatty acid-anticancer compositions is within the scope of a skilled artisan, and would not require undue experimentation.
• a conjugate of DHA and paclitaxei can be supplied at lOOmg/ml in EtOH.
• the concentrated conjugate can be diluted diluted 2:3 with a 4:1 Cremophor EL:EtOH surfactant/solvent mixture, resulting in an intermediate solution of 40 mg/ml DHA- paclitaxel in a Cremophor/ EtOH vehicle.
• This intermediate solution can be diluted 1 :5 into an injection vehicle such as normal saline 5% dextrose to give a final composition of 8 mg/ml DHA- paclitaxei in Cremophor/EtOH.
• Anti-cancer compounds include, but are not limited to, the following compounds and classes of compounds: Antineoplastic agents such as: Acivicin; Aclarubicin: Acodazole Hydrochloride; Acronine:
• Adozelesin Adriamycin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate;
• Aminoglutethimide Amsacrine; Anastrozole; Anthramycin; Asparaginase: Asperlin; Azacitidine:
• Crisnatol Mesylate Cyclophosphamide; Cytarabine; dacarbazine; DACA (N-[2-(Dimethyl- amino)ethyl]acridine-4-carboxamide); Dactinomycin; Daunorubicin Hydrochloride; Daunomycin; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate: Diaziquone; Docetaxel;
• Doxorubicin Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone
• Gemcitabine Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin Hydrochloride;
• Losoxantrone Hydrochloride Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride;
• Megestrol Acetate Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate;
• Mitomalcin Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride: Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxei; Pegaspargase; Peliomycin;
• Pentamustine Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone
• Procarbazine Hydrochloride Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine;
• Vinleurosine Sulfate Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole
• anti-neoplastic compounds include: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
• 10-hydroxy- camptothecin canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS) castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin
• UBC inhibitors UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zino statin stimalamer.
• Antiproliferative agent Piritrexim Isothionate.
• Antiprostatic hypertrophy Sitogluside.
• Benign prostatic hyperplasia therapy agent Tamsulosin Hydrochloride.
• Prostate growth inhibitor Pentomone.
• Radioactive agents Fibrinogen 1 125; Fludeoxyglucose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131 ; lobenguane I 123; lodipamide Sodium I 131 ; lodoantipyrine I 131 ; Iodocholesterol 1 131; Iodohippurate Sodium I 123; Iodohippurate Sodium I 125; Iodohippurate Sodium 1 131; Iodopyracet I 125; Iodopyracet 1 131; Iofetamine Hydrochloride I 123; Iomethin I 125; Iomethin I 131; Iothalamate Sodium I 125; Iothalamate Sodium I 131; lotyrosine 1 131 Liothyronine I 125; Liothyronine
• Tricyclic anti-depressant drugs e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline
• non-tricyclic anti-depressant drugs e.g., sertraline, trazodone and citalopram
• Ca " antagonists e.g., verapamil. nifedipine, nitrendipine and caroverine
• Calmodulin inhibitors e.g., prenylamine, trifluoroperazine and clomipramine
• Amphotericin B Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihypertensive drugs (e.g., reserpine); Thiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL.
• the compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
• Preferred anticancer agents include: gemcitabine (1000 mg/m 2 ); methotrexate (15 gm/m 2 i.v.+ leuco. ⁇ 500 mg/m 2 i.v. w/o leuco); 5-FU
• a taxane is a molecule that possesses a tricyclic carbon-atom connectivity network, which may incorporate carbon-carbon multiple bonds, and which through the involvement of carbon-atom-noncarbon-atom bonds may include substituents, functional groups, and additional rings.
• the structure of taxanes, as used herein, is shown in U.S. patent 5,795,909.
• a taxoid is a molecule structurally related to a taxane in which the above taxane carbon- atom connectivity network is altered, for example, by cleavage of one or more of the carbocyclic rings, by deletion or addition of carbon substituents, by connection of carbon atoms normally not bonded to each other, by disconnection of carbon atoms normally bonded to each other, or by some other reorganization of or adjustment to the taxane carbon-atom connectivity network, but in which one or more structural features characteristic of the taxane carbon-atom connectivity network are conserved.
• the compounds useful in the invention may be delivered in the form of anti-cancer cocktails.
• An anti-cancer cocktail is a mixture of any one of the compounds useful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s).
• another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s).
• the use of cocktails in the treatment of cancer is routine.
• a common administration vehicle e.g., pill, tablet, implant, injectable solution, etc.
• a common administration vehicle e.g., pill, tablet, implant, injectable solution, etc.
• the anti-cancer conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders other than cancer, including psoriasis, actinic keratosis, etc.
• compositions according to this aspect of the invention comprise substantially pure crystals of a conjugate of a fatty acid and a drug.
• the fatty acids are polyunsaturated fatty acids.
• the fatty acid is preferably a C16-C26 unbranched, naturally occurring fatty acid.
• the fatty acid can be selected from the group consisting of C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 (palmitic acid), C16:l (palmitoleic acid), C16J, C18:0 (stearic acid), C18J (oleic acid), C18J-7 (vaccenic), C18J-6 (linoleic acid), C18:3-3 ( ⁇ -linolenic acid), C18J-5 (eleostearic), C18J-6 ( ⁇ -linolenic acid), Cl 8:4-3, C20:l (gondoic acid), C20J-6, C20J-6 (dihomo-y-linolenic acid), C20:4-3, C20:4-6 (arachidonic acid), C20:5-3 (eicosap
• the fatty acid can be linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, 2-octanoate, 2-hexanoate, CH 3 -hexanoate, CH 3 -butanoate, or oleic acid.
• the fatty acid is linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid.
• the drug according to this aspect of the invention can be any drug that can form a conjugate with a fatty acid.
• the drug has free groups reactive with a free acid of the fatty acid. More preferably, the drug has a free -OH or -NH 2 group.
• Drugs include, but are not limited to, the following agents: adrenergic agent; adrenocortical steroid; adrenocortical suppressant; alcohol deterrent; aldosterone antagonist; amino acid; ammonia detoxicant; anabolic; analeptic; analgesic; androgen; anesthesia, adjunct to; anesthetic; anorectic; antagonist; anterior pituitary suppressant; anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic: anti-anginal; anti-anxiety; anti-arthritic; anti-asthmatic: anti-atherosclerotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; anticonvulsant; antidepressant; antidiabetic; antidiarrheal: antidiuretic; antidote
• Anti-infectives include Difloxacin Hydrochloride; Lauryl Isoquinolinium Bromide;
• Nitromersol Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;
• Anti-bacterials include: Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine;
• Amdinocillin Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin;
• Amikacin Sulfate Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate;
• Carbenicillin Potassium Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandole; Cefamandole
• Cefmenoxime Hydrochloride Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium;
• Cefotiam Hydrochloride Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil;
• Cefroxadine Cefsulodin Sodium; Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone
• Chlortetracycline Bisulfate Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin;
• Ciprofloxacin Hydrochloride Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride;
• Clindamycin Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate
• Demecycline Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Sodium;
• Dihydrostreptomycin Sulfate Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin;
• Fleroxacin Floxacillin; Fludalanine; Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Fusidic Acid;
• Gentamicin Sulfate Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium;
• Lincomycin Hydrochloride Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline; Meclocycline Sulfosahcylate; Megalomicin Potassium
• Methenamine Hippurate Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium;
• Minocycline Minocycline Hydrochloride
• Mirincamycin Hydrochloride Monensin
• Monensin Monensin
• Nifurpirinol Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin;
• Oxolinic Acid Oxytetracycline; Oxytetracycline Calcium; Oxytetracycline Hydrochloride;
• Penicillin V Penicillin V
• Penicillin V Benzathine Penicillin V Hydrabamine
• Penicillin V Potassium Penicillin V
• Pentizidone Sodium Phenyl Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium;
• Relomycin Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine;
• Rosaramicin Propionate Rosaramicin Sodium Phosphate
• Rosaramicin Stearate Rosaramicin Stearate
• Rosoxacin Rosaramicin
• Sulfadiazine Sodium Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine;
• Sulfamethizole Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole
• Talampicillin Hydrochloride Teicoplanin; Temafloxacin Hydrochloride; Temocillin; Tetracycline;
• Tetracycline Hydrochloride Tetracycline Phosphate Complex
• Tetroxoprim Thiamphenicol
• Thiphencillin Potassium Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin;
• Trimethoprim Trimethoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin
• Anti-virals include: Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine;
• Cidofovir Cipamfylline
• Cytarabine Hydrochloride Delavirdine Mesylate
• Desciclovir
• Ganciclovir Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine
• Zinviroxime and integrase inhibitors Zinviroxime and integrase inhibitors.
• Neurological agents including anti-psychotics, include, but are not limited to:
• Acetophenazine Maleate Alentemol Hydrobromide; Alpertine; Azaperone; Batelapine Maleate;
• Cinperene Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide; Clopipazan Mesylate;
• Fluspirilene Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol; Haloperidol
• Trifluperidol Triflupromazine; Triflupromazine Hydrochloride; Ziprasidone Hydrochloride;
• Benztropine Mesylate Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Carmantadine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide; Levodopa;
• Selegiline Hydrochloride Tolcapone; Trihexyphenidyl Hydrochloride; Felbamate; Loreclezole; Tolgabide; Adatanserin Hydrochloride: Adinazolam; Adinazolam Mesylate; Alaproclate;
• Aletamine Hydrochloride Amedalin Hydrochloride; Amitriptyline Hydrochloride; Amoxapine;
• Intriptyline Hydrochloride Iprindole; Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine; Maprotiline; Maprotiline Hydrochloride; Melitracen Hydrochloride;
• Nisoxetine Nitrafudam Hydrochloride
• Nomifensine Maleate Nortriptyline Hydrochloride
• Seproxetine Hydrochloride Sertraline Hydrochloride; Sibutramine Hydrochloride; Sulpiride;
• Viloxazine Hydrochloride Zimeldine Hydrochloride; Zometapine; Albutoin; Ameltolide; Atolide;
• Fluzinamide Fosphenytoin Sodium; Gabapentin; Ilepcimide; Lamotrigine;
• Preferred antipsychotics include: Lorazepam; chlordiazepoxide; clorazepate; diazepam; alprazolam; hydroxyzine; buspirone; venlafaxine; mephobarbital; meprobamate; doxepin; perphenazine; hydroxyzine pamoate; venlafaxine; mirtazapine; nefazodone; bupropion; phenelzine; tranylcypromine; citalopram; paraxefine; sertraline; amitrptyline; protriptyline; divalproex; clonazepam; clozapine; haloperidol; loxapine; molindone; thiothixene; pimozide; risperidone; quefiapine; thiothixen; olanzapine; quetiapine; prochlorperazine; mesoridazin;
• the compounds of the invention when used alone or in cocktails, are administered in therapeutically effective amounts.
• a therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor growth.
• the formulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients.
• the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
• Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric. maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic.
• pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
• Suitable buffering agents include: acetic acid and a salt (1-2% W/N); citric acid and a salt (1-3% W/N); boric acid and a salt (0.5-2.5% W/N); and phosphoric acid and a salt (0.8-2% W N).
• Suitable preservatives include benzalkonium chloride (0.003-0.03%) W/N); chlorobutanol
• the active compounds of the present invention may be a pharmaceutical composition having a therapeutically effective amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier.
• pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal.
• carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
• the components of the pharmaceutical compositions are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
• compositions suitable for parenteral administration conveniently comprise a sterile preparation of the conjugates of the invention.
• This preparation may be formulated according to known methods.
• Formulations for taxanes can be found in Chapter 9 of Taxol: Science and Applications. CRC Press, Inc., 2000 Corporate Boulevard, ⁇ .W., Boca Raton, FL 33431.
• Taxol has been formulated as a 6 mg/ml Cremophor EL® (polyoxyethylated castor oil)/ethanol mixture, which is diluted to final volume with normal saline or 5% dextrose.
• Cremophor EL® polyoxyethylated castor oil
• a 15mg/ml solution of Taxotere has been formulated in polysorbate 80 (polyoxyethylene sorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose. This is in contrast to the formulations described herein.
• the sterile preparation thus may be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono or di-glycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
• a subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.
• the conjugates of the invention are administered in effective amounts.
• An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated.
• an effective amount for treating cancer will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ.
• effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
• Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.
• daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/m 2 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
• Preferred dosing schedules, including concentration, length of administration, and the like are described herein elsewhere (see Examples). A variety of administration routes are available.
• the particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy.
• the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
• modes of administration include oral, rectal, sublingual, topical, nasal, transdermal, intradermal or parenteral routes.
• parenteral includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred for taxanes.
• compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
• Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound.
• Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
• Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician.
• Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like.
• a pump-based hardware delivery system can be used, some of which are adapted for implantation.
• a long-term sustained release implant also may be used.
• Long-term release as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days.
• Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting localized, high-doses of the compounds of the invention.
• TaxoprexinTM is a covalent conjugate of DHA and paclitaxei. Its chemical structure, synthesis, purification and in vitro action are described in U.S Patent 5,795,909, the entire disclosure of which is incorporated by reference herein. In addition, a crystalline form of this conjugate was obtained using the following protocol:
• the weight (W) of the chromatographically purified DNA-paclitaxel conjugate (obtained as described in U.S Patent 5,795,909) is recorded.
• the volume of water as calculated above is measured and added dropwise to the ethanol solution in the Erlenmeyer flask. Stirring is continued during the entire addition period. Even after the complete addition of the water, stirring is continued. The entire Erlenmeyer flask, including its mouth, are then covered with aluminum foil. Stirring is continued at room temperature for at least 4 hours. The crystallization start, stop and total crystallization times are recorded. If after 4-18 hours of stirring, crystal growth is not present, the Erlenmeyer flask may be placed in the refrigerator or a cold room for at least 24 hours.
• the contents of the Erlenmeyer flask are then filtered through a Buchner funnel equipped with a filter paper to an appropriately sized filter flask under vacuum (through a vacuum pump).
• the crystals collected are washed once with ice-cold ethanol (ethanol which has been previously placed at a below - 15 °C temperature for at least 1 hour), and washed once with ice-cold hexane (hexane previously placed at a below -15 °C temperature for at least 1 hour).
• ice-cold ethanol ethanol which has been previously placed at a below - 15 °C temperature for at least 1 hour
• ice-cold hexane hexane previously placed at a below -15 °C temperature for at least 1 hour.
• the crystals from the Buchner funnel are scraped out into a clean flask. The entire flask is covered with aluminum foil and is placed under high vacuum to dry the crystals for at least 24 hours. These crystals are then used as the source of a pure DHA-paclitaxel formulation.
• DHA-paclitaxel The active ingredient of Taxoprexin ®
• Example 1 the effects of taxoprexin and paclitaxei against M 109 lung carcinoma in mice.
• mice Syngeneic mice were injected with mouse lung tumor line M (Madison) 109 sub- cutaneously in the flank.
• M mouse lung tumor line
• Both drugs were dissolved in 10% cremophor EL/10% ethanol/80% saline.
• Tumor volume was estimated from tumor width and length. The results show that paclitaxei retarded tumor growth for about four days. In contrast, taxoprexin completely eliminated all measurable tumors in eight out of eight mice.
• Example 2 the effects of taxoprexin and paclitaxei against M 109 lung carcinoma in mice.
• Example 3 response of human NCI-H522 lung tumor to treatment with taxoprexin and paclitaxei in mice.
• the Southern Research Institute studied the anti-tumor activity of taxoprexin against human NCI-H522 lung tumor growing in nude mice.
• the tumors were implanted sub-cutaneously. Tumor mass was determined by calculation from tumor length and width.
• the drugs were dissolved in 12.5% cremophor EL/12.5% ethanol/75% saline and delivered i.v. into the tail vein, once a day for 5 days, from day 15 to 19 after tumor implantation.
• the results show that taxoprexin at 50 mg/kg/day x 5 days and paclitaxei at 20 mg/kg/day x 5 days eliminated all measurable tumors in 10/10 mice.
• Example 4 the pharmacokinetic parameters of taxoprexin and paclitaxei in rats.
• Taxoprexin has - 100 fold lower clearance rate and volume of distribution (see Table 1). Table 1.
• Example 5 plasma concentration of taxoprexin and paclitaxei in rats following IN. administrations of taxoprexin.
• Rats were given a 3 minute intravenous infusion of taxoprexin through the tail vein at 0 time.
• the drug was dissolved in 10% cremophor EL/10% ethanol/80% saline.
• the dose was 6.8 mg/kg.
• the concentrations in serum of both paclitaxei and taxoprexin as a function of time were measured in a reverse phase HPLC assay (see Table 2). Table 2.
• Taxoprexin ® plasma concentration (ng/ml) following administration of Taxoprexin ® in Rats
• Example 6 plasma and tumor concentrations of paclitaxei derived from an IN. dose of 50 mg/kg of taxoprexin to mice bearing M 109 or M 5076 tumors.
• mice with tumors derived from Ml 09 or M5076 were given a bolus does of taxoprexin through the tail vein at 0 time.
• the drug was dissolved in 10% cremophor EL/10% ethanol/80% saline. Mice were sacrificed and tumors immediately excised as a function of time after injecting the drug. Tumor tissue was homogenized and paclitaxei extracted. The concentration of paclitaxei was measured in a reverse phase HPLC assay. Blood was collected at the same time intervals and the amount of paclitaxei determined. The results show that after 24 hours the concentration of paclitaxei derived from taxoprexin is about 3 ⁇ M, 40 times higher than the plasma concentration,
• Paclitaxei has a t 1/2 of
• Example 7 dose comparisons (MTD and Est LD ⁇ ) of taxoprexin and paclitaxei in various animal species except humans.
• Dose comparisons for paclitaxei and taxoprexin were made in mice, rats and dogs.
• the maximum tolerated dose (MTD) for mice, rats and dogs were about 4-5 times higher for taxoprexin than for paclitaxei on a mg/kg basis, or 3-3.5 times higher on a molar paclitaxei equivalent basis.
• Dose limiting toxicity for rats and dogs is due to decreases in platelets, neutrophils and lymphocytes. Taxoprexin is less toxic to mice, rats and dogs than is paclitaxel(see
• taxoprexin thus appears to have a 100 fold lower clearance rate and volume of distribution than paclitaxei.
• EITHER 1) 8 mg PO at 12 hours prior and 8 mg PO at 6 hours prior,
• the first vial contains 200 mg of DHA-paclitaxel in ethanol at a concentration of 100 mg/mL
• the second vial, DILUENT FOR Taxoprexin ® Concentrate contains 30 mL of a 4 to 1 (volume to volume) mixture of Cremophor ® EL-P with ethanol. Prior to use, two (2) parts by volume of Concentrate are mixed with three (3) parts by volume of the
• DHA-paclitaxel Diluent in a sterile, dry, glass mixing bottle.
• the resulting "Preparation" of DHA-paclitaxel is then diluted into a standard IV infusion solution of 5% dextrose in water (D5 W) or normal sterile saline (NS).
• D5 W dextrose in water
• NS normal sterile saline
• the final concentration of DHA-paclitaxel in D5W or NS must be adjusted to be in the range of 0.8 to 8.0 mg/mL.
• TAXOPREXIN ® is dosed on a body surface area basis. It is important to determine the proper body surface area (BSA) for the patient's height and weight
• the appropriate number of vials of Concentrate are removed from the refrigerator.
• the vials are allowed to stand at room temperature for one (1) hour.
• Each vial is inspected to ensure that the solution is clear and free of crystals or particulates. If particulates are present, the vials are sonicated at room temperature for thirty (30) seconds and reinspected. If crystals are present or if particulates remain following sonication, the vials are discarded.
• the combined contents of the mixing bottle are gently rotated to assure complete mixing of the Concentrate and Diluent. This yields a premix Preparation concentration of 40 mg DHA- paclitaxel/mL. 7.
• the TAXOPREXIN ® premix Preparation (40 mg DHA-paclitaxel/mL) should be clear; however, there may be some foam on top of the solution due to the Cremophor® EL-P.
• the premix Preparation is allowed to stand for five (5) minutes until most of the foam dissipates prior to continuing the dilution process.
• the infusion solution is thoroughly mixed by manual rotation.
• TAXOPREXIN ® is inspected visually for particulate matter or discoloration prior to administration. If the TAXOPREXIN ® premix Preparation or infusion solution is not clear or appears to be precipitation, the solution should not be used.
• the TAXOPREXIN ® infusion solution is administered intravenously over a period of two (2) hours under ambient room temperature and lighting conditions.
• the rate of administration depends on the final volume of the final infusion solution, and a person of ordinary skill can easily determine such rate.
• Unopened vials of Taxoprexin ® CONCENTRATE are stored in a refrigerator at 2-8°C (36- 46°F), in their original package, to protect from light. Unopened vials of DILUENT for Taxoprexin ® Concentrate are stored in their original package at controlled room temperature ( 15- 30°C).
• TAXOPREXIN ® premix Preparation 40 mg DHA-paclitaxel/mL
• fully prepared TAXOPREXIN ® infusion solution in either D5W or NS, are (and must be) used within 24 hours following removal of the Taxoprexin ® CONCENTRATE vials from the refrigerator. Opened or premixed vials of TAXOPREXIN ® or TAXOPREXIN ® infusion solution must not be frozen or returned to a refrigerator. How Supplied:
• Taxoprexin ® CONCENTRATE is supplied as 2.0 mL of a non-aqueous solution in a sterile, pyrogen-free, single-dose vial.
• DILUENT for Taxoprexin ® CONCENTRATE (4:1 v/v mixture of Cremophor ® EL-P and ehtanol) is supplied as 30 mL of a sterile, pyrogen-free, single-dose vial.
• TAXOPREXIN ® infusion solution is stored in glass bottles and administered through a polyethylene-lined Omni-Flow nitroglycerine administration set using an Abbott No. 4524 in-line latex-free high-pressure filter with a 0J2 micron microporous membrane.
• TAXOPREXIN ® is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handlingand preparing TAXOPREXIN ® solutions.
• Example 8 the pharmacokinetic parameters of Taxoprexin ® in human subjects.
• DHA-paclitaxel has a small volume of distribution (-7 L). low clearance (-4 mL/min) and a long terminal half-life (-24 hours, -30% longer terminal t, /2 than paclitaxei alone).
• DHA-paclitaxel exposure increased with increasing doses of Taxoprexin ® DHA-paclitaxel
• Example 9 the pharmacokinetic parameters of paclitaxei following administration of Taxoprexin* in human subjects.
• C max maximum plasma concentration
• AUC area under the concentration-time curve
• Paclitaxei exposure represented ⁇ 1% of taxoprexin.
• paclitaxei plasma concentrations > 0.05 ⁇ M
• taxoprexin at 660 & 880 mg/m 2
• interpatient variability in paclitaxei exposure was -3 to 4-fold.
• Paclitaxei t I/2 appeared to be prolonged (mean ⁇ SD, 40 ⁇ 22 hrs) following treatment with taxoprexin.
• the time plasma concentrations remain above a threshold concentration may be related to neutropenia. All references disclosed herein are incorporated by reference.

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