US20040082565A1 - Formulations and methods of administration of cephalotaxines including homoharringtonine - Google Patents

Formulations and methods of administration of cephalotaxines including homoharringtonine Download PDF

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US20040082565A1
US20040082565A1 US10/617,927 US61792703A US2004082565A1 US 20040082565 A1 US20040082565 A1 US 20040082565A1 US 61792703 A US61792703 A US 61792703A US 2004082565 A1 US2004082565 A1 US 2004082565A1
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solution
contacting
homoharringtonine
hht
extraction mixture
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Dennis Brown
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Teva Pharmaceuticals International GmbH
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ChemGenex Therapeutics Inc
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Priority to US10/617,927 priority Critical patent/US20040082565A1/en
Assigned to CHEMGENEX THERAPEUTICS, INC. reassignment CHEMGENEX THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BROWN, DENNIS M.
Publication of US20040082565A1 publication Critical patent/US20040082565A1/en
Assigned to CHEMGENEX PHARMACEUTICALS, INC. reassignment CHEMGENEX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BROWN, DENNIS M.
Priority to US11/497,739 priority patent/US7683050B2/en
Priority to US12/698,367 priority patent/US20110009388A1/en
Priority to US13/294,776 priority patent/US20120058991A1/en
Priority to US15/596,940 priority patent/US20170319640A1/en
Assigned to TEVA PHARMACEUTICALS INTERNATIONAL GMBH reassignment TEVA PHARMACEUTICALS INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEMGENEX PHARMACEUTICALS PTY LTD, CHEMGENEX PHARMACEUTICALS LIMITED, CHEMGENEX PHARMACEUTICALS, INC.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/13—Coniferophyta (gymnosperms)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention is directed to compositions and methods for the treatment of patients with cephalotaxines, for example, homoharringtonine.
  • cephalotaxines for example, homoharringtonine.
  • the invention is also directed to improvements in the purity, manufacturing process, formulation and administration of homoharringtonine for the treatment of cancer and other aberrant cellular diseases.
  • the invention also provides methods and compositions for antiparasitic, antifungal, antiviral and antibacterial treatments.
  • Cephalotaxanes are alkaloids extracted from skins, stems, leaves and seeds of Cephalotaxus fortunei Hook and other related species, such as Cepholotaxus sinensis Li, C. hainanensis and C. wilsoniana , including C. oliveri mast and C. harringtonia .
  • Cephalotaxanes exhibit a unique structure, as shown in FIG. 1. Although cephalotaxine (wherein X in FIG. 1 is —OH) is abundant in C. harringtonia , it is devoid of biological activity. The presence of an ester side chain at C-3 appears to be critical to the antitumor potency.
  • HHT Homoharringtonine (4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl), “HHT”) is the butanediocate ester of cephalotaxine. HHT is a naturally occurring cephalotaxine compound and has the structure shown in FIG. 2.
  • HHT can be chemically synthesized with purity greater than 99.8% and total related impurity less than 0.5% (see L. Keller, et. al., Tetrahed. Lett., 42, 1911-1913 (2001)); international publication WO 02/32904 A1). Although at least 50% of Cephalotaxus alkaloids are cephalotaxine, the use of cephalotaxine as a source for semi-synthesis of HHT has not yet been economically justified.
  • HHT can also be prepared from cultured cells of C. harringtonia (U.S. Pat. No. 4,152,214).
  • whole plant-derived HHT has been clinically tested in various cancers including a number of forms of leukemia and preleukemic conditions, such as myelodysplastic syndrome (MDS).
  • MDS myelodysplastic syndrome
  • HHT derived from whole plants has been widely used in China as the front-line chemotherapy for acute myeloid leukemias, particularly acute promyelocytic leukemia (APL).
  • APL acute promyelocytic leukemia
  • HHT has dose-limiting toxicities, including myelosuppression, cardiotoxicity, and hypotension. Therefore, it is highly desirable to improve the dosage form of the drug, dosage amounts, and schedule of administration. Thus, improvements are sought to improve efficacy, reduce side effects, improve quality of life and increase survival of patients.
  • HHT For naturally occurring products like HHT, it is desirable to increase the purity of HHT preparations away from related analogs, as well as reduce or eliminate additives, preservatives or excipients used to make the agent more pharmaceutically acceptable. More purified preparations will reduced physiologic stresses arising from the metabolic processing of or physiological responses to unwanted impurities and undesirable excipients.
  • additives such as sodium bisulfite, used as an antioxidant in pharmaceutical preparations, are known to cause allergic or hypersensitivity reactions in some patients. This also occurs for pharmaceutical diluents such as cremophor EL.
  • mannitol a pharmaceutical excipient, can cause hypotension for some patients.
  • An object of the present invention was to provide a stable, therapeutically acceptable, intravenously injectable dosage form of HHT that does not require lyophilization and reconstitution, and that can be packaged and shipped as a single vial instead of a dual-vial package.
  • the invention described herein encompasses a method for the manufacture of homoharringtonine in scale suitable for pharmaceutical product development.
  • a pharmaceutical composition which comprises a therapeutically amount of HHT purified from the natural plant according to methods described herein, is provided.
  • the invention allows for the use of HHT as a soluble liquid dosage form, stable at room temperature for over two years in a convenient form for further dilution prior to administration to patients.
  • the liquid dosage form is further diluted for intravenous administration in dosages ranging from 1 to 5 mg/m 2 as an infusion. Administration is intermittent or continuous for 1 to 21 days per month.
  • compositions and methods are designed for improved therapeutic benefit for patients suffering with drug sensitive disease conditions, for example, cancer, for example, leukemias, preleukemia conditions or other hyperproliferative or aberrant cellular conditions.
  • drug sensitive disease conditions for example, cancer, for example, leukemias, preleukemia conditions or other hyperproliferative or aberrant cellular conditions.
  • One aspect of the invention is a process for producing homoharringtonine.
  • the process comprises
  • the contacting of step a) is for at least 48 hours.
  • the adjusting of step b) is to pH 8.5.
  • the process of the invention may further comprise concentrating the extraction mixture of step b) under reduced pressure, contacting the concentrated extraction mixture with citric acid, extracting the concentrated extraction mixture with chloroform, and adjusting the pH of the concentrated extraction mixture to between about 5 and 8.
  • the contacting of step h) is at a temperature between 4° C. and 10° C. According to another aspect, the contacting of step h) is for at least 16 hours.
  • the homoharringtonine produced by the claimed method is at least 98% pure. According to a preferred embodiment, the homoharringtonine produced by the claimed method is at least 99% pure.
  • homoharringtonine produced by the claimed method is dissolved in water or buffered saline without pharmaceutical excipients.
  • compositions obtained by the process of the invention do not include mannitol. According to another aspect, the compositions do not require lyophilization to create a pharmaceutically acceptable dosage form.
  • the method of treatment includes administering a composition of the invention by intravenous administration for 5 to 25 days per month.
  • the method of treatment includes administering the compositions of the invention by a non-intravenous route.
  • the non-intravenous route is intramuscular, subcutaneous, oral or intraocular administration.
  • the composition of the invention can alternatively be administered as a depot.
  • aqueous solutions of HHT are also included in the invention.
  • an aqueous solution of HHT which is stable, is in a unit dosage form, and is suitable for administration by injection, is covered by the present invention.
  • the aqueous solution in some aspects, has a concentration between 0.1 and 50 mg/mL HHT. According to other aspects, the HHT concentration is between 1 and 5 mg/mL.
  • the aqueous solution preferably has a pH at between about 3.0 and 5.0. According to other aspects, the aqueous solution has a pH of about 4.0.
  • the aqueous solution is, in some aspects, provided in a sealed container.
  • the method comprises contacting a host with a cephalotaxine in an amount sufficient to modulate the aberrant cellular condition.
  • the contacting occurs for at least 5 consecutive days.
  • the cephalotaxine is homoharringtonine.
  • the aberrant cellular condition in some aspects, is cancer, leukemia, a preleukimic condition, or myelodysplastic syndrome.
  • the homoharringtonine is administered by infusion in a dose between 1 and 5 mg/m 2 .
  • FIG. 1 depicts the general structure of a cephalotaxane.
  • the X at position 3 is a substituent group, examples of which are shown in Table I.
  • FIG. 2 depicts the structure of homoharringtonine (4-methyl-2-hydroxy-2-(4-hydroxy-4-methylpentyl), “HHT”).
  • Homoharringtonine is extracted from Cephalotaxus fortunei Hook, f and other related species.
  • the process comprises extraction with citric acid or 90% ethanol, pH is then adjusted to alkaline range (pH 8.5-9.5) with ammonia or sodium carbonate.
  • the solution is extracted with chloroform, and the chloroform is then removed under reduced pressure.
  • the dried material is dissolved in citric acid and extracted with chloroform at gradient pH range, e.g. pH 5-7.
  • the purified material is passed through liquid chromatography column packed with silica gel and monitored by TLC. The resulting mixture is separated by countercurrent distribution with chloroform and pH 5 buffer or tartaric acid. After removal of chloroform, the material is recrystallized from methanol.
  • the employed process results HHT with yield about 0.002%, at least 98% pure with individual impurities less than 0.8% in concentration.
  • compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • HHT can be delivered via drug delivery devices such as cellulose acetate membranes, osmotic pump, and the like, also through target delivery system such as liposomes.
  • drug delivery devices such as cellulose acetate membranes, osmotic pump, and the like
  • target delivery system such as liposomes.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • tablets and capsules represent a particularly advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • inactive ingredients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used.
  • Previous HHT dosage forms have required a lyophilized preparation containing mannitol as an excipient to improve the lyophilization process, stability, reconstitution characteristics, dosage form homogeneity and solubility.
  • a stable, sterile, aqueous solution of HHT in a sealed container for example, an ampoule or vial.
  • the solution is provided in unit dosage form suitable intravenous administration.
  • the solution has a concentration of HHT between about 0.1 and about 10 mg/mL.
  • the solution has a concentration of HHT of about 1 mg/mL.
  • the solution has a pH at between 3.0 and 5.0. More preferably, the solution has a pH of about 4.0.
  • the HHT solution is free of any other added chemicals. “Free of other added chemicals” means that the solution consists of HHT as purified according to the methods of the invention, dissolved in water.
  • the HHT solution also contains a customary, physiologically acceptable excipient or carrier, for example, a preservative or buffer.
  • the HHT solution is preferably a stable solution.
  • a “stable” solution is one that exhibits less than 5% loss of potency as measured by high performance liquid chromatography (HPLC) upon storage for 7 weeks at 60° C.
  • HPLC high performance liquid chromatography
  • a “stable” solution is stable at room temperature for periods of at least one year such that the active compound does not degrade by more than 5% within that time period.
  • the HHT solution is provided in a suitable dosage with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the HHT solution for intravenous injection or infusion is provided in combination with one or more chemotherapeutic drugs.
  • the liquid dosage form may range from less than 1 mg/mL of diluent to greater than 1 mg/mL including from less than 0.1 mg/ml to soluble concentrations greater than 1 mg/ml with appropriate adjustment of pH with buffers such as tartrate, phosphate, citrate, carbonate, etc. in ranges common or standard in pharmaceutical practice.
  • the drug dose can be introduced subcutaneously, for example, as a depot administration, where an intravenous administration is less advantageous.
  • a depot administration is utilized in concentrations where drug particles are employed to dissolve slowly for sustained drug release.
  • a liquid dosage form, a buffered water soluble form without pharmaceutical excipients such as mannitol are infused over a duration of days preferably between 5 and 25 days per month 5 more preferably between 7 and 21 days utilizing dosages between 1 and 5 mg/m 2 , preferably between about 2 and 4 mg/m 2 .
  • anti-proliferative effects are achieved in patients suffering from cancer, including leukemia including acute promyelocytic leukemia (APL), acute mycloid leukemia (AML) and chronic myeloid leukemia (CML) and preleukemia conditions including myelodysplastic syndrome or patients with other hyperproliferative aberrant cellular conditions through administration of HHT produced as a liquid dosage form, stable at room temperature of at least 98% purity dissolved in buffered water or saline without excipients such as mannitol administered by infusion to patient for a duration of 5 days or greater.
  • the dosage form can be administered with other chemotherapeutics such as antineoplastics including Gleevec, interferon, retinoic acids and the like.
  • the agents are provided in amounts sufficient to modulate aberrant cellular conditions such as solid cancers, leukemias, pre-leukemia conditions such as myelodysplastic syndrome, lymphomas and other aberrant hyperproliferative conditions.
  • modulation of an aberrant cellular condition comprises a reduction in tumor cell number or growth.
  • modulation of an aberrant cellular condition comprises inhibition of cell division and tumor cell growth.
  • modulation of an aberrant cellular condition comprises cytostasis.
  • specific dosages, blood concentrations are delivered to the patient to affect cellular targets or enzymes unique to the actions of the compounds such as enzymes like telomerase, histone deacetylase or cellular targets such as histones, G protein coupled receptors and the like.
  • modulation of an aberrant cellular condition comprises cytostasis or cytotoxicity.
  • Cytostasis is the inhibition of cells from growing, while “cytotoxicity” is defined as the killing of cells.
  • a therapeutically effective dose of the compositions of the invention are administered to a patient in need of treatment.
  • therapeutically effective dose herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, as well as the age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.
  • a “patient” for the purposes of the present invention includes both humans and other animals, particularly mammals. Thus, the methods are applicable to both human therapy and veterinary applications. In the preferred embodiment the patient is a mammal, and in the most preferred embodiment the patient is human.
  • treatment in the instant invention is meant to include therapeutic treatment, as well as prophylactic, or suppressive measures for the disease or disorder.
  • successful administration of composition of the invention prior to onset of the disease results in “treatment” of the disease.
  • successful administration of HHT after clinical manifestation of the disease to combat the symptoms of the disease comprises “treatment” of the disease.
  • Treatment also encompasses administration of HHT after the appearance of the disease in order to eradicate the disease.
  • Successful administration of an agent after onset and after clinical symptoms has been developed, with possible abatement of clinical symptoms and perhaps amelioration of the disease, comprises “treatment” of the disease.
  • Those “in need of treatment” include mammals already having the disease or disorder, as well as those prone to having the disease or disorder, including those in which the disease or disorder is to be prevented.
  • the portions containing HHT is dried, then dissolved in 5 times volume of chloroform and extracted 4 times with tartaric acid. After removal of chloroform, the dried material is dissolved in methanol and precipitated at 4-10° C. for about 16 hours. The methanol/water mixture (1:2) is filtered, rinsed and dried. The crystallization step is repeated until the color is changed from dark reddish brown to canary. Then, the crystal is crystallized in methanol and discolored with activated carbon. The recrystallization step is repeated several times until the color changed to off-white.
  • the purified material is dried under vacuum at 40-60° C. for 7 days.
  • the process if the invention can produce the homoharringtonine with a typical yield of about 0.05 g homoharringtonine per kg of Cephalotaxus fortunei Hook, f, and with a purity of greater than 99%.
  • Liquid form is less expensive. Lyophilization is an expensive manufacturing process (equipment, time, energy, etc.).
  • Liquid form requires less packaging. Lyophilized product requires dual vial packaging, containing lyophilized vial and diluent vial, extra manufacturing, packaging and labeling costs, and extra room for storage, shipping.
  • Liquid form preparation involves less time, expense, waste and risk. More preparation steps are required for a lyophilized product, more hazardous waste is generated, and risks associated with contamination and safety are increased.
  • HHT is chromatographed on a reverse-phase isocratic HPLC system employing a mobile phase consisting of 24% of acetonitrile and 76% acetic acid (pH adjusted to 6.5 with 0.5% triethyleneamine) with a Keystone BDS Hypersil 5- ⁇ m C18 column. Detection is achieved by monitoring the UV absorbance at 288 nm and quantification is accomplished by peak area measurement with external calibration. Specificity; linearity, precision and accuracy have been demonstrated.
  • This method is applicable to bulk powder and liquid dosage formulations.
  • the liquid or lyophilized dosage forms can be administered by intravenous infusion by adding the drug product in diluent including, but not limited to, Sterile Water for Injection, Bacteriostatic Water for Injection, Dextrose (2.5%, 5%, 10%), Dextrose-saline combination, Fructose (10%), Fructose in saline, Ringer's Injection, Lactated Ringer's Injection, Sodium Chloride (0.45%, 0.9%) or combination with one or more additional drugs.
  • diluent including, but not limited to, Sterile Water for Injection, Bacteriostatic Water for Injection, Dextrose (2.5%, 5%, 10%), Dextrose-saline combination, Fructose (10%), Fructose in saline, Ringer's Injection, Lactated Ringer's Injection, Sodium Chloride (0.45%, 0.9%) or combination with one or more additional drugs.
  • step 8 Use other acid solution (e.g. hydrochloric acid, acetic acid) in step 8 to replace tartaric acid.
  • acid solution e.g. hydrochloric acid, acetic acid
US10/617,927 2002-07-17 2003-07-10 Formulations and methods of administration of cephalotaxines including homoharringtonine Abandoned US20040082565A1 (en)

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Application Number Priority Date Filing Date Title
US10/617,927 US20040082565A1 (en) 2002-07-17 2003-07-10 Formulations and methods of administration of cephalotaxines including homoharringtonine
US11/497,739 US7683050B2 (en) 2002-07-17 2006-08-01 Formulations and methods of administration of cephalotaxines, including homoharringtonine
US12/698,367 US20110009388A1 (en) 2002-07-17 2010-02-02 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US13/294,776 US20120058991A1 (en) 2002-07-17 2011-11-11 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US15/596,940 US20170319640A1 (en) 2002-07-17 2017-05-16 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine

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US10/617,927 US20040082565A1 (en) 2002-07-17 2003-07-10 Formulations and methods of administration of cephalotaxines including homoharringtonine

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US11/497,739 Expired - Fee Related US7683050B2 (en) 2002-07-17 2006-08-01 Formulations and methods of administration of cephalotaxines, including homoharringtonine
US12/698,367 Abandoned US20110009388A1 (en) 2002-07-17 2010-02-02 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US13/294,776 Abandoned US20120058991A1 (en) 2002-07-17 2011-11-11 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
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US12/698,367 Abandoned US20110009388A1 (en) 2002-07-17 2010-02-02 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US13/294,776 Abandoned US20120058991A1 (en) 2002-07-17 2011-11-11 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine
US15/596,940 Abandoned US20170319640A1 (en) 2002-07-17 2017-05-16 Formulations and Methods of Administration of Cephalotaxines, Including Homoharringtonine

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Cited By (10)

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US20040186095A1 (en) * 2001-03-21 2004-09-23 Jean-Pierre Robin Highly purified and crystalline form of harringtonines their process of preparation by purification of crude alkaloids from natural synthetic or semi-synthetic sources allowing their use for blending in pharmaceutical composition particularly useful for treatment of cancer in using oral mode of administration
US20050090484A1 (en) * 1998-03-20 2005-04-28 Jean-Pierre Robin Cephalotaxane derivatives and their processes of preparation and purification
US20050142214A1 (en) * 2000-04-12 2005-06-30 Chemgenex Therapeutics, Inc. Naphthalimide compositions and uses thereof
US20050170015A1 (en) * 2000-10-31 2005-08-04 Brown Dennis M. Antiproliferative colchicine compositions and uses thereof
US20050288310A1 (en) * 2004-06-04 2005-12-29 Chemgenex Pharmaceuticals, Inc. Methods of treating cellular proliferative disease using naphthalimide and PARP-1 inhibitors
US20060193893A1 (en) * 2005-02-10 2006-08-31 Chemgenex Pharmaceuticals, Inc. Medical devices
US20060211648A1 (en) * 2000-04-12 2006-09-21 Chemgenex Pharmaceuticals, Inc. Naphthalimide compositions and uses thereof
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US20100240887A1 (en) * 2009-03-23 2010-09-23 Yaguang Liu New methods of producing HHT
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US7683050B2 (en) 2010-03-23
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US20110009388A1 (en) 2011-01-13
EP1534295A4 (de) 2009-08-05
WO2004009092A1 (en) 2004-01-29
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CA2492456A1 (en) 2004-01-29

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