[go: up one dir, main page]

WO2009089138A1 - Administration orale d'ixabépilone - Google Patents

Administration orale d'ixabépilone Download PDF

Info

Publication number
WO2009089138A1
WO2009089138A1 PCT/US2009/030085 US2009030085W WO2009089138A1 WO 2009089138 A1 WO2009089138 A1 WO 2009089138A1 US 2009030085 W US2009030085 W US 2009030085W WO 2009089138 A1 WO2009089138 A1 WO 2009089138A1
Authority
WO
WIPO (PCT)
Prior art keywords
ixabepilone
dose
active ingredient
weight
particles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/030085
Other languages
English (en)
Inventor
David Chuan Lee
Francis Y. Lee
Marvin Barry Cohen
Ronald A. Peck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of WO2009089138A1 publication Critical patent/WO2009089138A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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 compound ixabepilone has the structural formula,
  • ixabepilone is (15,35,75,10 ⁇ ,115,125,16R)-7,11-dihydroxy- 8,8,10,12,16-pentamethyl-3-[(lE)- 1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]- 17-oxa-4- azabicyclo[14.1.0] heptadecane-5,9-dione. See also, US 6,605,599, US 7,125,899, US 6,670,384B2, US 6,670,384Cl, US 7,022,330 B2, US 6,518,421, R ⁇ I 39356, US
  • Ixabepilone has been approved by the US Food and Drug Administration for treatment of metastatic breast cancer, and is sold by Bristol-Myers Squibb Company (BMS) under the tradename IX ⁇ MPRA® .
  • BMS Bristol-Myers Squibb Company
  • IX ⁇ MPRA® The approved product IX ⁇ MPRA®
  • IX ⁇ MPRA intravenously over 3 hours every 3 weeks.
  • ixabepilone under the current, IV has the potential for adverse side effects in patients, more particularly, such side effects may include peripheral neuropathy and/or myelosuppression, primarily neutropenia. These side effects can affect or limit the dose to be administered. It is currently recommended that when ixabepilone is administered to patients, that the patients be monitored for symptoms of neuropathy, primarily sensory, and for neutropenia with peripheral blood cell counts, and it is also recommended that these side effects be managed by dose adjustment(s) and delays.
  • Oral administration of a capsule or tablet would offer advantages as compared with IV administration not limited to ease of use and accessibility.
  • Oral administration of ixabepilone presents many issues, however. One such issue involves preparing a suitable formulation (e.g., tablet or capsule) for oral administration. Other issues relate to providing a suitable dose and/or regime for administration to achieve an optimal efficacious level of ixabepilone in patients while minimizing toxicity and managing side effects.
  • FIG. 1 shows the results of in vivo preclinical mice studies (in mice bearing sc M 109 carcinoma) in which ixabepilone was administered and clinical neurotoxicity measured relative to efficacy (LCK) for administrations a) orally, every 4th days for 3 doses, as compared with b) the same dose administered via IV every 4 days, and c) the same dose administered via IV as a split dose;
  • LCK efficacy
  • FIG. 2 shows the results of in vivo preclinical mice studies (in mice bearing sc M5076 taxol resistant fibrosarcoma) in which tumor weight was measured as a function of days post-tumor implant for a control, as compared to a) taxol, and b) ixabepilone administered daily (10, QD); and c) ixabepilone administered as a split dose; and
  • FIG. 3 shows the results of in vivo preclinical mice studies (in mice bearing 16/C mammary carcinoma) in which tumor weight was measured as a function of days post- tumor implant for a control as compared with ixabepilone administered as a split dose (24 mpk, twice a day) and a daily dose (48 mpk, once daily).
  • novel uses of administering ixabepilone are provided that are more convenient and practical than IV administration and achieve a surprising efficacy to safety profile.
  • the ixabepilone is administered as 3 oral unit dosages separated by six hours on Day 1 of an intermittent daily dosing cycle (e.g., in one embodiment, every 21 days), and an efficacious dose of ixabepilone is achieved, with substantially reduced risk of side effects such as neuropathy and/or neutropenia. More particular aspects of the invention are described further below.
  • ixabepilone in the manufacture of a medicament for treating cancer in a human patient, wherein said medicament is orally administered to said human patient according to a split daily dose administered on an intermittent dosing cycle.
  • the cycle dose, or amount of ixabepilone administered at each cycle is administered according to a "split" daily unit dose, i.e., of two or more administrations separated by one or more hours on Day 1 of the cycle, and then again at each Day of the cycle at which drug is to be administered.
  • the split doses are separated by a period of time from 3 to 12 hours, more preferably, from 4 to 8 hours, and most preferably by 6 hours.
  • the cycle dose can be split into two, three or four unit daily dosages, or more preferably, into three unit daily dosages, separately by 4 to 8 hours each.
  • they can be separated by 6 hours on Day 1 of an intermittent dosing cycle, and then again, the same dose and cycle can be applied on the next Day of drug administration.
  • Each unit dosage is independently selected from 10-60 mg of ixabepilone (more preferably 20-50 mg ixabepilone), and the dosing cycle is selected from 10, 15, and 21 day cycles, more preferably from a 21 day cycle.
  • human patients are administered a cycle dose of ixabepilone of 150 mg, administered orally.
  • the patients are suffering from cancer, typically breast, prostate, small cell lung, or renal cancer.
  • patients receive 3 Attorney Docket No. 11188PCT
  • the patients in this embodiment receive 150 mg every 21 days, with the 150 mg being administered as three unit doses of 50 mg separated by 6 hours on Day 1, then every 21 days.
  • a surprisingly advantageous safety-to-efficacy profile is achieved.
  • the ixabepilone is highly efficacious in treating the cancer, and there are reduced manifestations of side effects, as compared with patient
  • Side effects that are effectively managed and/or may be surprisingly reduced with the oral administration according to the split dose may include, without limitation, neuropathy, neutropenia, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, musculoskeletal pain, palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation, leukopenia, anemia, and/or thrombocytopenia.
  • ixabepilone as stated above, or otherwise herein, wherein the unit dosage administered 3 times on Day 1 of the intermittent dosing cycle is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of ixabepilone, and/or 5 mg increments therebetween.
  • the amount of ixabepilone selected for each unit dosage can be variably selected to achieve the overall desired, cycle dose.
  • the ixabepilone is administered wherein the cycle dose is 145-155 mg, more preferably 150 mg, and the unit dosage is at each administration 45 to 55 (more preferably at 50 mg).
  • ixabepilone as stated above, or otherwise herein, wherein the unit dosage is administered as at least a split dose on Day 1 of the intermittent dosing cycle and wherein the overall cycle dose is selected from 100 to 160 mg, more preferably 120 to 155 mg, even more preferably 140-155 mg, and most preferably 150 mg.
  • dosing cycles may be selected to administer the split dose.
  • a shorter cycle may be selected with a reduction in the overall cycle dose.
  • dosing cycles may be every 7, 10, 15, 18 or 21 days. Preferably, a 21 day cycle is applied.
  • an oral unit dosage of ixabepilone in the manufacture of a medicament for treatment of cancer, Attorney Docket No. 11188PCT
  • Figure 1 shows the results of in vivo preclinical mice studies (in mice bearing sc M 109 carcinoma) in which ixabepilone was administered and clinical neurotoxicity measured relative to efficacy (LCK) for administrations performed (a) orally, every 4th days for 3 doses, as compared with (b) the same dose administered via IV every 4 days, and (c) the same dose administered via IV as a split dose.
  • LCK efficacy
  • the data shows the split dose regime, as compared with a single large dose, is surprisingly advantageous in reducing neurotoxicity and achieving an advantageous efficacy/safety profile.
  • the BID regime even when administered IV produced greater absolute efficacy overall (>2 LCK).
  • the split dose regime consistently produced superior antitumor activity. This remarkable improvement in efficacy/safety profile may be a consequence of an improved pharmacokinetics profile.
  • the oral administration as described herein involves an improved formulation with favorable pharmacokinetics and/or tissue distribution profiles. Further, as seen on Figure 1 , the oral administration demonstrated an improved safety/efficacy profile as compared with the IV administration.
  • Example 2
  • FIG. 2 shows the results of in vivo preclinical mice studies (in mice bearing sc M5076 taxol resistant fibrosarcoma) in which tumor growth was measured as a function of days post-tumor implant for a control group, as compared to a) taxol, and b) ixabepilone administered as a single dose per day every 4 days for 3 doses (10 mpk, Q4Dx3, IV); and Attorney Docket No. 11188PCT
  • FIG. 3 shows the results of in vivo preclinical mice studies (in mice bearing 16/C mammary carcinoma) in which tumor weight was measured as a function of days post- tumor implant for a control as compared to ixabepilone administered orally as a split dose (24 mpk, twice-a-day) and orally once-a-day dose (48 mpk, once daily).
  • the oral split dose demonstrated surprisingly superior activity in controlling tumor growth, i.e., showing complete tumor growth inhibition for over 60 days post tumor implant.
  • E-R exposure-response
  • An existing population PK (PPK) model for ixabepilone given via IV was extended by including an oral absorption component in the model, to estimate oral bioavailability and describe plasma concentration-time profiles of ixabepilone following oral administration and predict the time above the threshold concentration.
  • the extended PPK model was coupled with an existing ER model for neutropenia, that had also been developed with data following IV administration of ixabepilone, and this ER model was used to assess the incidence and severity of neutropenia for a number of alternative oral schedules. From this modeling and simulation of clinical trial results, a schedule of 3 doses given every 6 hours was Attorney Docket No. 11188PCT
  • Ixabepilone is orally administered every 21 days in human patients with advanced cancer (e.g., breast, renal, small cell lung, and/or prostate cancer).
  • the starting dose level is a 30 mg/dose for ixabepilone given as 3 oral doses separated by 6 hours on day 1 of a 21 -dosing cycle.
  • the starting dose may be adjusted in 10 mg increments to cohorts of patients.
  • Dose escalation levels are defined in the following table:
  • Dose Level (mg for each of 3 doses) Number of Patients Cohort Dl of a 21-Day Cycle
  • DLT is an adverse event considered related to ixabepilone and occurring during the first cycle of drug administration, including: Grade 4 neutropenia for > 5 consecutive days or febrile neutropenia with or without sepsis with an ANC ⁇ 1000 cells/mm 3 ; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding requiring platelet transfusion; Grade 3 or 4 nausea, vomiting, or diarrhea; any other > Grade 3 non-hemato logic toxicity excluding those that are not clinically significant
  • the MTD will be based on Cycle 1 data and is the maximum dose which can be given to 6 subjects such that not more than 1 subject experiences a DLT (or ⁇ one-third if there are more than 6 treated subjects).
  • PK samples are obtained during Cycle 1.
  • three human patients suffering from cancer are orally administered ixabepilone as 3 oral unit dosages of 30 mg, separated by 6 hours on Day 1 every 21 days; advantageous results are achieved, and three human patients suffering from cancer are orally administered ixabepilone as 3 oral unit dosages of 40 mg, separated by 6 hours on Day 1 every 21 days; again, advantageous results are achieved and six human patients suffering from cancer are orally administered ixabepilone as 3 oral unit dosages of 50 mg, separated by 6 hours on Day 1 every 21 days. Additional clinical trials and data evaluation is on-going.
  • Ixabepilone is useful as a microtubule-stabilizing agent. Ixabepilone is useful in the treatment of a variety of cancers and other proliferative diseases including, but not limited to, the following:
  • -carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, and skin, including squamous cell carcinoma;
  • lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma;
  • -hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia; -tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas;
  • -tumors of mesenchymal origin including fibrosarcoma, rhabdomyoscaroma, and osteosarcoma;
  • tumors including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma.
  • ixabepilone and the methods of administration described herein are used to treat human patients diagnosed with renal, prostate, and/or breast cancer.
  • Ixabepilone is useful for treating patients who have been previously treated for cancer, as well as those who have not previously been treated for cancer.
  • the methods and compositions of this invention, including the enteric coated beads, can be used in first-line and second-line cancer treatments and for treating refractory or resistant cancers.
  • Ixabepilone will inhibit angiogenesis, thereby affecting the growth of tumors and providing treatment of tumors and tumor-related disorders.
  • Such anti-angiogenesis Attorney Docket No. 11188PCT
  • properties will also be useful in the treatment of other conditions responsive to anti- angiogenesis agents including, but not limited to, certain forms of blindness related to retinal vascularization, arthritis, especially inflammatory arthritis, multiple sclerosis, restinosis, and psoriasis.
  • Ixabepilone will induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
  • the subject compounds as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including, but not limited to, cancer and precancerous lesions, immune response related diseases, viral infections, kidney disease, and degenerative diseases of the musculoskeletal system.
  • the ixabepilone may also be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in administering therapies associated with the aforementioned conditions.
  • Ixabepilone may be formulated with agents to prevent nausea, hypersensitivity, and gastric irritation, such as antiemetics, and Hi and H 2 antihistamines.
  • the above therapeutic agents, when employed in combination with ixabepilone, may be used in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • a oral unit dosage of ixabepilone in the manufacture of a medicament for treatment of cancer, in which such treatment comprises a combination with a unit dosage of one or more inhibitors of CYP3A4/5 enzymes, for concurrent or sequential use, in any order. It is contemplated that this combination may provide particular advantages than obtainable with the unit dosage of ixabepilone, or unit dosage of CYP3 A4/5 inhibitor, alone.
  • Cytochrome P450 enzymes include a number of human cytochrome P450 enzymes, including the CYP3A family of enzymes, i.e., CYP3A4 and CYP3A5. References to "CYP3A4/5" are intended to include either or both of CYP3A4 and CYP3A5. This family of enzymes catalyzes oxidative and reductive reactions and has activity towards a chemically diverse group of substrates. These enzymes are the major catalysts of drug biotransformation reactions and also serve an important detoxification Attorney Docket No. 11188PCT
  • CYP3A4/5 inhibitors interfere with the body's ability to detoxify.
  • developing pharmaceuticals for human consumption that inhibit CYP3A4/5, and/or that may effectively and safely be used in combination with compounds that inhibit CYP3A4/5 presents particular challenges. See, for example, the Guidance for Industry: In Vivo Drug Metabolism/Drug Interaction Studies— Study Design, Data Analysis, and Recommendations for Dosing and Labeling prepared by the Food and Drug Administration (November 1999).
  • CYP3A4/5 inhibition may be considered an undesirable activity, and efforts are directed in research to develop compound that do not inhibit CYP3 A4/5. See, e.g. , US 6,992, 193 B2, "Sulfonylamino phenylacetamide derivatives and methods of their use.”
  • CYP3A4/5 inhibitors include HIV protease inhibitors (indinavir, nelfmavir, ritonavir), amiodarone, cimetidine, clarithromycin, diltiazen, erythromycin, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, mibefradil, nefazodone, troleandomycin, and verapamil.
  • Lapatinib an FDA approved tyrosine kinase inhibitor available from Glaxosmith Kline, is also a CYP3A4/5 inhibitor.
  • CYP3A4/5 inhibitors as used herein include each of these substances, as well as any other CYP3A4/5 inhibitors well known in the field. See, e.g., WO 2005/007631.
  • Potent CYP3A4/5 inhibitors which are of particular interest in view of their potency, include ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, nelfmavir, delavirdine, and voriconazole.
  • Ketoconazole one of the potent CYP3A4/5 inhibitors, is an imidazole compound used as an antifungal agent.
  • Ketoconazole is cis-l-acetyl-4-[4-[[2-(2,4-di-chlorophenyl)- 2-(lH-imidazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]piperazine, and has the structure:
  • Ketoconazole was originally described in US Pat. 4,335,125, incorporated herein, with its principal utility being as an antifungal agent. Ketoconazole and formulations are well known and widely described, for example, see US Pat. 4,569,935; US 2005/0013834 Al, "Pharmaceutical Formulations Comprising Ketoconazole”; US 2004/0063722A1, "Antifungal Keoconazole Composition for Topical Use”; Rotstein et al., J. Med Chem. (1992) 35, 2818-2825 (describing stereoisomers of ketoconazole).
  • Applicant herein has discovered that a combination of orally-administered ixabepilone with CYP3A4/5 inhibitors provides surprisingly advantageous results.
  • an enteric coated bead comprising ixabepilone may be used to orally administer ixabpilone to a patient.
  • the enteric coated bead may comprise a coated particle, wherein the active ingredient ixabepilone is encapsulated by an enteric coating.
  • the enteric coating is capable of protecting the ixabepilone, which is susceptible to degradation, decomposition, or deactivation during exposure to acidic conditions, from low pH gastric fluids typically encountered during passage through the stomach into the intestine.
  • the enteric coating is capable of minimizing or preventing exposure of the active ingredient layer to stomach acid. This prevents ixabepilone from being released in the stomach or the stomach acid from penetrating through to the active ingredient layer.
  • the enteric coated bead may comprise a coated particle encapsulated by an enteric coating.
  • the coated particle may comprise a monolithic particle of ixabepilone, ixabepilone mixed with other inert or active ingredientis, and/or a base particle, which may provide a seed particle for the application of an active ingredient layer.
  • the base particle may comprise a pharmaceutically acceptable material that is capable of carrying the active ingredient layer.
  • the base particle may comprise, for example, a pharmaceutically inert material, such as, for example, sugar, starch, microcrystalline cellulose, lactose, or combinations thereof.
  • the base particle may further comprise one or more active agents.
  • the shape of the base particle is typically spherical or semispherical, although other shapes are contemplated. Average diameters for the base particles are typically, for example, in the range of from about 0.1 millimeters to about 5 millimeters. Examples of suitable base particles include Nu- PareilTM Sugar Spheres NF (Chr. Hansen, Inc., WI) and CelphereTM microcrystalline cellulose spheres (Asahi Kasei Kogyo Kabushiki Kaisha Corp., Japan).
  • the enteric coated bead may comprise, for example, from about 10 to about 80 weight % base particle, preferably from about 15 to about 70 weight % base particle, and more preferably from about 20 to about 65 weight % base particle, based on the weight of the enteric coated bead.
  • the base particle is substantially free of moisture. More preferably, the base particle may comprise less than 3 weight % water, based on the weight of base particle.
  • the coated particle may comprise a monolithic particle or a multiple- component particle, e.g. , wherein an active ingredient layer is disposed around the base particle.
  • the active ingredient layer may be applied to the base particle and may form a surface layer on the surface of the base particle, absorb into the base particle, or a combination thereof.
  • the active ingredient layer may be completely or partially distributed on, in, and/or beneath the surface of the base particle.
  • Preferred is an active ingredient layer that is uniformly disposed on the surface of the base particle.
  • the active ingredient layer may comprise ixabepilone, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof.
  • the active Attorney Docket No. 11188PCT the active Attorney Docket No. 11188PCT
  • ingredient layer may optionally comprise at least one additional active agent, such as an anticancer drug.
  • the active ingredient may comprise a mixture of ixabepilone and a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug of ixabepilone.
  • the active ingredient layer may comprise a mixture of ixabepilone and a clathrate of ixabepilone.
  • Suitable levels of ixabepilone include, for example, those in the range of from about 0.1 weight % to about 10 weight %, preferably from about 0.2 weight % to about 5 weight %, and more preferably from about 0.5 weight % to about 4 weight %, based on the weight of the enteric coated bead.
  • the ixabepilone particles as used in the oral tablets or capsules have sizes as shown below:
  • the D50 value refers to a parameter for a population of particles in which 50% of the particles have diameters less than the D50 value and 50% of the particles have diameters greater than the D50 value, based on volume distribution.
  • the D90 value refers to a parameter representing the minimum value at which 90% of the particles have diameters less than the D90 value.
  • the D50 and the D90 values may be determined by a suitable static laser light scattering technique, such as by measurement with the HoribaTM LA-910 Laser Diffraction Particle Size Analyzer (Horiba, Ltd., Japan).
  • average particle diameter refers to the D 50 value.
  • Optical microscopy may be employed to verify the absence of large agglomerates Attorney Docket No. 11188PCT
  • the active ingredient layer also may comprise binder.
  • the binder may be employed to improve adhesion of ixabepilone to the base particle and/or to provide cohesion of the active ingredient layer.
  • Materials suitable as binders include, for example, starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, sodium alginate, methyl cellulose, carboxymethylcellulose, and polyvinylpyrrolidone (PVP) polymers and copolymers such as polyvinylpyrrolidone/polyvinyl acetate (PVP-PVA) copolymers; celluloses such as ethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose; polyethylene glycol; and waxes.
  • PVP polyvinylpyrrolidone
  • suitable commercially available materials include AvicelTM PH 101 , AvicelTM RC 591 , and AvicalTM CL611 cellulose crystallite materials, (FMC Corp., PA).
  • One or more different binders may be used in the active ingredient layer.
  • One or more optional ingredients that may be included in the active ingredient layer are, for example, buffers, antifoam agents, and plasticizers.
  • the enteric coated bead may comprise, for example, from about 2 to about 80 weight % of the active ingredient layer, preferably from about 10 to about 70 weight % of the active ingredient layer, and more preferably from about 20 to about 60 weight % of the active ingredient layer, based on the weight of the enteric coated bead.
  • the active ingredient layer is substantially free of moisture.
  • the tablet or capsule of ixabepilone preferably has an enteric coating that encapsulates the active ingredient.
  • the enteric coating is insoluble or has low solubility in acid solutions characteristic of gastric fluids encountered in the stomach, such pH values of less than about 3.
  • the enteric coating dissolves to allow the release of ixabepilone.
  • Examples of the higher pH values encountered in the small intestine include pH values of greater than about 4.5, preferably pH values of greater than about 5, and most preferably pH values in the range of from about 5 to about 7.2.
  • Suitable materials for forming the enteric coating include, for example, enteric coating polymers, such as, for example, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, acrylic acid copolymers, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.
  • enteric coating polymers such as, for example, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, acrylic acid copolymers, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.
  • enteric coating polymers such as, for example, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, acrylic acid copolymers, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.
  • copolymer dispersion which may comprise an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ethyl ester groups of approximately 1 :1, and a mean molecular weight of approximately 250,000, and is supplied as an aqueous dispersion containing 30 weight % solids.
  • EudragitTM L- 30-D 55 aqueous copolymer dispersion is supplied by R ⁇ hm-Pharma Co., Germany.
  • the enteric coated bead may comprise, for example, from about 5 to about 55 weight % of the enteric coating, preferably from about 10 to about 45 weight % of the enteric coating, and more preferably from about 15 to about 40 weight % of the enteric coating, based on the weight of the enteric coated bead.
  • the enteric coating is substantially free of moisture.
  • the enteric coating optionally comprises other materials, such as plasticizers, colorants, antifoam agents, and anti-adherents.
  • the enteric coated bead may optionally comprise one or more subcoat layers that are situated between the base particle and the active ingredient layer, or the active ingredient layer and the enteric coating.
  • a subcoat layer may be employed to minimize contact between ixabepilone contained in the active ingredient layer and an enteric coating comprising acid groups, such as methacrylic acid copolymer.
  • the enteric coated bead may comprise from about 0.1 to about 10 weight % of the subcoat layer, preferably from about 0.5 to about 5 weight % of the subcoat layer, and more preferably from about 2 to about 4 weight % of a subcoat layer, based on the weight of the enteric coated bead.
  • Suitable materials to form the subcoat layer include starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, sodium alginate, methyl cellulose, carboxymethylcellulose, and polyvinylpyrrolidone (PVP) polymers and copolymers such as PVP-PVA copolymers; celluloses such as ethylcellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; polyethylene glycol, and waxes.
  • starch starch
  • gelatin sugars such as sucrose, glucose, dextrose, molasses, and lactose
  • natural and synthetic gums such as acacia, sodium alginate, methyl cellulose, carboxymethylcellulose, and polyvinylpyrrolidone (PVP) polymers and copolymers such as PVP-PVA copolymers
  • celluloses such as ethylcellulose, hydroxyprop
  • the subcoat layer may further comprise one or more plasticizers, such as polyethylene glycol, propylene glycol, triethyl citrate, triacitin, diethyl phthalate, tributyl sebecate, or combinations thereof.
  • the enteric coated bead may optionally comprise a subcoat layer interposed between the active ingredient layer and the enteric coating.
  • the enteric coated bead may comprise from about 0.1 to about 10 Attorney Docket No. 11188PCT
  • the subcoat layer preferably from about 0.5 to about 5 weight % of the subcoat layer, and more preferably from about 2 to about 4 weight % of a subcoat layer, based on the weight of the enteric coated bead.
  • the subcoat layer is substantially free of moisture.
  • the enteric coated bead optionally comprises other materials such as flavoring agents, preservatives, or coloring agents as may be necessary or desired.
  • the enteric coated bead is substantially free of moisture.
  • substantially free of moisture it is meant that the enteric coated bead comprises less than about 4 weight % water, preferably less than about 3 weight % water, and more preferably, less than about 2 weight % water, based on the weight of the enteric coated bead.
  • the enteric coated bead may be contacted with a hydrophobic material such as talc, magnesium stearate, or fumed silica to form a hydrophobic layer on the surface of the enteric coated bead.
  • a hydrophobic material such as talc, magnesium stearate, or fumed silica to form a hydrophobic layer on the surface of the enteric coated bead.
  • the hydrophobic layer is useful to reduce agglomeration of the individual enteric coated beads and/or to reduce static during the handling of the enteric coated beads.
  • the enteric coated beads of ixabepiloe for use with this invention may be prepared by a process that reduces the exposure of ixabepilone to moisture, heat, or a combination of moisture and heat. Such a process ensures high potency and good uniformity of the active pharmaceutical agent, since ixabepilone is susceptible to degradation or decomposition in the presence of water, and especially a combination of moisture and heat.
  • a process for preparing the enteric coated bead for a capsule or tablet may comprise: a) providing base particles; b) applying an active ingredient mixture and binder to the base particles, wherein the active ingredient mixture may comprise: i) ixabepilone, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and ii) solvent, water, or a mixture thereof; c) drying the base particles having application of the active ingredient mixture to provide coated particles; and d) applying enteric coating to the coated particles to provide the enteric coated beads.
  • the active ingredient mixture may comprise: i) ixabepilone, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and ii) solvent, water, or a mixture thereof.
  • the active ingredient mixture may also comprise the binder, thus allowing co-application of a single mixture.
  • the active ingredient mixture and a solution comprising the binder may be premixed immediately prior to application.
  • the active ingredient mixture may comprise ixabepilone in solvent, water, or a mixture thereof.
  • the active ingredient mixture may be a solution comprising ixabepilone dissolved in the solvent, water, or mixture thereof.
  • the active ingredient mixture may be an active agent suspension comprising particles of ixabepilone dispersed in the solvent, water, or mixture thereof.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, n-propanol, and isopropanol; and acetone.
  • the active ingredient mixture may be prepared by admixing ixabepilone in solvent, water, or a mixture thereof.
  • the binder may be included in the active ingredient mixture, ixabepilone and the optional binder may be combined in any order with the solvent, water, or mixture thereof.
  • mixing is required to minimize any localized concentrations of ixabepilone or the optional binder in the solvent, water, or mixture thereof.
  • Mixing may be provided by a mechanical device, such as a magnetic or overhead stirrer.
  • the enteric coated bead for use with this invention is prepared by applying an active ingredient suspension and binder to the base particles.
  • the active ingredient suspension is an aqueous active ingredient suspension comprising the particles of ixabepilone dispersed in an aqueous medium.
  • the aqueous medium may comprise greater than about 50 weight % water and optionally, one or more water miscible solvents, based on the weight of the aqueous medium.
  • the aqueous medium may comprise at least about 65 weight % water, more preferably at least about 75 weight % water, and most preferably at least about 85 weight % water, based on the weight of the aqueous medium.
  • the aqueous suspension of the ixabepilone particles provides a reduction in contact between the aqueous medium and ixabepilone, compared to a solution of ixabepilone, and thus decreases the rate of degradation or decomposition of ixabepilone.
  • the aqueous active ingredient suspension may be prepared by admixing ixabepilone particles and optionally, the binder, in water and optionally, water miscible solvent.
  • the ixabepilone particles and the optional binder may be combined with the Attorney Docket No. 11188PCT
  • ixabepilone particles include, for example, from less than about 1000 microns, preferably less than about 500 microns, and more preferably less than about 250 microns.
  • the ixabepilone particles may be amorphous or crystalline.
  • the ixabepilone particles are crystalline. Examples of crystalline forms of ixabepilone, such as Form A and Form B, are disclosed in U.S. Patent 6,689,802.
  • the active ingredient suspension may comprise from about 1 to about 50 weight % ixabepilone particles, preferably from about 2 to about 30 weight % ixabepilone particles, and more preferably from about 3 to about 20 weight % ixabepilone particles, based on the weight of the active ingredient suspension.
  • the active ingredient suspension has a pH in the range of from about 6 to about 9, more preferably in the range of from about 6.5 to about 8, and most preferably in the range of from about 6.5 to about 7.5.
  • the active ingredient suspension may optionally comprise other ingredients, such as buffers; dispersing agents such as surfactants or low molecular weight polymers; antifoaming agents, and pH adjusting agents such as acids and bases.
  • the binder may be provided as a solution or dispersion in water.
  • the active ingredient mixture may comprise, for example, from about 1 to about 30 weight % of the at least one binder, preferably from about 2 to about 20 weight % of the at least one binder, and more preferably from about 3 to about 10 weight % of the at least one binder, based on the weight of the active ingredient mixture.
  • the active ingredient mixture and the binder solution may be applied to the base particles as a spray or a stream while base particles are in motion. The conditions are preferably controlled to minimize particle agglomeration of the base particles. Subsequently, the solvent and/or water is removed from the applied active ingredient mixture leaving the coated particles having the active ingredient layer disposed on the base particle.
  • the enteric coating may be applied to the coated particles by applying a mixture of the enteric coating as a spray or stream while the coated particles are in motion.
  • the enteric coating mixture may be a solution or a suspension.
  • the conditions are preferably controlled to minimize particle agglomeration.
  • the enteric coating Attorney Docket No. 11188PCT
  • the mixture may comprise the enteric coating material in an aqueous or nonaqueous solvent or mixture thereof.
  • suitable solvents include, for example, alcohols such as methanol and isopropanol; and acetone. Mixtures of solvents or mixtures of water and one or more water miscible solvents may be used.
  • the enteric coating material may be dissolved into the solvent to provide a solution, or alternatively, may be a dispersion of particles, to provide a suspension, such as an aqueous copolymer dispersion.
  • the enteric coating mixture may comprise, for example, from about 5 to about 50 weight % of the enteric coating material, and preferably from about 10 to about 40 weight % of the enteric coating material, based on the weight of the enteric coating mixture.
  • Drying to remove the solvent and/or water may be applied during and/or after application of the enteric coating mixture.
  • the drying conditions include an inlet drying air temperature in the range of from about 2O 0 C to about 7O 0 C, an inlet air humidity of less than about 50% relative humidity, a product bed temperature in the range of from about 2O 0 C to about 4O 0 C, and air flow that is sufficient to remove the free water vapor.
  • a fluid bed spraying apparatus may be employed to spray the active agent suspension onto the base particles, and/or to spray the enteric coating mixture onto the coated particle.
  • a fluid bed coater is an apparatus that can fluidize particles such as beads while simultaneously spraying on and drying a film coat.
  • the fluidizing air is heated to the desired temperature and the air flow adjusted to the flow rate for proper fluidization and drying.
  • a pan coater is an apparatus in which particles are tumbled in a pan while spraying a film coat. Simultaneously air of the proper temperature and airflow passes through the bed of particles to dry the applied film coat.
  • One aspect of the invention comprises orally administering a capsule comprising a multitude of the enteric coated beads.
  • the capsule may be prepared by filling a capsule shell, such as a gelatin capsule shell, with the enteric coated beads. The capsule allows for easier swallowing during oral administration of the enteric coated beads.
  • the capsule may comprise at least one hydrophobic material to reduce agglomeration of the individual enteric coated beads in the capsule and/or to reduce static during the loading of the enteric coated beads into the capsule.
  • the amount of Attorney Docket No. 11188PCT is a hydrophobic material to reduce agglomeration of the individual enteric coated beads in the capsule and/or to reduce static during the loading of the enteric coated beads into the capsule.
  • the optional hydrophobic material is preferably kept to a level where it is just enough to prevent particle sticking after the capsule shell has dissolved, but not too much to retard dissolution.
  • suitable hydrophobic materials include talc, magnesium stearate, stearic acid, glyceryl behenate, hydrogenated cottonseed oil, trimyristin, triplamitan, tristearin, and fumed silica.
  • commercially available hydrophobic materials include LubritalTM additive (Penwest Pharmaceutical Co., NJ); DynasanTM 114, DynasanTM 116, and DynasanTM 118 additives (Sasol North America, TX); and CompritolTM 888 ATO additive (Gattefosse Co., France).
  • a preferred hydrophobic material is talc. Below are some specific examples for making the enteric coated beads of ixabepilone that may be used in the present invention methods and Uses.
  • Tris powder tris(hydroxymethyl aminomethane)
  • 500 ml water, and 1 N HCl were mixed to provide a 0.046 M Tris buffer solution having a pH of 8.1.
  • a mixture of 43.5 g Tris buffer solution (43.5 g) and 2.5 g OpadryTM Clear Coat powder (Colorcon, Inc., PA), as the binder was prepared.
  • 4 g of ixabepilone, as crystals was added and stirred for approximately 30 minutes to provide the active ingredient suspension.
  • the active ingredient suspension was passed through a 60 mesh screen to remove any agglomerates.
  • the coated particles were prepared by applying the active ingredient suspension onto base particles.
  • the base particles were 18/20 mesh sugar beads, (Sugar
  • the active ingredient suspension was applied to the base particles by spraying using a fluid bed processor that was set up as a Wuster spray coating system.
  • the spray coating system included an Aeromatic-Fielder MP-MICROTM fluid bed processor (Niro)
  • the active ingredient suspension was applied to the base particles with the following application and drying parameters: a spray rate of 1.1 g/minute with a spray atomization pressure of 1.8 bar (180 kilopascals), an inlet temperature of 68 0 C, an outlet temperature of 32 0 C, a product bed temperature of 32 0 C, and a fan speed of 4 m 3 /hr.
  • an inlet temperature of 68 0 C an outlet temperature of 32 0 C
  • a product bed temperature of 32 0 C a product bed temperature of 32 0 C
  • a fan speed 4 m 3 /hr
  • the resulting coated particles contained 2.75 weight % of ixabepilone, based on the weight of the coated particle.
  • a subcoat can be applied to the coated particles.
  • the subcoat solution can be prepared by combining 5 g OpadryTM Clear Coat powder and 95 g water and stirring until a clear solution was obtained.
  • the fluid bed processor used to prepare the coated particles was employed.
  • the fluid bed processor which contained 80 g of the coated particles, was preheated to approximately 5O 0 C for several minutes.
  • the subcoat layer was applied using the application and drying parameters disclosed hereinabove to the preparation of the coated particles.
  • the subcoated solution was slowly stirred.
  • the inlet temperature was maintained at the final inlet temperature until the bed product temperature reached 40 0 C.
  • the resulting coated particles, which had a subcoat contained approximately 2 weight % subcoat, based on the total weight of the resulting coated particles.
  • An enteric coating was applied onto the coated particles having a subcoat.
  • the enteric coating solution was prepared by first filtering EudragitTM L30D55 polymer dispersion (Rohm GmbH and Co., Darmstadt, Germany) through a 60 mesh screen.
  • EudragitTM L30D55 polymer dispersion is an aqueous suspension containing methacrylic acid copolymer.
  • the filtered Eudragit polymer dispersion (20Og) was diluted with 89.5 g Attorney Docket No. 11188PCT
  • the fluid bed processor used to prepare the coated particles was employed.
  • the fluid bed processor which contained 70 g of the coated particles, was preheated to approximately 5O 0 C for several minutes.
  • the enteric coating solution was applied using the following application and drying parameters: 0.8 mm spray tip, 1.1 g/minute spray rate, spray atomization pressure was 1.8 bar, inlet temperature 65 0 C, outlet temperature 3O 0 C, product bed temperature 3O 0 C, and fan speed of 3.5 m 3 /hr.
  • the enteric coating solution was slowly stirred.
  • the inlet temperature was maintained at the final inlet temperature until the bed product temperature reached 40 0 C.
  • the resulting enteric coated beads had an average particle diameter of 1 mm.
  • Table 1 lists the composition of the enteric coated beads prepared in this example. The composition is reported as weight % of each ingredient based on the total weight of the enteric coated bead. It should be again noted that the subcoat layer is optional.
  • Tris powder tris(hydroxymethyl aminomethane)
  • 484.5 g water and 12.7 g 1 N HCl were mixed to provide a 0.046 M Tris buffer solution having a pH of 8.1 ⁇ 0.1.
  • 2.4 g OpadryTM Clear Coat powder (Colorcon, Inc., PA), as the binder, was added and stirred for approximately 30 minutes to provide the active ingredient suspension.
  • the active ingredient suspension was passed through a 60 mesh screen to remove agglomerates.
  • the coated particles were prepared by applying the active ingredient suspension onto base particles.
  • the base particles were 14/18 mesh sugar beads, (Sugar Spheres, NF particles, (Chr. Hansen, Inc., WI)) having particle diameters of greater than 1 mm and less than 1.4 mm.
  • the active ingredient suspension was applied to the base particles by spraying using a fluid bed processor that was set up as a Wuster spray coating system.
  • the spray coating system included an Aeromatic-Fielder MP-MICROTM fluid bed processor (Niro Inc., Maryland) equipped with a 0.8 mm spray tip.
  • the fluid bed processor was charged with 70 g of the sugar beads and then preheated to 30-50 0 C.
  • the active ingredient suspension was applied to the base particles with the following application and drying parameters: a spray rate of 1.0 to 1.2 g/minute with a spray atomization pressure of 1.8 bar (180 kilopascals), an inlet temperature of 65-70 0 C, an outlet temperature of 28-32 0 C, a product bed temperature of 27-32 0 C, and a fan speed of 3.8 to 4.2 m 3 /hr. During the application process, the active ingredient suspension was slowly stirred.
  • the subcoat solution was prepared by combining 8 g OpadryTM Clear Coat powder and 92 g water and stirring until a clear solution was obtained.
  • the fluid bed processor used to prepare the coated particles was employed.
  • Drug coated particles (65 g), were preheated to approximately 30-50 0 C in the fluid bed processor.
  • the subcoat layer was applied using the application and drying parameters disclosed hereinabove to the preparation of the coated particles.
  • the subcoated solution was slowly stirred.
  • the inlet temperature was maintained at the final inlet temperature until the bed product temperature reached 38-42 0 C.
  • Application of Enteric Coating An enteric coating was applied onto the drug coated particles having a subcoat.
  • the enteric coating solution was prepared by first filtering EudragitTM L30D55 polymer dispersion (Rohm GmbH and Co., Darmstadt, Germany) through a 60 mesh screen.
  • EudragitTM L30D55 polymer dispersion is an aqueous suspension containing methacrylic acid copolymer.
  • the filtered Eudragit polymer dispersion (133.34 g) was diluted with 55.61 g water.
  • 6 g diethyl phthalate was added to the diluted Eudragit polymer dispersion, followed by the addition of 5.05 g of 1 N NaOH solution.
  • the pH of the resulting enteric coating solution was 5.0 ⁇ 0.1.
  • the fluid bed processor used to prepare the drug coated particles was employed.
  • the fluid bed processor which contained 65 g of the sub-coated particles, was preheated to 30-50 0 C.
  • the enteric coating solution was applied using the following application and drying parameters: 0.8 mm spray tip, 1.0 to 1.2 g/minute spray rate, spray atomization pressure was 1.8 bar, inlet temperature 65- 7O 0 C, outlet temperature 30-36 0 C, product bed temperature 28-32 0 C, and fan speed of 3.9- 4.1 m 3 /hr.
  • the enteric coating solution was slowly stirred. After application of the enteric coating solution was completed, the inlet temperature was maintained at the final inlet temperature until the bed product Attorney Docket No. 11188PCT
  • the resulting enteric coated beads had an estimated average particle diameter of 1.4 mm.
  • Table 2 lists the composition of the enteric coated beads prepared in this example. The composition is reported as weight % of each ingredient based on the total weight of the enteric coated bead. It should be again noted that the subcoat layer is optional.
  • Enteric coated beads comprising ixabepilone were prepared as described below. A summary of the enteric coated bead compositions is shown in Table 3. As can be seen, the subcoat layer and pre-coat layer are optional.
  • Example Precoat layer active ingredient layer subcoat layer enteric coating Attorney Docket No. 11188PCT
  • the size of the sugar beads was 18/20 mesh.
  • the coating solutions and suspensions used were as follows:
  • Buffered Opadry Pre-coat This consisted of 8% (w/w) solution of Opadry® Clear (YS-1-19025-A) in 0.046 M Tris buffer (pH 8.1 ⁇ 0.1). Applied to obtain -4% weight gain.
  • Opadry Sub coat This consisted of 8% (w/w) solution of Opadry® Clear in MiIIiQ water. Applied to obtain ⁇ 4 % weight gain
  • Buffered Drug Coat This consisted of 5% (w/w) solution of Opadry® Clear in 0.046 M Tris buffer (pH 8.1 ⁇ 0.1) containing 12% (w/w) ixabepilone. Applied to obtain ⁇ 3.7 % weight gain.
  • Un-buffered Drug Coat This consisted of 5% (w/w) solution of Opadry® Clear in MiIIiQ water and containing 12% (w/w) ixabepilone. Applied to obtain ⁇ 3.7 % weight gain.
  • Enteric Coat This consisted of 66.67 % (w/w) Eudragit® L30D-55 (30% solids), 3% diethyl phthalate in MiIIiQ water and the suspension pH was adjusted to 5.0 ⁇ 0.1 with IN NaOH. Applied to obtain ⁇ 35 % weight gain Attorney Docket No. 11188PCT
  • the enteric coated beads of Capsule Preparation Examples 3.1-3.5 were placed in scintillation glass vials and stored at 4O 0 C for 8 weeks.
  • the enteric coated beads were assayed by HPLC using the following assay procedure:
  • Needle washing sol Water: acetonitrile (50:50) Column Temperature: Ambient Sample Temperature: 4°C
  • the standard solution was prepared by weighting -50.0 mg ixabepilone into a
  • the enteric coated beads were prepared for assay using a Tablet Process Workstation (Caliper Lifescience, Hopkinton, MA). Sample preparation: (0.2mg/mL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles modalités d'administration d'ixabépilone, à savoir une administration orale d'ixabépilone avec une efficacité surprenante par rapports aux profils d'innocuité, ces modalités impliquant un fractionnement de la dose orale en deux ou plusieurs doses unitaires quotidiennes administrées en un cycle de dosage intermittent.
PCT/US2009/030085 2008-01-04 2009-01-05 Administration orale d'ixabépilone Ceased WO2009089138A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1904308P 2008-01-04 2008-01-04
US61/019,043 2008-01-04

Publications (1)

Publication Number Publication Date
WO2009089138A1 true WO2009089138A1 (fr) 2009-07-16

Family

ID=40578487

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/030085 Ceased WO2009089138A1 (fr) 2008-01-04 2009-01-05 Administration orale d'ixabépilone

Country Status (1)

Country Link
WO (1) WO2009089138A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058700A1 (fr) * 2001-01-25 2002-08-01 Bristol-Myers Squibb Company Procedes relatifs a l'administration d'analogues de l'epothilone pour le traitement du cancer
US20040053978A1 (en) * 2002-05-15 2004-03-18 Lee Francis Y. F. Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
WO2006105399A1 (fr) * 2005-03-31 2006-10-05 Bristol-Myers Squibb Company Methodes d'administration d'ixabepilone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058700A1 (fr) * 2001-01-25 2002-08-01 Bristol-Myers Squibb Company Procedes relatifs a l'administration d'analogues de l'epothilone pour le traitement du cancer
US20040053978A1 (en) * 2002-05-15 2004-03-18 Lee Francis Y. F. Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
WO2006105399A1 (fr) * 2005-03-31 2006-10-05 Bristol-Myers Squibb Company Methodes d'administration d'ixabepilone

Similar Documents

Publication Publication Date Title
US6541014B2 (en) Antiviral product, use and formulation thereof
CN1886119B (zh) 泮托拉唑多颗粒制剂
CN101977593B (zh) 包含弱碱性药物以及有机酸的给药系统
EP1867326B1 (fr) Granule entérique enrobé et son procédé de préparation
JP6888226B2 (ja) オラパリブの経口徐放性医薬組成物及びその使用
US20030104056A1 (en) Delayed release anti-viral product, use and formulation thereof
JP2002532425A (ja) 新規な医薬製剤
SK656388A3 (en) Pharmaceutical preparation consisting of granules with tetracycline compound
HU214590B (hu) Eljárás ellenőrzött hatóanyag-felszabadítású gyógyszerkészítmények előállítására
PL192293B1 (pl) Peletka dojelitowa, preparat dojelitowy, kapsułka żelatynowa i sposób wytwarzania peletek dojelitowych
JPS6238323B2 (fr)
CN102805733A (zh) 颗粒制剂及其制造方法
WO2004056336A2 (fr) Systemes d'administration de medicaments a unites multiples et a liberation controlee
CN103316026B (zh) 含芬特明和托吡酯的联合产品及其制备方法
JP2009527554A (ja) コハク酸メトプロロールｅ．ｒ．の錠剤およびその調製方法
CN110062628A (zh) 一种瑞卡帕布口服缓控释药物组合物及其用途
WO2012018761A2 (fr) Méthode de traitement de cancers induits par les androgènes
WO2018108151A1 (fr) Composition pharmaceutique à libération contrôlée et prolongée de véliparib et son utilisation
KR20070104392A (ko) 로시글리타존을 포함하는 경구 투여 제형
JP2000053563A (ja) 苦味がマスクされた速放性細粒剤
EP4486303A1 (fr) Formulations de cannabinoïdes sous forme de poudre sèche à enrobage entérique
RU2349319C1 (ru) Гранула, покрытая энтеросолюбильной оболочкой, содержащая иксабепилон, и способ ее приготовления
MXPA04008137A (es) Preparaciones de liberacion sostenida y procedimiento para producir las mismas.
EP3630074A1 (fr) Forme posologique orale multiparticulaire permettant une libération prolongée de tapentadol
WO2009089138A1 (fr) Administration orale d'ixabépilone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09700568

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09700568

Country of ref document: EP

Kind code of ref document: A1