WO2002064132A2 - Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability - Google Patents
Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability Download PDFInfo
- Publication number
- WO2002064132A2 WO2002064132A2 PCT/US2002/000497 US0200497W WO02064132A2 WO 2002064132 A2 WO2002064132 A2 WO 2002064132A2 US 0200497 W US0200497 W US 0200497W WO 02064132 A2 WO02064132 A2 WO 02064132A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- paclitaxel
- cellulosic polymer
- surfactant
- group
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/42—Oxazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates generally to formulations of chemotherapeutic agents and more specifically to formulations of paclitaxel and analogs thereof for oral administration.
- Paclitaxel is a clinically effective chemotherapeutic agent approved for the treatment of various cancers.
- paclitaxel has very low water solubility ( ⁇ 10 ⁇ g/ml) which, due to a lack in suitable chemical functionality for salt formation, cannot be increased by pH adjustment, formulation of paclitaxel has proven difficult.
- most of the formulation work known in the art has been based on the use of co-solvents, surfactants and excipients (i.e., cyclodextrin) for intravenous (IV) formulations.
- IV intravenous
- Taxol® contains 6 mg/ml of paclitaxel, 527 mg/ml of a surfactant, (Cremophor EL, a polyethoxylated castor oil), and 49.7% (v/v) of absolute ethanol. This formulation requires a 5 to 20 fold dilution with either 5% dextrose or 0.9% NaCl solution which is then delivered by an intravenous infusion into the patient.
- paclitaxel/cremophor formulations patients are often required to receive premedication and/or prolonged paclitaxel infusion duration time of up to 24 hours.
- These measures carry significant disadvantages.
- the long infusion duration is inconvenient for patients, and is expensive due to the need to monitor the patients for the entire 6 to 24-hour infusion duration and the patient's prolonged stay in a hospital or treatment clinic.
- premedication increases patient discomfort and increases the expense and duration of treatment.
- such measures normally would not completely eliminate the side effects.
- U.S. Patent No. 5,641,803 to Canetta et. al. discloses a method of administering paclitaxel dosages of about 135 mg/m 2 via infusions of less than 6 hours duration. This method requires pretreatment of the patients with steroids, antihistamines, and H 2 -receptor antagonists sufficient to prevent fatal anaphylactic-like reactions.
- U.S. Pat. Nos. 6,136,846 and 6,319,943 disclose an oral formulation of paclitaxel which comprises paclitaxel, a solvent, and a pharmaceutically-acceptable, water-miscible solubilizer forming micelles, the solubilizer being selected from the group consisting of solubilizers having the general structures: Rl COOR2, Rl CONR2, and Rl COR2, wherein Rl is a hydrophobic C3 -C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety and wherein the solubilizer is selected such that it does not have a pKa less than about 6.
- the concentration of paclitaxel in the composition disclosed in U.S. Pat. Nos. 6,136,846 and 6,319,943 is 5-20 mg/g.
- U.S. Patent No. 5.648,090 to Rahman et. al. discloses a liposomal-encapsulated paclitaxel or an anti-neoplastic derivative thereof that is used to effect a therapeutically enhanced method of treating cancer, and may be used advantageously in combination with hyperthermia.
- the liposomes confer enhanced stability and solubility characteristics to paclitaxel or derivatives thereof.
- U.S. Patent No. 5,424,073 to Rahman et. al. discloses a liposomal-encapsulated paclitaxel or an anti-neoplastic derivative thereof which comprises a liposome forming material, cardiolipin, paclitaxel and a pharmaceutically acceptable carrier.
- the liposome forming material is phosphatidyl choline, cholesterol, and the like and the liposomes formed thereby may have a positive, negative or neutral charge.
- the liposomes confer enhanced stability and solubility to paclitaxel or derivatives thereof.
- U.S. Patent No. 6,090,955 to Reszka et. al. discloses a liposome-encapsulated paclitaxel composition that consists of a high paclitaxel concentration with high stability and hence a high therapeutic effect.
- the invention involves the development of specific forms of paclitaxel encapsulation and the use of these, optionally in combination with other substances, in the treatment of various types of tumor.
- the liposome consists of a lipid, an amphiphillic material, a polymer and a carrier liquid.
- the liposome-encapsulated paclitaxel is characterized in that it is prepared by high-pressure homogenization or by aerosol formulation.
- U.S. Patent No. 5,415,869 to Straubinger et. al. discloses a pharmaceutical composition for use in treatment of cancer patients comprised of at least one taxane and a mixture of one or more negatively charged phospholipids and one or more zwitterion (i.e. neutral) phospholipids.
- This mixture entraps the taxane in what is believed to be a liposome.
- the mixture contains a ratio of negatively charged phospholipids to zwitterion phospholipids of 1 :9 to 7:3.
- the paclitaxel is present in an amount of 1.5-8.0 mole percent taxane.
- the composition is in the form of particles having a size of 0.025 to 10 microns with substantially no taxane crystals.
- One of the negatively charged phospholipids is diphosphatidyl choline, i.e. cardiolipin.
- U.S. Patent No. 5,683.715 to Boni et. al. discloses liposomal taxane formulations where the liposomal lipid is a phosphatidylcholine; these formulations are useful for treating animals afflicted with cancers.
- U.S. Patent No. 5,728,687 to Bissery discloses pharmaceutical compositions having therapeutic synergy comprising paclitaxel or taxotere or analogues thereof combined with at least one other therapeutically useful substance for treating neoplastic diseases.
- the other therapeutic substance is selected from the group consisting of an alkylating agent, epidophylloptoxin, an anti-metabolite or a vinca alkaloid.
- U.S. Patent No. 6,096,331 to Desai et. al. discloses and claims compositions and methods that are useful for the in-vivo delivery of taxane, wherein the taxane is formulated with a polymeric biocompatible material such as human serum albumin.
- the compositions are substantially cremophor-free and a variety of neoplastic tumors are treatable thereby.
- U.S. Patent No. 5,908,835 to Bissery discloses anti-tumor compositions comprising paclitaxel, taxotere or their derivatives in combination with an anthacycline antibiotic, the combination having a synergistic pharmacological activity greater than the expected additive effect of its individual components.
- U.S. Patent Nos. 5,665,382 and 4,498,421 to Grinstaff disclose and claim pharmaceutical compositions in which an active agent is encapsulated within a polymer shell whose cross- sectional dimension is no greater than lO ⁇ .
- the shell consists of a biocompatible material such as proteins, lipids, polysaccharides and polynucleic acids all of which possess sulfhydryl groups that are cross-linked to form the shell.
- the pharmaceutical agent is any one of a number of generically disclosed groups excluding anti-cancer compounds.
- U.S. Patent Nos. 5,916.596 and 5,439,686 to Desai et. al. disclose pharmaceutical compositions comprising emulsions of polymer-encapsulated pharmaceutical agents including protein encapsulated paclitaxel.
- the polymer is a protein, polysaccharide, polypeptide or polynucleic acid cross-linked by disulfide bonds.
- the emulsion is any one of a wide variety of organic solvents. Accordingly, there exists a clear need for oral compositions of paclitaxel that are easy to prepare, contain a high concentration of paclitaxel but a low surfactant level, cause fewer side effects, have improved stability and have high oral bioavailability.
- An object of the present invention is to provide pharmaceutical compositions containing paclitaxel and analogs thereof which possess high oral bioavailability.
- Another object of the present invention is to provide pharmaceutical compositions containing paclitaxel and analogs thereof which generate a supersaturated solution of the drag state in vivo whereby the oral bioavailability of paclitaxel is further enhanced.
- a further object of the present invention is to provide a pharmaceutical composition containing a high drug load of paclitaxel for convenient administration.
- Another object of the present invention is to provide pharmaceutical compositions which exhibit adequate physical and chemical stability as self-emulsifying formulations.
- Still another object of the present invention is to provide pharmaceutical compositions containing paclitaxel which should cause fewer side effects in patients receiving the formulations.
- Still another object of the present invention is to provide pharmaceutical formulations for paclitaxel which contain less polyethoxylated castor oil.
- the present invention provides pharmaceutical compositions of paclitaxel in a form of self-emulsifying liquid composition comprising: a) paclitaxel or an analog thereof, b) a pharmaceutically acceptable solvent, c) a pharmaceutically acceptable surfactant, and d) a substituted cellulosic polymer.
- compositions are self-emulsifying, capable of generating a supersaturated emulsion or a supersaturated microemulsion upon their exposure to an aqueous medium such as water or gastrointestinal fluid.
- the emulsion or a microemulsion permits rapid and efficient absorption of the paclitaxel resulting in enhanced bioavailibility of paclitaxel.
- the compositions of the present invention are primarily for oral administration. Li a particular embodiment, the compositions further comprise a diglyceride or a mixture of diglyceride and monoglyceride.
- the amount of paclitaxel in the compositions can be up to about 100 mg/g.
- the high paclitaxel load in the compositions permits a reduced volume of the composition to be administered to the patients.
- the preferred solvents of the present invention include polyethylene glycol (PEG series), propylene glycol, ethanol, or a mixture thereof.
- the preferred surfactants include polyoxyl 40 hydrogenated castor oil (Cremophor RH40®), polyoxyl 35 castor oil (Cremophor EL®), polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Pluronics), and vitamin E-TPGS 1000, with the more preferred surfactant being Cremophor EL®.
- the ratio of paclitaxel to the surfactant such as Cremophor in the composition of the present invention is generally less than 1:20, that means that for each part of paclitaxel less than twenty parts of the surfactant is required in the composition.
- the reduced amount of the surfactant in the composition as compared with that in the Taxol® formulation would significantly and desirably reduce the side effects caused by the Cremophor.
- the addition of HPMC in the formulation leads to surprisingly higher paclitaxel concentrations in the SGF medium, generating a supersaturated paclitaxel solution.
- Figure 2 is a graph depicting the levels of paclitaxel in plasma samples taken over a period of 8 hours from groups of rats.
- the composition of Example 3 which contains HPMC was administered orally.
- the commercial formulation Taxol® was administered orally.
- a paclitaxel composition substantially similar to that of Example 3 with the major exception that it contained no HPMC was administered orally.
- the total dose of paclitaxel administered to each rat in each group was 10 mg/kg.
- Example 3 the composition of Example 3 which contains HPMC shows rapid absorption with a high Cmax of about 300 ng/ml as compared to a low Cmax (around 13 ng/ml) with a formulation of similar composition without HPMC (Example 6). Approximately a 20-fold enhancement in the Cmax is observed from the composition of Example 3 and this is attributed to the presence of HPMC.
- the commercial product, Taxol® (BMS) shows a Cmax only around 26 ng/ml (Group B in Figure 2) when it is dosed orally, and this is approximately 10-fold lower than that obtained with the compositions of the present invention.
- Novel pharmaceutical compositions comprise: a) paclitaxel or an analog thereof, b) a pharmaceutically acceptable solvent, c) a pharmaceutically acceptable surfactant, and d) a substituted cellulosic polymer.
- compositions of the present invention are self-emulsifying liquid formulations.
- self-emulsifying liquid formulations refers to concentrated liquid compositions capable of generating emulsions or microemulsions upon mixing with sufficient aqueous media such as water, infusion fluids, simulated gastric fluid, or actual gastrointestinal fluid.
- simulated gastric fluid used herein refers to an aqueous solution of about 0.01 M hydrochloric acid with about 0.15 M sodium chloride, having a pH of about 2.
- the size of the emulsion or microemulsion droplets generated by the compositions of the present invention are generally below 500 nm and preferably below 150 nm.
- the paclitaxel compositions of the present invention can contain paclitaxel generally in an amount up to about 100 mg/gm, preferably from about 10 to about 80 mg/gm, more preferably from about 30 to 70 mg/gm, and even more preferably from about 40 mg/gm to about 65 mg/gm.
- the pharmaceutically acceptable solvents suitable for the present invention include polyethylene glycol (PEG series such as PEG 300, 400, 600, etc), propylene glycol, efhanol, glycerol, triacetin, glycofurol, propylene carbonate, dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidinone, or a mixture thereof.
- the preferred solvents of the present invention include polyethylene glycol (PEG series), propylene glycol, ethanol, or a mixture thereof.
- the total amount of the solvent present in the composition is generally from about 100 to about 700 mg/g and preferably from about 250 to about 400 mg/g.
- the pharmaceutically acceptable surfactants suitable for the present invention are non-ionic surfactants including polyoxyl 40 hydrogenated castor oil (sold under the trade name Cremophor RH40®), polyoxyl 35 castor oil (sold under the trade name Cremophor EL®), polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Pluronics), vitamin E- TPGS 1000 (VE-TPGS 1000), polyoxyethylene alkyl ethers, Solutol HS-15, Tagat TO, Peglicol 6-oleate, polyoxyethylene sterates, or saturated polyglycolyzed glycerides, all of which are commercially available.
- non-ionic surfactants including polyoxyl 40 hydrogenated castor oil (sold under the trade name Cremophor RH40®), polyoxyl 35 castor oil (sold under the trade name Cremophor EL®), polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Plur
- the preferred surfactants include polyoxyl 40 hydrogenated castor oil (Cremophor RH40®), polyoxyl 35 hydrogenated castor oil (Cremophor EL®), polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Pluronics), and vitamin E-TPGS 1000.
- the total amount of the surfactant present in the composition is generally from about 100 to about 700 mg/g, and preferably from about 300 to about 500 mg/g.
- the weight ratio of paclitaxel to the surfactant, such as polyethoxylated castor oil, in the compositions of the present invention is preferably between 1:3 to 1:20, and more preferably between 1 :5 to 1 : 10 by weight.
- the content of polyethoxylated castor oil relative to the content of paclitaxel in the composition is considerably lower in the compositions of the present invention than that in the Taxol® formulation.
- substituted cellulosic polymer used herein refers to a cellulosic polymer having at least a portion of substitutable hydroxyl groups substituted with methoxyl and/or hydroxypropyl groups.
- compositions of the present invention comprise at least one substituted cellulosic polymer.
- the substituted cellulosic polymer is substantially water-soluble.
- Examples of the preferred substituted cellulosic polymers suitable in the present invention include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethylcellulose, maltodextrin, and povidones. More preferably, the substituted cellulosic polymer is HPMC, HPC, hydroxyethylcellulose, methylcellulose, and povidones. Even more preferably, the substituted cellulosic polymer is HPMC.
- Suitable HPMCs that are relatively hydrophilic in nature are illustratively available under the brand names MethocelTM (Dow Chemical Co.) and MetoloseTM (Shin-Etsu Chemical Co.).
- HPMC useful in the present invention preferably has a viscosity of about 1 to about 100,000 cps when the concentration is about 2% (w/w) in water.
- the low viscosity HPMC polymer is preferred.
- HPMC polymers that show a viscosity of 3 to 500 cps in water with 2% concentration is most preferred.
- HPMC polymers vary in the degree of substitution of available hydroxyl groups on the cellulosic backbone by methoxyl groups and by hydroxypropyl groups. With increasing hydroxypropyl substitution, the resulting HPMC becomes more hydrophilic in nature.
- the HPMC polymer preferably have about 15% to about 35%, more preferably about 19% to about 30%, and most preferably about 19% to about 24%, methoxyl substitution, and having about 3% to about 15%, more preferably about 4% to about 12%, and most preferably about 7% to about 12%, hydroxypropyl substitution.
- HPMC types 2208 and 2910 which have a normal viscosity of about 1 to 100,000 cps when the polymer concentration is 2% in water.
- An especially preferred HPMC type is 2910 denoting about 28% to 30% methoxyl substitution and about 7% to about 12% hydroxypropyl substitution, and with a nominal viscosity of about 2 to 4000 cps when the HPMC concentration is 2% in water (w/w).
- the cellulosic polymer can be suspended or dissolved in the liquid formulation of the invention, or alternatively, the substituted cellulosic polymer may be present as a component of the wall of the capsule wherein a liquid formulation of the invention is encapsulated.
- substantially no HPMC or other substituted cellulosic polymer is present in the liquid but the capsule wall comprises HPMC.
- the capsule wall preferably comprises predominantly of HPMC.
- the substituted cellulosic polymer is present in an amount sufficient to substantially either retard or inhibit drug precipitation and/or crystallization upon dilution of the composition in an aqueous medium.
- An amount sufficient to "substantially inhibit drag precipitation and/or crystallization” herein means an amount sufficient to prevent, slow, inhibit or delay precipitation of drug from solution and/or to prevent, or inhibit or retard, or delay formation of crystalline drug particles from dissolved drug.
- the specific amount required of the substituted cellulosic polymer type depends on factors such as the particular polymer type being used and the paclitaxel concentration in the composition.
- the amount of the substituted cellulosic polymer needed to inhibit drug crystallization and/or precipitation can be determined according to Test I described below, which can also be used to determine whether a particular polymer type or a mixture of polymers is useful as a crystallization inhibitor in a particular composition of the invention.
- a volume of a test composition, either in unencapsulated or encapsulated form, having a polymer component is placed in a volume of simulated gastric fluid (SGF) to form a mixture having a fixed ratio of about 1 g to about 2 g of the composition per 100 ml of SGF.
- SGF simulated gastric fluid
- the mixture is maintained at a constant temperature of about 37°C and is stirred using type II paddles (USP 24) at a rate of 75 rpm for a period of 4 hours.
- type II paddles USP 24
- test is repeated identically with a comparative formulation that is substantially similar to the test formulation except that it lacks the polymer component.
- the polymer component in the test formulation is present as a component in the solvent liquid, it is replaced in the comparative formulation by polyethylene glycol.
- the polymer component in the test formulation is present as a component of a capsule wall, it is replaced in the comparative formulation with gelatin.
- the polymer component present in the test formulation is deemed to substantially inhibit precipitation and/or crystallization of the drag in simulated gastric fluid.
- a crystallization inhibitor such as HPMC when present in the formulation, is generally present in a total amount of about 1% to about 20%, preferably about 1% to about 15%, and most preferably about 1% to about 10%, by weight of the formulation.
- the higher the drug concentration in the composition the more of the cellulosic polymer will be required to provide a crystallization-inhibiting effect.
- the cellulosic polymer and drug are present in a ratio of about 50: 1 to about 0.1 : 1 , preferably about 10: 1 to about 0.1:1 and more preferably about 5:lto about 0.5:1, by weight.
- HPMC as a crystallization inhibitor as provided herein advantageously and substantially improves the bioavailability of paclitaxel and permits a reduction in the amount of the surfactant which is known to cause undesirable side effects when administered orally in large amounts.
- a typical composition of the present invention comprises: a) paclitaxel or an analog thereof at an amount of up to 100 mg/g; b) a pharmaceutically acceptable solvent in an amount of from about 100 to about 700 mg/g; c) a pharmaceutically acceptable surfactant in an amount of from about 100 to about 700 mg/g; and d) a substituted cellulosic polymer in an amount of from about 10 to about 300 mg/g.
- the composition of the present invention comprises: a) paclitaxel or an analog thereof at an amount of up to 100 mg/g; b) a pharmaceutically acceptable solvent selected from the group consisting of polyethylene glycol (PEG series), propylene glycol, ethanol, or a mixture thereof. c) a pharmaceutically acceptable surfactant selected from the group consisting of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, polyoxyethylene sorbitan fatty acid esters, poloxamers, and Vitamin E-TPGS 1000; and d) a substituted cellulosic polymer selected from the group consisting of HPMC, HPC, methylcellulose, hydroxyethylcellulose, and povidones.
- a pharmaceutically acceptable solvent selected from the group consisting of polyethylene glycol (PEG series), propylene glycol, ethanol, or a mixture thereof.
- the pharmaceutical compositions according to the present invention may further comprise a diglyceride or a mixture of diglyceride and monoglyceride.
- the diglycerides and monoglycerides suitable in the present invention are those that contain fatty acids of a carbon chain having 8 to 22 carbons with 0 to 3 double bonds.
- suitable fatty acids for the diglycerides and monoglycerides include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and docosahexaenoic acid.
- the fatty acids that are contained in the diglycerides and monoglycerides suitable for the present invention have a carbon chain of 16 to 18 carbons with 1-2 double bonds, such as oleic acid and linoleic acid.
- the preferred diglyceride is diolein, dilinoleate, or a mixture of diolein and dilinoleate.
- the most preferred diglyceride is diolein.
- the preferred monoglyceride is monoolein, monolinoleate, or a mixture of monoolein and monolinoleate.
- the most preferred monoglyceride is monoolein.
- All of the glycerides of the present invention are known and can be prepared by conventional methods.
- the mixture of diglyceride and monoglyceride may be prepared by mixing individual diglyceride and monoglyceride in appropriate relative proportion or by partial hydrolysis of triglyceride, or by transesterification reaction of triglycerides, or diglycerides with glycerol.
- the diglyceride in the absence of monoglyceride in the composition, or the mixture of the diglyceride and monoglyceride present in the composition is generally from about 10% to about 90%, preferably from about 40% to about 70%, and more preferably from about 50% to about 60%, by weight relative to the total weight of the composition.
- the ratio of diglyceride to monoglyceride (diglyceride : monoglyceride) by weight is preferably from about 9: 1 to about 6:4.
- compositions of the present invention for use by oral administration may further comprise a P-glycoprotein inhibitor.
- P-glycoprotein inhibitors Through the use of P-glycoprotein inhibitors, the paclitaxel more readily transverses the mucosal cells of the small intestine and is therefore more readily absorbed into the systemic circulation.
- compositions of the present invention comprises: a) paclitaxel or an analog thereof; b) a pharmaceutically acceptable surfactant; c) a pharmaceutically acceptable solvent; d) a substituted cellulosic polymer; and e) a P-glycoprotein inhibitor.
- composition containing a P-glycoprotein inhibitor as defined above further comprises a diglyceride or a mixture of diglyceride and monoglyceride.
- the P-glycoprotein inhibitors useful in the compositions of the present invention are those that are described in U.S. Pat. Nos 5,968,972 and 6,028,054.
- the compounds that may be used as p-glycoprotein inhibitors and the amounts of such compounds that are required to sufficiently inhibit p-glycoprotein can be identified by the method and process described in U.S. Pat. No. 6,028,054.
- the full disclosure of U.S. Pat. Nos 5,968,972 and 6,028,054 is incorporated herein by reference.
- Examples of the preferred P-glycoprotein inhibitors useful in the compositions of the present invention include alginates, xanthan, gellan gum,CRK- 1605, cyclosporin A, verapamil, tamoxifen, quinidine, valspodar, SDZ PSC 833, GF120918 (GG918, GW0918), ketocomazole, Psoralens, sucroster-15, R101933, OC144-093, Erythromycin, azithromycin, RS-33295-198, MS-209, XR9576, phenothiazine.
- the P- glycoprotein inhibitor is incorporated in the paclitaxel compositions of the present invention in an amount of from about 0.1 to about 20 mg/kg body weight. The specific amount of the P- glycoprotein inhibitor required in the composition depends on factors such as the particular P- glycoprotein inhibitor used and the weight of the patients being treated.
- compositions of the present invention may be prepared in a conventional manner, for example, by dissolving paclitaxel in the solvent, then adding the surfactant, the substituted cellulosic polymer, and optionally the diglyceride or the mixture of diglyceride and monoglyceride.
- the resulting solution can then be formulated into the desired dosage form such as, for example, soft elastic gelatin capsules or hard gelatin capsules by known manufacturing technology.
- the cellulosic polymer is not suspended in fill solution, but, instead, the cellulosic polymer is in the capsule shell as in an HPMC capsule.
- compositions of the present invention can be prepared in any one of a number of alternate delivery systems known in the art.
- the composition may be filled into a soft or hard gelatin capsule, or other oral dosage forms.
- Any suitable encapsulation material for example, gelatin or HPMC, can be used.
- HPMC can be an advantageous material for use in the capsule wall because it can act as a precipitation and/or crystallization inhibitor upon exposure of the composition to the gastrointestinal fluid.
- a substituted cellulosic polymer component such as HPMC is "present in the capsule wall” or is a “capsule wall component” as described herein if the polymer is (a) dispersed or mixed together with any other capsule wall component(s), (b) the only capsule wall component, or (c) present as a coating on the outside or inside of the capsule wall.
- a substituted cellulosic polymer as described hereinabove preferably HPMC
- HPMC a substituted cellulosic polymer as described hereinabove
- the suitable capsule wall can comprise any additional component useful in the art such as gelatin, starch, carrageenan, sodium alginate, plasticizers, potassium chloride, coloring agents, etc.
- the solution or solution/suspension contained therein can additionally, but optionally, comprise a further amount of the same polymer or a different substituted cellulosic polymer.
- Concentrated solutions or solutions/suspensions can be encapsulated by any method known in the art including the plate process, vacuum process, or the rotary die process. See, for example, Ansel et al. (1995) in Pharmaceutical Dosage Forms and Drag Delivery Systems. 6th ed., Williams & Wilkins, Baltimore, MD, pp. 176-182.
- liquid encapsulation material for example gelatin
- metered fill material is injected between ribbons at the same moment and the dies form pockets within the ribbons. These pockets of fill-containing encapsulation material are then sealed by pressure and heat, and the capsules are dispersed from the machine.
- Soft gelatin capsules can be manufactured in different shapes including round, oval, oblong, and tube-shape, among others. Additionally, by using two different ribbon colors, two-tone capsules can be produced.
- Capsules that comprise HPMC are known in the art and can be prepared, sealed and/or coated, by way of non-limiting illustration, according to processes disclosed in the patents and publications listed below, each of which is individually incorporated herein by reference.
- Non-limiting illustrative examples of suitable HPMC-comprising capsules include capsules manufactured and distributed by BioProgress (XGelTM), Capsugel, and Shionogi QualicapsTM.
- compositions of the invention are provided that are required to be diluted to provide a dilution suitable for direct, imbibable administration.
- the compositions of the present invention are added, in a therapeutically effective dosage amount, to about 1 ml to about 20 ml of an inert liquid.
- compositions of the present invention are added to about 2 ml to about 15 ml, and more preferably to about 5 ml to about 10 ml, of inert liquid.
- inert liquid refers to pharmaceutically acceptable, preferably palatable liquid carriers. Such carriers are typically aqueous. Examples include water, fruit juices, carbonated beverages, etc.
- Example 1 is an example of the procedures that can be used to prepare the compositions of the present invention.
- Examples 2 - 4 are provided to more specifically detail particular embodiments of the novel compositions of the present invention.
- Examples 1 - 4 are provided for illustrative purposes only however, and it is recognized that minor changes and alterations can be made with respect to the particular ingredients and their disclosed amounts, or with respect a particular step of the procedure for preparing the composition. It is to be understood that to the extent any such changes do not in fact materially alter and/or re-formulate the final composition, such changes are to be considered as falling within the spirit and scope of the invention as recited by the claims that follow.
- compositions of Examples 5 and 6 below are provided for comparative purposes only.
- the composition of Example 5 is substantially similar to the composition of Example 2 except that it contains no substituted cellulosic polymer (HPMC).
- HPMC substituted cellulosic polymer
- compositions of Examples 6 is substantially similar to the composition of Example 3 except that it contains no substituted cellulosic polymer (HPMC).
- HPMC substituted cellulosic polymer
- Drug is placed in a vial and the appropriate amount of solvent or a mixture of solvents (such as PEG 400 and ethanol with an appropriate ratio) is added into the vial.
- the vial is then capped.
- the vial is put into a water bath of about 50-60 °C and shaken gently until all of the drug material is completely dissolved.
- an appropriate amount of surfactant such as Cremophor EL
- the vial is then capped and placed into the water bath of about 50-60 °C.
- the vial is shaken gently to obtain a clear, uniform solution.
- This solution can be filled into HPMC capsules and stored at room temperature before oral dosing.
- the substituted polymer powders such as HPMC
- the substituted polymer powders can be added into the solution with adequate agitation (i.e., stirring, shaking) to obtain a uniform polymer suspension.
- the resulting composition can then be filled into either soft gelatin or hard gelatin capsules and stored at room temperature before oral dosing.
- Paclitaxel 57.2 Absolute ethanol 152.1 PEG-400 152.1 Cremophor EL 400 Glyceryl dioleate 190 HPMC-E5 47.6 Total 1000
- Paclitaxel 60 Absolute ethanol 150 PEG-400 150
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02718808A EP1365759A2 (en) | 2001-01-18 | 2002-01-14 | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
CA002434641A CA2434641A1 (en) | 2001-01-18 | 2002-01-14 | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
JP2002563926A JP2004520398A (en) | 2001-01-18 | 2002-01-14 | Paclitaxel chemotherapy microemulsion composition with improved oral bioavailability |
MXPA03006404A MXPA03006404A (en) | 2001-01-18 | 2002-01-14 | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26255501P | 2001-01-18 | 2001-01-18 | |
US60/262,555 | 2001-01-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002064132A2 true WO2002064132A2 (en) | 2002-08-22 |
WO2002064132A3 WO2002064132A3 (en) | 2003-05-30 |
Family
ID=22998000
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/000497 WO2002064132A2 (en) | 2001-01-18 | 2002-01-14 | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1365759A2 (en) |
JP (1) | JP2004520398A (en) |
AR (1) | AR032642A1 (en) |
CA (1) | CA2434641A1 (en) |
MX (1) | MXPA03006404A (en) |
NZ (1) | NZ539046A (en) |
PE (1) | PE20020833A1 (en) |
WO (1) | WO2002064132A2 (en) |
ZA (1) | ZA200305086B (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004009075A1 (en) * | 2002-07-20 | 2004-01-29 | Korea Institute Of Science And Technology | Composition for solubilization of paclitaxel and preparation method thereof |
US6750246B1 (en) | 2000-02-03 | 2004-06-15 | Bristol-Myers Squibb Company | C-4 carbonate taxanes |
EP1498120A1 (en) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Semi-solid formulations for the oral administration of taxoids |
EP1499304A1 (en) * | 2002-04-15 | 2005-01-26 | Laurence Paris | Liquid compositions for soft sustained-release capsules and method for production thereof |
WO2005014048A1 (en) * | 2003-07-18 | 2005-02-17 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
JP2007506782A (en) * | 2003-09-25 | 2007-03-22 | アクティブバイオティクス インコーポレイティッド | Rifalazil formulation |
WO2009045837A1 (en) * | 2007-09-28 | 2009-04-09 | Zomanex, Llc | Methods and formulations for converting intravenous and injectable drugs into oral dosage forms |
WO2012063182A1 (en) | 2010-11-08 | 2012-05-18 | Cadila Pharmaceuticals Limited | Pharmaceutical composition of taxoids |
CN103110581A (en) * | 2013-02-26 | 2013-05-22 | 西南大学 | Taxol microemulsion drug composition and preparation method thereof |
US9655860B2 (en) | 2006-10-27 | 2017-05-23 | Capsugel Belgium Nv | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
CN108136030A (en) * | 2015-07-30 | 2018-06-08 | 大化制药株式会社 | The pharmaceutical composition for oral medication containing high concentration taxane |
EP3213746A4 (en) * | 2014-10-31 | 2018-06-27 | Dae Hwa Pharma. Co., Ltd | Pharmaceutical composition for oral administration comprising taxane |
CN108601759A (en) * | 2016-02-04 | 2018-09-28 | 上海宣泰医药科技有限公司 | A kind of taxol drug composition and its pharmaceutical preparation, preparation method and purposes |
EP3701943A1 (en) * | 2019-02-26 | 2020-09-02 | CAPNOMED GmbH | Delayed delivery of anticancer drugs |
WO2023220109A1 (en) * | 2022-05-11 | 2023-11-16 | Eli Lilly And Company | Glp1 pharmaceutical compositions |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2611592A1 (en) * | 2005-06-17 | 2006-12-21 | Hospira Australia Pty Ltd | Liquid pharmaceutical formulations of docetaxel |
KR101053780B1 (en) * | 2008-02-29 | 2011-08-02 | 동아제약주식회사 | Single liquid stable pharmaceutical composition containing docetaxel |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH688504A5 (en) * | 1997-03-26 | 1997-10-31 | Marigen Sa | Spontaneously dispersible concentrate containing a taxol analogue |
WO1998053811A1 (en) * | 1997-05-27 | 1998-12-03 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
WO1998058927A1 (en) * | 1997-06-20 | 1998-12-30 | Baker Norton Pharmaceuticals, Inc. | Soluble prodrugs of paclitaxel |
WO1999045918A1 (en) * | 1998-03-10 | 1999-09-16 | Napro Biotherapeutics, Inc. | Methods and compositions for delivery of taxanes |
US6057359A (en) * | 1996-09-24 | 2000-05-02 | Marigen S.A. | Spontaneously dispersible concentrates comprising esters of baccatin-III compounds having antitumor and antiviral activity |
WO2000033862A1 (en) * | 1998-12-11 | 2000-06-15 | Pharmasolutions, Inc. | Self-emulsifying compositions for drugs poorly soluble in water |
US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
WO2000072827A2 (en) * | 1999-05-27 | 2000-12-07 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
WO2000078247A1 (en) * | 1995-10-26 | 2000-12-28 | Baker Norton Pharmaceuticals, Inc. | Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same |
WO2002043765A2 (en) * | 2000-11-28 | 2002-06-06 | Transform Pharmaceuticals, Inc. | Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof |
-
2002
- 2002-01-14 CA CA002434641A patent/CA2434641A1/en not_active Abandoned
- 2002-01-14 WO PCT/US2002/000497 patent/WO2002064132A2/en not_active Application Discontinuation
- 2002-01-14 MX MXPA03006404A patent/MXPA03006404A/en unknown
- 2002-01-14 EP EP02718808A patent/EP1365759A2/en not_active Withdrawn
- 2002-01-14 NZ NZ539046A patent/NZ539046A/en unknown
- 2002-01-14 JP JP2002563926A patent/JP2004520398A/en active Pending
- 2002-01-17 AR ARP020100158A patent/AR032642A1/en unknown
- 2002-01-17 PE PE2002000030A patent/PE20020833A1/en not_active Application Discontinuation
-
2003
- 2003-06-30 ZA ZA200305086A patent/ZA200305086B/en unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000078247A1 (en) * | 1995-10-26 | 2000-12-28 | Baker Norton Pharmaceuticals, Inc. | Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same |
US6057359A (en) * | 1996-09-24 | 2000-05-02 | Marigen S.A. | Spontaneously dispersible concentrates comprising esters of baccatin-III compounds having antitumor and antiviral activity |
CH688504A5 (en) * | 1997-03-26 | 1997-10-31 | Marigen Sa | Spontaneously dispersible concentrate containing a taxol analogue |
WO1998053811A1 (en) * | 1997-05-27 | 1998-12-03 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
WO1998058927A1 (en) * | 1997-06-20 | 1998-12-30 | Baker Norton Pharmaceuticals, Inc. | Soluble prodrugs of paclitaxel |
WO1999045918A1 (en) * | 1998-03-10 | 1999-09-16 | Napro Biotherapeutics, Inc. | Methods and compositions for delivery of taxanes |
WO2000033862A1 (en) * | 1998-12-11 | 2000-06-15 | Pharmasolutions, Inc. | Self-emulsifying compositions for drugs poorly soluble in water |
WO2000072827A2 (en) * | 1999-05-27 | 2000-12-07 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
WO2002043765A2 (en) * | 2000-11-28 | 2002-06-06 | Transform Pharmaceuticals, Inc. | Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof |
Non-Patent Citations (3)
Title |
---|
EISEMAN, J.L. ET AL: "Plasma pharmacokinetics and tissue distribution of paclitaxel in cd2f1 mice" CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 34, no. 6, 1994, pages 465-471, XP001085493 * |
SHARMA D ET AL: "NOVEL TAXOL(R) FORMULATION: POLYVINYLPYRROLIDONE NANOPARTICLE-ENCAPSULATED TAXOL(R) FOR DRUG DELIVERY IN CANCER THERAPY" ONCOLOGY RESEARCH, PERGAMON PRESS, NEW YORK, NY, US, vol. 8, no. 7/8, 1996, pages 281-286, XP001036566 ISSN: 0965-0407 * |
SLATER, L. ET AL: "Comparison of cyclosporin A, verapamil, PSC-833 and Cremophor EL as enhancing agents of VP-16 in murine lymphoid leukemias" LEUKEMIA RESEARCH, vol. 19, no. 8, - 1995 pages 543-548, XP002218026 * |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6750246B1 (en) | 2000-02-03 | 2004-06-15 | Bristol-Myers Squibb Company | C-4 carbonate taxanes |
EP1499304A1 (en) * | 2002-04-15 | 2005-01-26 | Laurence Paris | Liquid compositions for soft sustained-release capsules and method for production thereof |
US8075917B2 (en) | 2002-07-20 | 2011-12-13 | Daehwa Pharm. Co., Ltd. | Composition for solubilization of paclitaxel and preparation method thereof |
WO2004009075A1 (en) * | 2002-07-20 | 2004-01-29 | Korea Institute Of Science And Technology | Composition for solubilization of paclitaxel and preparation method thereof |
EP1498120A1 (en) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Semi-solid formulations for the oral administration of taxoids |
WO2005013968A1 (en) * | 2003-07-18 | 2005-02-17 | Aventis Pharma S.A. | Semi-solid formulations for the oral administration of taxoids |
WO2005014048A1 (en) * | 2003-07-18 | 2005-02-17 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
AU2004262495B2 (en) * | 2003-07-18 | 2011-02-03 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
JP2007506782A (en) * | 2003-09-25 | 2007-03-22 | アクティブバイオティクス インコーポレイティッド | Rifalazil formulation |
US10004692B2 (en) | 2006-10-27 | 2018-06-26 | Capsugel Belgium Nv | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
EP3594248A1 (en) * | 2006-10-27 | 2020-01-15 | Capsugel Belgium NV | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
US9655860B2 (en) | 2006-10-27 | 2017-05-23 | Capsugel Belgium Nv | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
EP3954715A3 (en) * | 2006-10-27 | 2022-05-04 | Capsugel Belgium NV | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
EP2078042B1 (en) * | 2006-10-27 | 2019-06-12 | Capsugel Belgium NV | Hydroxypropyl methyl cellulose hard capsules and process of manufacture |
WO2009045837A1 (en) * | 2007-09-28 | 2009-04-09 | Zomanex, Llc | Methods and formulations for converting intravenous and injectable drugs into oral dosage forms |
EP2637655A4 (en) * | 2010-11-08 | 2016-11-02 | Cadila Pharmaceuticals Ltd | Pharmaceutical composition of taxoids |
WO2012063182A1 (en) | 2010-11-08 | 2012-05-18 | Cadila Pharmaceuticals Limited | Pharmaceutical composition of taxoids |
CN103110581A (en) * | 2013-02-26 | 2013-05-22 | 西南大学 | Taxol microemulsion drug composition and preparation method thereof |
CN103110581B (en) * | 2013-02-26 | 2015-07-22 | 西南大学 | Taxol microemulsion drug composition and preparation method thereof |
EP3213746A4 (en) * | 2014-10-31 | 2018-06-27 | Dae Hwa Pharma. Co., Ltd | Pharmaceutical composition for oral administration comprising taxane |
US10653663B2 (en) | 2014-10-31 | 2020-05-19 | Dae Hwa Pharma. Co., Ltd. | Pharmaceutical composition for oral administration comprising taxane |
RU2683326C2 (en) * | 2014-10-31 | 2019-03-28 | Дэ Хва Фарма.Ко., Лтд. | Pharmaceutical composition for oral admission containing taxan |
CN108136030A (en) * | 2015-07-30 | 2018-06-08 | 大化制药株式会社 | The pharmaceutical composition for oral medication containing high concentration taxane |
EP3326652A4 (en) * | 2015-07-30 | 2018-12-26 | Dae Hwa Pharma. Co., Ltd | Pharmaceutical composition for oral administration comprising high concentration taxane |
CN108136030B (en) * | 2015-07-30 | 2021-01-26 | 大化制药株式会社 | Pharmaceutical composition for oral administration containing high concentration of taxane |
US10987335B2 (en) | 2015-07-30 | 2021-04-27 | Dae Hwa Pharma. Co., Ltd. | Pharmaceutical composition for oral administration comprising high concentration taxane |
EP3412286A4 (en) * | 2016-02-04 | 2019-09-11 | Sinotherapeutics Inc. | Taxol drug composition and pharmaceutic preparation, preparation method therefor and use thereof |
US10940135B2 (en) | 2016-02-04 | 2021-03-09 | Sinotherapeutics Inc. | Paclitaxel pharmaceutical composition and pharmaceutical preparation thereof, preparation process and use thereof |
CN108601759A (en) * | 2016-02-04 | 2018-09-28 | 上海宣泰医药科技有限公司 | A kind of taxol drug composition and its pharmaceutical preparation, preparation method and purposes |
EP3701943A1 (en) * | 2019-02-26 | 2020-09-02 | CAPNOMED GmbH | Delayed delivery of anticancer drugs |
WO2020173643A1 (en) * | 2019-02-26 | 2020-09-03 | CAPNOMED GmbH | Delayed delivery of anticancer drugs |
WO2023220109A1 (en) * | 2022-05-11 | 2023-11-16 | Eli Lilly And Company | Glp1 pharmaceutical compositions |
Also Published As
Publication number | Publication date |
---|---|
PE20020833A1 (en) | 2002-09-19 |
NZ539046A (en) | 2006-11-30 |
WO2002064132A3 (en) | 2003-05-30 |
ZA200305086B (en) | 2004-06-30 |
MXPA03006404A (en) | 2004-12-02 |
JP2004520398A (en) | 2004-07-08 |
AR032642A1 (en) | 2003-11-19 |
EP1365759A2 (en) | 2003-12-03 |
CA2434641A1 (en) | 2002-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7115565B2 (en) | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability | |
US6306434B1 (en) | Pharmaceutical composition comprising cyclosporin solid-state microemulsion | |
JP3276368B2 (en) | Two-phase release formulation for lipophilic drugs | |
EP1365759A2 (en) | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability | |
ES2326783T3 (en) | COMPOSITIONS OF N-BENZOILESTAUROSPORINA SPONTANEAMY DISPERSABLE. | |
EA029996B1 (en) | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative | |
CN101926757A (en) | Liquid composition of indissolvable medicines and preparation method thereof | |
BRPI0809563A2 (en) | MODIFIED DOSAGE FORMS OF TACROLIMUS | |
US20210346302A1 (en) | Pharmaceutical Formulation | |
JPH0451528B2 (en) | ||
CN112168781B (en) | Tacrolimus self-microemulsion composition and preparation method thereof | |
CN101269012A (en) | Supersaturation self-microemulsion oral preparation of paclitaxel and its derivative | |
JP3585245B2 (en) | Sertraline gelatin encapsulated solution dosage form | |
AU2002249926A1 (en) | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability | |
US20100010083A1 (en) | Pharmaceutical composition for oral administration | |
Gao et al. | Design and development of supersaturatable self-emulsifying drug delivery systems for enhancing the gastrointestinal absorption of poorly soluble drugs | |
US20230310465A1 (en) | Nano lipid carrier system for improving permeation of active ingredients | |
JP2002540158A (en) | Pharmaceutical emulsion for retroviral protease inhibitors | |
AU2922800A (en) | Pharmaceutical compositions for oral administration comprising a benzamide and at least an absorption promoter | |
CN117771249A (en) | Lapattinib self-microemulsion composition and preparation method thereof | |
BR102018016507A2 (en) | GUAIFENESIN EXTENDED RELEASE NET COMPOSITION | |
JP2010513351A (en) | Gelatin capsule containing acid | |
MXPA99012099A (en) | Gelatine encapsulated solution dosage forms of sertraline | |
AU2006277879A1 (en) | Microparticle compositions of the topoisomerase I inhibitor 7-tert-butoxyiminomethylcamptothecin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002249926 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002718808 Country of ref document: EP Ref document number: 2434641 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 526977 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/006404 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002563926 Country of ref document: JP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2002718808 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2002718808 Country of ref document: EP |