WO2014147631A1 - Formulation comprenant du géfitinib comme suspension orale - Google Patents

Formulation comprenant du géfitinib comme suspension orale Download PDF

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Publication number
WO2014147631A1
WO2014147631A1 PCT/IN2013/000194 IN2013000194W WO2014147631A1 WO 2014147631 A1 WO2014147631 A1 WO 2014147631A1 IN 2013000194 W IN2013000194 W IN 2013000194W WO 2014147631 A1 WO2014147631 A1 WO 2014147631A1
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Prior art keywords
agents
oral
agent
gefitinib
suspension
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Ceased
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PCT/IN2013/000194
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English (en)
Inventor
Durga Maheswari PARVATENENI
Deepthi SOMA
Venkata Satyanarayana APPADWEDULA
Kali Satya Bhujanga Rao Adibhatla
Venkaiah Chowdary NANNAPENENI
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Natco Pharma Ltd
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Natco Pharma Ltd
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Priority to PCT/IN2013/000194 priority Critical patent/WO2014147631A1/fr
Publication of WO2014147631A1 publication Critical patent/WO2014147631A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to pharmaceutical compositions of gefitinib and process of preparation thereof.
  • Gefitinib is an antineoplastic agent and it is chemically designated as 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-mo holi ) propoxy] with molecular formula C 22 H2 4 C1FN 4 0 3 and currently indicated for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.
  • Gefitinib is a useful addition to treatment of patientsj ⁇ ith.locaU-v-ad-vaneed-head-and'n ' euk cancer.
  • Gefitinib is commercially available as film coated tablets of 250 mg strength under the trade name of Iressa ® manufactured by Astrazeneca.
  • Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK).
  • EGFR is expressed on the cell surface of many normal cells and cancer cells.
  • Gefitinib is slowly absorbed after oral administration with peak plasma levels occurring 3-7 hours after dosing. It was also reported that mean oral bioavailability is 60%. Biotransformation of gefitinib is via hepatic metabolism and cytochrome P450 enzymes (especially CYP3A4). .
  • Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and a 1 -acid glycoprotein) is 90% and is independent of drug concentrations.
  • Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
  • U.S. Patent nos. 5457105, 5616582, 5770599 discloses synthesis of gefitinib and pharmaceut-iGall-y-aeeeptable-saltsT ⁇ he ingredients for formulation of conventional tablets detailed in this prior art comprise active ingredient, lactose, croscarmellose sodium, maize starch, polyvinyl pyrrolidone, magnesium stearate.
  • EP 0823900 Bl and WO 96/33980 disclose the same.
  • WO 2005/070909, WO 2010/076810 and U.S. Patent application no. 20100137586 discloses process for preparation of gefitinib.
  • WO 2006/090413 describes a stable novel crystalline form of gefitinib and a process for the preparation of the same which is useful in the treatment of a variety of solid tumors.
  • the prior art discloses methods and pharmaceutical composition of a therapeutic agent which enhances sensitivity of a cancer to a molecular target drug in U.S. Patent application no. 20120064090, U.S. Patent no. 8017321 corresponding PCT application no. PCT/US2005/002325.
  • U.S. Patent application no. like 201 10294686, 20070270505 also disclose the same.
  • U.S. Patent application no. 20090098138 corresponding PCT application no. PCT/US07/66857 and U.S. Patent application no. 20100173285 discloses a method of detecting the expression of a protein from circulating cancer cells and EGFR mutations to determine patient responsiveness to gefitinib administration.
  • U.S. Patent application no. 20090185999 and 20090186892 discloses quinazoline derivatives for treating lung cancers.
  • Gefitinib is presently available as tablet dosage form in market. None of the above said prior arts discloses and/or envisages an oral suspension. Hence, the development of an oral suspension alleviates problems associated with swallowing tablets in head and neck cancer patients.
  • the oral suspension dosage form can also be a viable alternative for geriatric patients who unable to or prefer not to swallow a solid dosage form since it o-ffer-s-impFOved-pat-ient-complianc ⁇ n n Eable with good organoleptic properties.
  • gefitinib is having all the above favorable features suitable to formulate an oral suspension, the work on present invention was taken up.
  • the present invention relates to design and development of an oral suspension containing gefitinib and a process for its preparation, indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.
  • the main objective of the present invention is to design and develop an oral suspension containing gefitinib for monotherapy treatment for locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.
  • Another objective of this invention is to provide a dosage form ensuring adequate therapeutic levels of drug concentration.
  • Another objective of this invention is to provide a desirable oral formulation for the — treatment-of-elderly ⁇ tteTiislto swallow easily.
  • Yet another objective of the present invention is to provide simple process for the preparation of a stable aqueous formulation of gefitinib.
  • Yet another objective of the present invention enhances patient compliance.
  • further objective of this invention is to provide the pharmaceutical composition of an oral suspension to ensure adequate therapeutic levels for the therapy against aforementioned diseases. Accordingly, further objective of this invention is to meet the particular needs of patients who find difficulty in swallowing solid oral dosage forms.
  • the objective of the present invention is to develop a process for preparing the oral suspension comprising active ingredient, one or more of a vehicle, suspending agent, preservatives, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and the like.
  • the main embodiment of the present invention is to design and develop a stable aqueous oral formulation that can be swallowed easily and comprising gefitinib, a process for its preparation, wherein the said formulation has pH in the range of about 2.5 to 5.5 for the monotherapy treatment of locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.
  • An aqueous suspension for oral administration in humans comprising of therapeutically effective amount of gefitinib, one or more of a vehicle, suspending agent, preservatives, wettm " g ⁇ ageTTts, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and the like intended to treat metastatic non-small cell lung cancer or unresectable head and neck cancer.
  • the formulation of the present invention comprises wherein the oral suspension contains a therapeutically effective pharmaceutical ingredient, gefitinib used in the range of about 0.1% to about 20%, by weight by volume of the total suspension.
  • compositions of the present invention include a vehicle which is pharmaceutically acceptable serves as the external phase of the suspensions.
  • a preferred vehicle of the present invention may include water, glycerin, propylene glycol and mixtures thereof.
  • other vehicles may include but not restricted to, sorbitol solution, polyethylene glycol and the like.
  • the formulation of the present invention may include an appropriate amount of suspending agents that can add a desired viscosity and flow to a formulation or effective to stabilize the pharmaceutically active agent within the aqueous composition.
  • suspending agents for example, in a suspension a viscosity enhancer will help to keep the active ingredient suspended to allow accurate dosing.
  • a preferred suspending agent of the present invention may include hypromellose, polyvinylpyrrolidone, magnesium aluminium silicate and xanthan gum.
  • suspending agents may include but not restricted to, carbomer, hydrocolloid gums like guar gum, gum tragacanth and cellulose derivatives for example methyl-, ethyl- and propyl celluloses; hydroxyalkyl-celluloses, hydroxyl propyl celluloses, hydroxylpropylalkyl celluloses, sodium carboxy methyl cellulose, micro
  • resins polyethylene glycol, polyethylene oxide, sodium alginate and the like.
  • compositions of the present invention may include an appropriate amount of preservatives to prevent growth of micro organisms.
  • a preferred anti microbial agents of the present invention is benzyl alcohol, methyl and propyl parabens.
  • preservatives may include but not restricted to, butyl paraben, ethyl paraben, sorbic acid, potassium sorbate, benzalkonium chloride, benzoic acid and its derivatives such as sodium benzoate and the like.
  • compositions of the present invention include wetting agents to increase suspendability of hydrophobic drugs in aqueous media by reducing interfacial tension between drug particles and the suspension vehicle, thereby allowing penetration of suspension vehicle into drug aggregates and/or drug particle pores.
  • a preferred wetting agent of the present invention may include sodium lauryl sulphate and polyoxyethylene derivatives of sorbitan esters (polysorbate 20, 40, 60 and 80).
  • wetting agents may include but are not restricted to, poloxamers (ethylene oxide propylene oxide block copolymers) of different HLBs, polyethylene glycols and the like.
  • compositions of the present invention may include an appropriate amount of sweetening agents used for better patient acceptability of the dosage form and also enhances the flavor system.
  • a preferred sweetening agent of the present invention may include sucralose, sorbitol solution and saccharin.
  • other sweetening agents may include but not restricted to, natural sweeteners such as sugars eg.
  • fructose sucrose, glucose, sugar alcohols such as mannitol or mixtures thereof and artificial sweeteners such as sodium saccharin, potassium saccharin, sodium cyclamate, aspartame, thaumatin, acesulfame potassium, altitame, neotame, xylose, ribose, mannose, galactose, neohesperidin dihydrochalcone and the like.
  • artificial sweeteners such as sodium saccharin, potassium saccharin, sodium cyclamate, aspartame, thaumatin, acesulfame potassium, altitame, neotame, xylose, ribose, mannose, galactose, neohesperidin dihydrochalcone and the like.
  • the sweetening agent used either single or in combinations in the range of about 0.01% to about 40%, by weight by volume of the total suspension.
  • compositions of the present invention may include an appropriate amount of buffering agents to adjust / maintain the pH of suspension.
  • the suspension according to present invention has a pH of about 2.5 to 5.5.
  • a preferred buffering agent of the present invention is selected from citric acid, sodium citrate or mixture thereof.
  • optionally other agents include but not restricted to, phosphoric acid, succinic acid, tartaric, lactic acid, acetic acid and salts thereof, sodium hydroxide, sodium phosphate, sodium chloride, disodium hydrogen phosphate, sodium hydrogen carbonate, monosodium phosphate, monopotassium phosphate, potassium citrate and mixtures thereof.
  • the buffering agents used either single or in combinations to adjust pH (2.5 to 5.5) in the range of about 0.01% to about 10%, by weight by volume of the total suspension.
  • compositions of the present invention include anticaking agent to prevent the formation of cake in formulation of suspension.
  • a pr.efexre.d_anticak-ing— g&nt— of— the— resent— invention may include colloidal silicon dioxide.
  • anticaking agent may include but not restricted to, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate and the like.
  • compositions of the present invention may include an appropriate amount of chelating agents in a suitable concentration range to stabilize the product during storage.
  • a preferred chelating agent of the present invention may include disodium edetate and the like.
  • other agents may include but not restricted to, edetic acid, tartaric acid, malic acid, citric acid and salts thereof.
  • compositions of the present invention may include an appropriate amount of antioxidants in a suitable concentration range to prevent oxidation.
  • a preferred antioxidant of the present invention may include sodium metabisulfite.
  • other agents include but not restricted to, ascorbic acid, sodium sulfite, sodium bisulfate, sodium thiosulfate, sodium ascorbate, sodium formaldehydesulfoxylate, malic acid, alkyl gallates like propyl gallate, lauryl gallate, or octyl gallate and the like.
  • the antioxidant used either single or in combinations in the range of about 0.01% to about 5%, by weight by volume of the total suspension.
  • compositions of the present invention comprise pharmaceutically acceptable aqueous or oil based flavoring agents to impart a pleasant flavor and often odor to a pharmaceutical preparation and can enhance patient— compliance— b-v— making— t-he-e&mpositrorr ⁇ m Te palatable.
  • a preferred flavoring agent of the present invention is lemon flavor.
  • non-limiting examples of flavoring agents may include but not restricted to orange sweet oil, spearmint oil, citronella oil, black pepper oil, pine apple, cherry, vanilla, honey, lemon, strawberry, raspberry, black current, caramel chocolate, mint cool, fantasy flavor, bubble gum, citrus, lemon, lime, apple, apricot, peppermint, spearmint peach, pear, plum flavor and the like.
  • the flavoring agent used either single or in combinations in the range of about 0.05% to about 10%), by weight by volume of the total suspension.
  • compositions of the present invention may include an appropriate amount of pharmaceutically acceptable aqueous or oil based colors to provide a product with a more aesthetic and/or distinctive appearance.
  • a preferred coloring agent of the present invention is D&C Yellow No.10.
  • other agents includes natural or synthetic dyes but not restricted to carmoisine, FD&C Yellow No.5, FD&C Yellow No.6, FD&C Red No.3, FD&C Red No.20, FD&C Blue No.2, D&C Green No.5, , D&C Yellow No.7, D&C Orange No.5, D&C Red No.8, caramel and the like.
  • the coloring agents used either single or in combinations in the range of about 0.001 % to about 2%, by weight by volume of the total suspension.
  • An aqueous suspension may further include one or more pharmaceutically acceptable additives.
  • the particle size of the present invention is measured using light scattering technique (Malvern Sizer).
  • the fine particle size contributes to homogeneity on prolonged storage,
  • the average particle size of the gefitinib in the present invention is less than about 50 ⁇ .
  • the present invention containing pharmaceutical active agent present at concentrations of 50 mg per mL, 25 mg per mL may be prepared with the above mentioned excipients using different proportions.
  • An aqueous suspension of the present invention is easily administrable for geriatric patients and thus patient compliance can be achieved.
  • a pharmaceutical composition of the present invention may be used in the treatment of the human or animal body by therapy.
  • a process for the preparation of an oral suspension comprising mixing therapeutically effective amount of Gefitinib with vehicle containing preservatives followed by addition of one or more suspending agent dispersed in water, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent and coloring agents where in the said suspension has a pH from 2.5 to 5.5.
  • the formulations of the present invention were found to be stable throughout the stability testing storage period.
  • Figure 1 shows the bioavailability study of the formulation of the present invention and tablet dosage form of gefitinib.
  • the details of the process of the invention are provided in the examples given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
  • the preparation of the present invention that can be administered by the oral route is carried out according to the following process: EXAMPLES
  • the present invention provides a process for preparation of a composition, which comprises intimately mixing gefitinib with a vehicle containing preservatives followed by addition of one or more suspending agent dispersed in water, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and mixed properly through high speed homogenizer until a homogeneous suspension is obtained or as mentioned under individual examples.
  • compositions of Example 1 to 20 contains the
  • Example 1 Example 2 Example 3 Example 4
  • Sorbitol solution (70% w/v) 20.00 20.00 20.00 20.00 20.00
  • Citric acid monohydrate 0.20 0.20 0.20 0.20 0.20 0.20
  • Purified water (qs to 100% w/v) as needed as needed as needed as needed as needed as needed as needed as needed.
  • the processing steps involved in manufacturing an oral suspension given in example 1 to 4 were given below.
  • step (1) Preservative was added to vehicle under stirring followed by addition of wetting agent and added to step (1) 3. pH of the suspension was adjusted to a desired value as needed by adding buffering agents and added to step (2).
  • Sorbitol solution (70% w/v) 0.00 0.00 0.00 20.00
  • Methyl paraben sodium 0.00 0.00 0.18 0.18
  • Citric acid monohydrate 0.20 0.20 0.00 0.00
  • Example 9 Example 10 Example 1 1 Example 12
  • Sorbitol solution (70% w/v) 0.00 . 20.00 20.00 20.00
  • Polysorbate 80 0.00 0.50 0.50 0.25
  • Methyl paraben 0.18 0.00 0.00 0.00
  • Citric acid monohydrate 0.20 0.20 0.20 0.20 0.20 0.20
  • Purified water (qs to 100% w/v) as needed as needed as needed as needed as needed as needed as needed
  • Sorbitol solution (70% w/v) 20.00 20.00 20.00 20.00 20.00
  • Citric acid monohydrate 0.20 0.20 0.20 0.20 0.20 0.20
  • Sorbitol solution (70% w/v) 20.00 20.00 20.00 20.00 20.00
  • Citric acid monohydrate 0.20 0.20 0.20 0.20 0.20 0.20
  • Purified water (qs to 100% w/v) as needed as needed as needed as needed as needed as needed as needed
  • the plasma kinetics of the oral suspension as described in above mentioned examples have been compared with those of the gefitinib tablets in a comparative study.
  • This comparative study was carried out with wistar albino rats; weighing 150-280 grams which were divided into different sets of study (one male and one female in each set) and fasted overnight prior to dosing, but were permitted water ad libitum. Both formulations were administered at the dose of 20 mg/kg body weight.
  • Blood samples were collected by puncturing retero-orbital sinus of the anaesthetized rats (with anesthetic light isoflurane) at different intervals post administration. Blood collection was done in prefilled heparin centrifugation tubes.
  • the blood samples collected were subjected for the subsequent centrifugation and followed by analytical procedure with the use of LCMS technique.
  • the areas under the blood drug concentration versus time curves were calculated by the trapezoidal rule. The analysis was done with respect to AUC (area under curve) and C ma x (maximum concentration).
  • compositions in accordance with the present invention exhibit adequate bioavailability (AUC and C max ) in comparison with the commercial tablet dosage form.
  • the aforementioned table gives an account of the bioavailability (AUC, C max ) of the Gefitinib tablet dosage form and formulation in the present invention.
  • ADVANTAGES OF THE INVENTION a) Oral suspension of an aniloquinazoline derivative for example gefitnib is prepared which is used as EGFR tyrosine kinase inhibitor for the monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.
  • Gefitinib oral suspension can be a viable alternative to patients who find it difficult to swallow solid dosage forms.
  • the advantage also lies in the attainment of adequate therapeutic levels of drug concentration in comparison with the commercial tablet dosage form.
  • the advantage further encompasses the stability aspects and the formulation is found to be stable throughout the period of the stability study.

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Abstract

L'invention concerne une suspension pharmaceutique appropriée pour une administration orale, contenant une quantité efficace de géfitinib pour améliorer l'appétibilité, assurant des niveaux thérapeutiques appropriés de concentration de médicament, par comparaison avec la forme dosifiée de comprimé commercial, et ainsi, l'observance de patient peut être obtenue. L'invention concerne également un procédé pour la préparation d'une formulation orale aqueuse stable qui peut être facilement avalée et comprenant un principe actif dans une concentration efficace pour la meilleure thérapie, en particulier pour la monothérapie, pour le traitement continu de patients ayant un cancer du poumon non à petites cellules localement avancé ou métastatique, ou un cancer de la tête et du cou non résécable.
PCT/IN2013/000194 2013-03-22 2013-03-22 Formulation comprenant du géfitinib comme suspension orale Ceased WO2014147631A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019162756A3 (fr) * 2018-02-20 2019-10-31 Ftf Pharma Private Limited Compositions pharmaceutiques liquides de médicaments anticancéreux
CN112566625A (zh) * 2018-08-18 2021-03-26 夫特弗制药私人有限公司 口服剂量的化学治疗药物悬浮液

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WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO2005070909A1 (fr) 2004-01-22 2005-08-04 Natco Pharma Limited Procede ameliore de preparation de gefitinib
WO2006090413A1 (fr) 2005-02-23 2006-08-31 Natco Pharma Limited Nouvelle forme cristalline de gefitinib et son procede de preparation
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US20090186892A1 (en) 2006-02-10 2009-07-23 Oncotherapy Science, Inc Methods for treating lung cancers
US20100137586A1 (en) 2007-04-16 2010-06-03 Cipla Limited Process for the Preparation of Gefitinib
US20100173285A1 (en) 2005-02-11 2010-07-08 Memorial Sloan-Kettering Cancer Center Methods and Compositions for Detecting a Drug Resistant Egfr Mutant
WO2010076810A2 (fr) 2008-12-30 2010-07-08 Ind-Swift Laboratories Limited Procédé d'élaboration de géfitinibe
US20100184801A1 (en) * 2009-01-16 2010-07-22 Xiong Cai Fused amino pyridines for the treatment of brain tumors
US20110294686A1 (en) 2008-09-11 2011-12-01 Drabkin Harry A Egfr inhibitor therapy responsiveness
US20120064090A1 (en) 2009-03-27 2012-03-15 Kringle Pharma Inc. Therapeutic agent for cancer having reduced sensitivity to molecular target drug and pharmaceutical composition for enhancing sensitivity to molecular target drug
WO2012151541A1 (fr) * 2011-05-05 2012-11-08 Novartis Ag Inhibiteurs de csf-1r pour le traitement de tumeurs cérébrales
WO2012151523A1 (fr) * 2011-05-05 2012-11-08 Novartis Ag Inhibiteurs de csf-1r pour traitement de tumeurs cérébrales

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US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5616582A (en) 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
US5770599A (en) 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
EP0823900B1 (fr) 1995-04-27 2000-12-27 AstraZeneca AB Derives de quinazoline
WO2005070909A1 (fr) 2004-01-22 2005-08-04 Natco Pharma Limited Procede ameliore de preparation de gefitinib
US8017321B2 (en) 2004-01-23 2011-09-13 The Regents Of The University Of Colorado, A Body Corporate Gefitinib sensitivity-related gene expression and products and methods related thereto
US20070270505A1 (en) 2004-01-23 2007-11-22 The Regents Of The University Of Colorado Gefitinib Sensitivity-Related Gene Expression and Products and Methods Related Thereto
US20100173285A1 (en) 2005-02-11 2010-07-08 Memorial Sloan-Kettering Cancer Center Methods and Compositions for Detecting a Drug Resistant Egfr Mutant
WO2006090413A1 (fr) 2005-02-23 2006-08-31 Natco Pharma Limited Nouvelle forme cristalline de gefitinib et son procede de preparation
US20090186892A1 (en) 2006-02-10 2009-07-23 Oncotherapy Science, Inc Methods for treating lung cancers
US20090098138A1 (en) 2006-04-18 2009-04-16 Wellstat Biologics Corporation Detection of proteins from circulating neoplastic cells
US20100137586A1 (en) 2007-04-16 2010-06-03 Cipla Limited Process for the Preparation of Gefitinib
US20090185999A1 (en) 2008-01-22 2009-07-23 Concert Pharmaceuticals Inc. Derivatives of gefitinib
US20110294686A1 (en) 2008-09-11 2011-12-01 Drabkin Harry A Egfr inhibitor therapy responsiveness
WO2010076810A2 (fr) 2008-12-30 2010-07-08 Ind-Swift Laboratories Limited Procédé d'élaboration de géfitinibe
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