WO2011068404A2 - Administration par inhalation de sel de mésylate de n-(3-éthynylphénylamino)-6,7-bis(2-méthoxyéthoxy)-4-quinazolinamine - Google Patents

Administration par inhalation de sel de mésylate de n-(3-éthynylphénylamino)-6,7-bis(2-méthoxyéthoxy)-4-quinazolinamine Download PDF

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Publication number
WO2011068404A2
WO2011068404A2 PCT/NL2010/050810 NL2010050810W WO2011068404A2 WO 2011068404 A2 WO2011068404 A2 WO 2011068404A2 NL 2010050810 W NL2010050810 W NL 2010050810W WO 2011068404 A2 WO2011068404 A2 WO 2011068404A2
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WO
WIPO (PCT)
Prior art keywords
bis
ethynylphenylamino
methoxyethoxy
mesylate salt
quinazolinamine
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PCT/NL2010/050810
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English (en)
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WO2011068404A3 (fr
Inventor
Evanthia Dova
Samir Kulkarni
Marcel Hoffmann
Mihaela Maria Pop
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Ultimorphix Technologies B.V.
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Publication of WO2011068404A2 publication Critical patent/WO2011068404A2/fr
Publication of WO2011068404A3 publication Critical patent/WO2011068404A3/fr

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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • the present invention relates to a formulation for the administration of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt (erlotinib mesylate salt) by inhalation.
  • the invention further relates to a method for treating cancer by delivering a therapeutically effective amount of N-(3-ethynylphenylamino)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine mesylate salt to a patients respiratory tract.
  • the invention further relates to the use of an inhalation formulation of N-(3-ethynylphenylamino)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine mesylate salt in the treatment of cancer.
  • the method allows clinicians flexible dosing and treatment cycles without the attended adverse effects common to systemic administration of N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine.
  • Bronchoalveolar Carcinoma (BAC) or alveolar cell carcinoma is a form of
  • adenocarcinoma a cell type of non-small cell carcinoma that can be found throughout the respiratory tract.
  • BAC represents approximately 10 to 25% of the adenocarcinoma of lung cases or 2-6% of all lung cancers. Sometimes these cancers have a distinct presentation and biological behavior. BAC is more common in women and in patients who do not smoke cigarettes then other histological types of cancers. BAC and certain types of non-small cell lung cancer caused by ErbB family tyrosine kinase activity such as the EGFR are responsive to treatment with N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine.
  • BAC may present as a solitary peripheral nodule, a multifocal lesion or a rapidly progressive form that appears as a diffuse infiltrate on chest radiographs.
  • the cells secrete mucin and surfactant apoprotein which can lead to bronchorrhea, an excessive discharge of mucus from the airway passages of the lungs.
  • Bronchoalveolar cancer may present as a more diffuse lesion then other types of cancer. When it is discovered as a single mass on a patient's X-ray, this type of lung cancer has an excellent prognosis. Five year survival after surgery is in the 75-90% range. If, however, it is found in its diffuse form (meaning it has spread beyond a single mass), the prognosis is quite poor.
  • the management and prognosis are essential the same as other types of non-small cell lung cancer.
  • Surgery is the preferred treatment if the tumor can be resected. Radiation therapy, chemotherapy and targeted therapy may be used in non-operable cases. Trials are underway to investigate treatments specific for bronchoalveolar carcinoma.
  • treatment of non-small cell lung cancer is by systemic administration of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine HCI salt (Erlotinib, TarcevaTM).
  • This systemic administration is typically done in the form of oral tablets.
  • Often such administration is associated with several adverse side effects including allergic reactions (skin rash, difficulties breathing, and swelling of the face, mouth or tongue), chest pain, severe and persistent diarrhea, nausea, vision problems, hepatic side effects and fatigue. These negative side effects severely influence the quality of life of patients.
  • erlotinib bromide is the bromide salt of N-(3-ethynylphenylamino)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine, i.e. the hydrochloride is replaced with hydrobromide etc.
  • W09955683 describes erlotinib mesylate for the treatment of cancer and describes parenteral application methods (i.e. non-oral). W09955683 does not describe an inhalable (i.e. oral application) formulation of erlotinib mesylate.
  • the present inventors have found that the aqueous solubility of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt (indicated herein also as erlotinib mesylate salt) allows for formulations of N-(3-ethynylphenylamino)- 6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt that can be administered non- parenterally to a patient's respiratory tract by inhalation, i.e. oral or nasal administration.
  • an aqueous formulation of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt can be inhaled by a patient using a nebulizer device.
  • a "patient”, “subject” or “host” to be treated by the subject matter may mean either a human or non-human animal.
  • therapeutic effect is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly human caused by a pharmacological active substance.
  • therapeutically-effective amount means that amount of the substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the therapeutically effective amount of a substance will vary depending upon the subject and the disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily determined by one of ordinary skill in the art.
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom or a condition or disease or preventing the occurrence of a condition or disease.
  • the present invention relates to an inhalable formulation of N-(3-ethynylphenylamino)- 6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt.
  • the inhalable formulation is suitable for non-parenteral (oral or nasal) administration.
  • N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt is the salt of N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and methane sulfonic acid (MSA).
  • MSA methane sulfonic acid
  • One embodiment of the present invention relates to a liquid composition comprising a therapeutically effective amount of N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine mesylate salt.
  • An inhalable formulation provided by the invention includes an aqueous liquid composition comprising N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine mesylate salt with a relative high dose of N-(3-ethynylphenylamino)-6,7- bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt.
  • mesylate salt of N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine based on the mesylate salt having an aqueous solubility of 40 mg/mL at about pH 2-4.
  • the N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt may be present in the final formulation at from about 20 mg/mL to about 400 mg/mL, more preferably from about 25-300 mg/ml, even more preferably from about 30-200 mg/ml, and preferable present at from about 35 mg/mL to about 100 mg/mL.
  • the liquid composition can be administered as an aerosol.
  • the liquid composition can be administered with a nebulization device.
  • the formulation according to the invention is suitable for the treatment of cancer, in one embodiment, the cancer is lung cancer.
  • the lung cancer is selected from the group consisting of non-small cell lung cancer and bronchoalveolar carcinoma.
  • the cancer is bronchoalveolar carcinoma.
  • the present invention features a method for treating a patient having cancer, such as bronchoalveolar carcinoma, comprising administering a liquid composition comprising N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine mesylate salt to the patient's respiratory tract.
  • cancer such as bronchoalveolar carcinoma
  • a method for treating lung cancer by delivering a therapeutically effective amount of a liquid composition comprising N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt to a patients respiratory tract.
  • the method allows for more effective treatment of patients with a reduction of systemic adverse side effects.
  • the liquid composition administered comprises N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt and pharmaceutically acceptable excipients (including co-solvents, salts, buffers, preservatives and surfactants) and is administered as an aerosol.
  • the liquid composition is an aqueous liquid composition.
  • Compositions are preferable adapted for use by inhalation, and more preferable for use in an inhalation delivery device for the composition's administration.
  • the inhalation system can be used for the treatment of lung cancer in both man and animal.
  • the nebulizable compositions according to the invention contain N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, preferably N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt and can be formulated with a pharmacological suitable fluid for the dissolution of the compound to facilitate nebulization and delivery of the compound to the lungs of a patient.
  • Pharmacological suitable fluids include, but are not limited to, polar solvents, including, but not limited to, compounds that contain hydroxyl groups or other polar groups.
  • Such solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, and glycerol and polyoxyethylene alcohols.
  • Polar solvents also include protic solvents, including, but not limited to, water, aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols, glycols or a mixture thereof.
  • protic solvents including, but not limited to, water, aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols, glycols or a mixture thereof.
  • suitable salts are those which display no or negligible pharmacological activity after administration.
  • mesylates have an inherent problem in the way that a toxic impurity in the form of ethyl methanesulfonate can be formed under certain conditions, for instance in the presence of alcohols such as ethanol. Furthermore, aqueous solutions of mesylates typically have an acidic ( below 7) pH. Therefore it is preferred to provide formulations that over come these problems.
  • the liquid composition is formulated to have a pH of from about 3 to about 8, preferably from about 3 to about 5
  • the pH is preferable adjusted by the addition of a suitable base such as an ammonium hydroxide, alkali hydroxide or TRIS base, preferably an alkali hydroxide such a s sodium or potassium hydroxide, most preferably sodium hydroxide.
  • a suitable base such as an ammonium hydroxide, alkali hydroxide or TRIS base, preferably an alkali hydroxide such a s sodium or potassium hydroxide, most preferably sodium hydroxide.
  • the composition further contain a buffer, including, but not limited to, citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidone, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagan), veronal acetate, MES (2-(N- morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)
  • a buffer including, but not limited to, citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidone, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagan), veronal acetate, MES (2-(N- morpholino)ethane
  • TRICINE N-tris(hydroxymethyl)methylglycine
  • GLY-GLY glycylglycine
  • BICINE N,N-bis(2- hydroxyethyl)glycine
  • HEPBS N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)
  • TAPS N-tris(hydroxymethyl(methyl-3-aminopropanesulfonic acid), AMPID (2-amino-2- methyl-1 ,3-propanediol), and/or any other buffers known to those of skill in the art.
  • the buffer is citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.
  • the buffer is a citrate buffer (citric acid/sodium citrate).
  • the buffer concentration may affect the stability of the composition.
  • concentrations for use herein include from about 0 or 0.01 mM to about 150 mM, or about 1 mM to about 20 mM. In one embodiment, the buffer concentration is about 5 mM. In another embodiment, the buffer concentration is about 1 mM to about 50 mM, or about 20 mM.
  • tonicity adjusting agents may be added to provide the desired ionic strength.
  • Tonicity adjusting agents for use herein includes those which display no or only negligible pharmacological activity after administration. Both inorganic and organic tonicity adjusting agents may be used in the compositions provided herein.
  • Tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodium
  • the liquid composition is formulated such that the liquid
  • composition is a saline composition.
  • a saline composition is preferred as it suppresses a cough reflex.
  • a too high saline concentration may lead to formation of the lesser soluble hydrochloride salt and may lead to precipitation.
  • the tonicity adjusting agent is sodium chloride, which is present at a concentration of from about 0 mg/mL to about 10, 15 or 20 mg/mL.
  • the compositions contain sodium chloride at a concentration of from about 0 mg/mL to about 7,5 mg/mL. In another embodiment, the compositions contain sodium chloride at a concentration of 0 mg/mL, 1 .5 mg/mL, 6.8 mg/mL, or 7.5 mg/mL. In these embodiments, the pharmacologically suitable fluid is aqueous saline. A preferred lower limit of sodium chloride is 0.001 mg/ml. The presence of chloride ions may lead to the formation of the erlotinib hydrochloride at lower pHs (i.e. below about 3) leading to precipitations of the (lower soluble) erlotinib hydrochloride and hence reduce the bioavailability of the formulation.
  • composition of the invention as a saline formulation having a pH from about 3 to about 8, preferably from about 3 to about 5 and a chloride content of about 10-40 mmols/ml.
  • the saline formulation can be added to a solution of the erlotinib mesylate.
  • compositions provided herein also may include excipients and additives such as those described in Remington-The Science and Practice of Pharmacy (21 st edition) (2005), Goodman & Gilman's The Pharmacological Basis of Therapeutics (1 1 st Edition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8th Edition), edited by Allen et al., Lippincott Williams & Wilkins. (2005).
  • excipients or additives for use in the nebulizable compositions provided herein may be determined empirically using methods well known to those of skill in the art.
  • Excipients and additives are any pharmacologically suitable and therapeutically useful substance which is not an active substance. Excipients and additives generally have no pharmacological activity or at least no undesirable pharmacological activity, The excipients and additives include, but are not limited to, surfactants, stabilizers, completing agents, antioxidants, or preservatives which prolong the duration of use of the finished
  • Complexing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof.
  • the complexing agent is EDTA.
  • Preservatives include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate.
  • Antioxidants include, but are not limited to, vitamins, provitamins, ascorbic acid, vitamin E or salts or esters thereof.
  • compositions provided herein also may include a co-solvent which increases the solubility of additives or the active ingredient(s).
  • a co-solvent which increases the solubility of additives or the active ingredient(s).
  • the particular co-solvent for use in the compositions for long term storage provided herein may be determined empirically using methods well known to those of skill in the art.
  • Co-solvents for use herein include, but are not limited to, hydroxylated solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, and polyoxyethylene alcohols. Inhalation devices
  • the inhalation delivery of the inhalation system can be a nebulizer or a metered dose inhaler (MDI).
  • the device can contain and be used to deliver a single dose of the composition comprising N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt or the device can contain and be used to deliver multi-doses of the composition of the present invention .
  • a nebulizer-type inhalation delivery device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension.
  • the nebulizer type delivery device may be driven ultrasonically, by compressed air, by other gases, electronically or mechanically (including, for example, a vibrating porous membrane).
  • the ultrasonic nebulizer device usually works by imposing a rapidly oscillating waveform onto the liquid film of the formulation via an electrochemical vibrating surface. At given amplitude the waveform becomes unstable, whereby it disintegrates the liquids film, and it produces small droplets of the formulation.
  • the nebulizer device driven by air or other gases operates on the basis that a high-pressure gas stream produces a local pressure drop that draws the liquid formulation into the stream of gases via capillary action. This fine liquid stream is then disintegrated by shear forces.
  • the nebulizer may be portable and hand held in design, and may be equipped with a self-contained electrical unit.
  • the nebulizer device can consist of a nozzle that has two coincident outlet channels of defined aperture size through which the liquid formulation can be accelerated. This results in impaction of the two streams and atomization of the
  • the nebulizer may use a mechanical actuator to force the liquid formulation through a multiorifice nozzle of defined aperture size(s) to produce an aerosol of the formulation for inhalation.
  • blister packs containing single doses of the formulation may be employed.
  • the nebulizer is employed to ensure the sizing of aqueous droplets containing the drug particles is optimal for positioning of the particle within, for example, the lungs.
  • Typical droplet sizes for the nebulized composition are from about 1 to about 5 microns.
  • the composition preferably contains an aqueous component.
  • aqueous component may include for example, saline.
  • the aqueous component may include up to about 50% by weight of an aqueous compatible solvent such as ethanol.
  • Total administration time using a nebulizer will depend on the flow rate and the concentration of the N-(3-ethynylphenylamino)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine mesylate salt in the composition. Variation of the total administration time is within the purview of those of ordinary skill in the art.
  • the flow rate of the nebulizer will be at least about 0.5 to 1 .3 mL/min, for example, a flow rate of about 1 mL/min is typical.
  • administering a dose of about 150 mg of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt would be about 6 minutes, assuming an output efficiency of 60% and 90% inhalable particles.
  • any composition of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the supplement. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compounds of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein. Also, the present invention contemplates mixtures of more than one subject compound, as well as other therapeutic agents. Further, the present invention contemplates administration of the therapeutic agent that is contained in a subject coordination complex (or a related agent) such as cyclodextrines or liposomal formulations.
  • a subject coordination complex or a related agent
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0. 1 g per kg, and more specifically in the range of about 100 ng to about I0 mg per kg.
  • An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular compound of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any compound and method of treatment or prevention may be assessed by administering the supplement and assessing the effect of the administration by measuring one or more indices associated with the neoplasm of interest, and comparing the post- treatment values of these indices to the values of the same indices prior to treatment.
  • the precise time of administration and amount of any particular compound that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like.
  • the guidelines presented herein may be used to optimize the treatment, e.g., determine the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during a 24-hour period.
  • Treatment, including supplement, amounts, times of administration and formulation may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters, the first such reevaluation typically occurring at the end of four weeks from the onset of therapy, and subsequent reevaluations occurring every four to eight weeks during therapy and then every three months thereafter. Therapy may continue for several months or even years. Adjustments of the amount(s) of agent administered and possibly to the time of administration may be based on these reevaluations.
  • Treatment may be initiated with smaller dosages which are less then the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • the combined use of the compound of the present invention with other therapeutic agents may reduce the required dosage for any individual component because the onset and duration of effect of the different components may be complimentary.
  • the different active agents may be delivered together or separately, and
  • Toxicity and therapeutic efficacy of subject compounds may be determined by standard pharmaceutical procedures in cell culture or animal, e.g. determining LD50 and ED50 values. Compositions that exhibit large therapeutic indices are preferred. Although compounds that exhibit toxic side effects may be used care should be taken to design a delivery system that targets the compound to the desired site in order to reduce side effects.
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any supplement, or alternatively of any components therein lies preferably within a range of circulating concentration that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information may be used to more accurately determine useful doses in humans.
  • Levels in plasma may be measured, for example, by high performance liquid
  • kits for conveniently and effectively implementing the methods of this invention comprise any of the compounds of the present invention or a combination thereof and a means for facilitating compliance with methods of this invention.
  • kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage, in the correct manner.
  • the compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.
  • Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.
  • Quantitative solubility determination was performed in water and / or buffers with or without co-solvents on N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine mesylate salt at room temperature.
  • Approximately 20 mg of N-(3- ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate salt was weighted in a 1 .8 ml screw cap glass vial and 400 ⁇ liquid (water or buffers with or without co-solvents) was added. The vial was then closed and equilibrated for 4h - 24 h at room temperature under continuous stirring.
  • the mother liquor was isolated from solids using a Tecan Genesis 200 liquid-handling robot. Subsequently two independent dilutions (factor of 10 and 200) were prepared with Tecan Genesis 200. The dilutions were measured by HPLC (wavelength 245 nm) or UV-VIS plate reader (wavelength 330 nm). Further, two separate calibration curves for the HPLC (Agilent HP1 100, UV-detector HP DAD) and the UV-VIS plate reader were made from two stock solutions of N-(3-ethynylphenylamino)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine free base in water (stock concentrations 0.3 mg/ml and 0.5 mg/ml). The solubility was determined from the peak area from the HPLC chromatogram or from the UV-VIS absorbance.
  • Example 2 The solubility was determined from the peak area from the HPLC chromatogram or from the UV-VIS absorbance.

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Abstract

La présente invention concerne une formule pharmaceutique inhalable comprenant le sel de mésylate de la N-(3-éthynylphénylamino)-6,7-bis(2-méthoxyéthoxy)-4-quinazolinamine ainsi que les méthodes de traitement du cancer comprenant l'administration d'une dose thérapeutiquement active à un patient le nécessitant d'une formule pharmaceutique inhalable comprenant le sel de mésylate de la N-(3-éthynylphénylamino)-6,7-bis(2-méthoxyéthoxy)-4-quinazolinamine, le cancer étant choisi dans le groupe constitué par le cancer du poumon non à petites cellules et le carcinome bronchoalvéolaire.
PCT/NL2010/050810 2009-12-02 2010-12-02 Administration par inhalation de sel de mésylate de n-(3-éthynylphénylamino)-6,7-bis(2-méthoxyéthoxy)-4-quinazolinamine WO2011068404A2 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999055683A1 (fr) 1998-04-29 1999-11-04 Pfizer Products Inc. Anhydrate et monohydrate de n-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate
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