WO2015145145A1 - Pharmaceutical composition comprising lapatinib - Google Patents

Pharmaceutical composition comprising lapatinib Download PDF

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Publication number
WO2015145145A1
WO2015145145A1 PCT/GB2015/050885 GB2015050885W WO2015145145A1 WO 2015145145 A1 WO2015145145 A1 WO 2015145145A1 GB 2015050885 W GB2015050885 W GB 2015050885W WO 2015145145 A1 WO2015145145 A1 WO 2015145145A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
lapatinib
composition according
inhibitor
tablet
Prior art date
Application number
PCT/GB2015/050885
Other languages
French (fr)
Inventor
Geena Malhotra
Preeti Raut
Original Assignee
Cipla Limited
Turner, Craig
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited, Turner, Craig filed Critical Cipla Limited
Publication of WO2015145145A1 publication Critical patent/WO2015145145A1/en

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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
    • A61K31/495—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor, a process for preparing such pharmaceutical composition and use of the said pharmaceutical composition for the treatment of cancer more specifically advanced or metastatic breast cancer.
  • Metastatic breast cancer also known as secondary or advanced or Stage IV breast cancer occurs when breast cancer cells spread from the first (primary) tumour in the breast through the lymphatic or blood system to other parts of the body.
  • the most common parts of the body that breast cancer spreads to are the bones, liver, lungs and brain.
  • a diagnosis of metastatic breast cancer means that the cancer cannot be cured, although it can be controlled, sometimes for years.
  • Metastatic cancer may be treated with systemic therapy (chemotherapy, biological therapy, targeted therapy or hormonal therapy), local therapy (surgery or radiation therapy) or a combination of these treatments.
  • systemic therapy chemotherapy, biological therapy, targeted therapy or hormonal therapy
  • local therapy therapy or radiation therapy
  • Lapatinib is human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HERl/EGFR/ERBBl) tyrosine kinases inhibitor. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding.
  • HER2/ERBB2 human epidermal growth factor receptor type 2
  • HERl/EGFR/ERBBl epidermal growth factor receptor
  • Lapatinib is indicated in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (human epidermal growth factor receptors 1 and 2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Further lapatinib is used in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
  • HER2 human epidermal growth factor receptors 1 and 2
  • Lapatinib is currently available under the brand name TYKERB ® sold by Glaxosmithkline.
  • Lapatinib is present as the monohydrate of the ditosylate salt, with chemical name N-(3- chloro- 4- ⁇ [(3-fluorophenyl)methyl]oxy ⁇ phenyl)-6-[5-( ⁇ [2-(methylsulfonyl)ethyl]amino ⁇ methyl)-2- furanyl]-4-quinazolinamine bis(4- methylbenzenesulfonate) monohydrate.
  • Lapatinib ditosylate monohydrate is structurally represented as
  • WO2010099150 discloses a tablet composition of lapatinib wherein the tablet core comprises lapatinib and wherein the tablet composition is produced by a process which comprises the steps of granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step with one or more extra-granular excipients to produce a granular blend, and iii) pressing the granular blend produced to form a tablet.
  • WO2010023187 discloses a composition of lapatinib wherein lapatinib is present in an amount of more than 60% by weight based on the total weight of the composition.
  • WO2006113649 discloses an oral composition of lapatinib and a binder, disintegrant, lubricant.
  • the recommended dose of lapatinib is 1250 mg daily.
  • Tablets comprising 250 mg lapatinib are sold under the trade name TYKERB ® .
  • the required dosage is comprised in five TYKERB ® tablets that have to be administered orally once a day.
  • lapatinib has pharmacokinetic properties that are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a "food effect".
  • the bioavailability or systemic exposure of lapatinib increases with food.
  • Lapatinib AUC values were approximately 3 and 4 times higher (C max approximately 2.5 and 3 times higher when administered with a low fat (5% fat) or with a high fat (50% fat) meal respectively.
  • patients receive specific instructions to administer TYKERB ® at least one hour before or one hour after a meal.
  • lapatinib may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of lapatinib.
  • lapatinib should be stable as well as exhibit optimal dissolution properties.
  • An object of the present invention is to provide a pharmaceutical composition comprising lapatinib and one or more pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib along with pharmaceutically acceptable excipients.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting improved surface area and solubility.
  • Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting improved surface area and solubility.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting increased bioavailability.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting increased bioavailability.
  • Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting minimal food effect.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting minimal food effect.
  • Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of lapatinib. Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of nanosized lapatinib.
  • Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib for once a day administration.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib for once a day administration.
  • Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising lapatinib.
  • Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising nanosized lapatinib.
  • Yet another object of the present invention is to provide a method of treatment of advanced or metastatic breast cancer which method comprises administering a pharmaceutical composition comprising lapatinib.
  • Yet another object of the present invention is to provide a method of treatment of advanced or metastatic breast cancer which method comprises administering a pharmaceutical composition comprising nanosized lapatinib.
  • Another object of the present invention is to provide the use of a pharmaceutical composition comprising lapatinib, in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
  • Another object of the present invention is to provide the use of a pharmaceutical composition comprising nanosized lapatinib, in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
  • Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib for the use in treatment of advanced or metastatic breast cancer.
  • Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib for the use in treatment of advanced or metastatic breast cancer.
  • a pharmaceutical composition comprising lapatinib and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising nanosized lapatinib, wherein the particles have an average particle size of less than about 2000 nm.
  • composition comprising nanosized lapatinib along with at least one pharmaceutically acceptable excipient.
  • a process for preparing a pharmaceutical composition comprising lapatinib with at least one or more pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical composition comprising nanosized lapatinib with at least one or more pharmaceutically acceptable excipients.
  • a method of treating advanced or metastatic breast cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lapatinib according to the present invention to a patient in need thereof.
  • a method of treating advanced or metastatic breast cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized lapatinib according to the present invention to a patient in need thereof.
  • a pharmaceutical composition comprising lapatinib according to the present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
  • a pharmaceutical composition comprising nanosized lapatinib according to present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
  • the pharmaceutical composition comprising lapatinib according to the present invention for use in treating advanced or metastatic breast cancer.
  • the pharmaceutical composition comprising nanosized lapatinib according to the present invention for use in treating advanced or metastatic breast cancer.
  • Lapatinib is commercially available as a conventional film coated tablet formulation for the treatment of metastatic or advanced breast cancer in combination with capecitabine and letrozole.
  • the required dosage is comprised in five lapatinib tablets that have to be administered once a day.
  • cancer patients are usually on a multiple drug regimen demanding the administration of large numbers of tablets or capsules often along with intravenous therapy.
  • Patient compliance in such a regimen can be addressed by decreasing the number of tablets or capsules administered as well as the type of dosage forms that are administered, with due consideration to the bioavailability of the administered drug .
  • the bioavailability of the drug cannot be compromised to meet patient compliance.
  • lapatinib as an active pharmaceutical agent used for treating breast cancer, would be, preferred in an oral composition with a low dose provided in such a dosage forms which exhibit desired therapeutic effect and at the same time would ensure patient compliance.
  • the present invention provides a pharmaceutical composition comprising lapatinib which would ensure patient compliance due to simplification of therapy, ease of administration, an acceptable dosing regimen, bioavailability and which nullifies the food effect.
  • the low dose which would be lower than the usual or the conventional dose, required to produce equal or higher therapeutic effect, would also reduce the plausible side effects thereby leading to limit the risk caused to the patient.
  • lapatinib is used in broad sense to include not only “lapatinib” per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
  • lapatinib is present in the form of lapatinib ditosylate monohydrate.
  • low dose or “reduced dose” as used herein refers to a therapeutically effective dose of lapatinib, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect.
  • the pharmaceutical composition of the invention may be administered at least once a day to a patient in need thereof. More preferably the pharmaceutical composition of the invention is administered once a day such that the total daily dose administered to a patient is a dose which is less than the conventionally administered daily dose.
  • the composition of the invention comprises less than 1250 mg of lapatinib. More preferably, the composition of the invention comprises from about 100 mg to about 1200 mg of lapatinib. Most preferably, the composition of the invention comprises from about 200 mg to about 1100 mg lapatinib.
  • the composition of the invention comprises from about 400 mg to about 1000 mg of lapatinib or from about 600 mg to about 800 mg of lapatinib.
  • Lapatinib is preferably present in pharmaceutical compositions of the invention in an amount of from about 15% to about 55% by weight of the composition. More preferably, lapatinib is present in the compositions in an amount of from about 25% to about 50% by weight of the composition. Most preferably, the lapatinib is present in an amount of from about 30% to about 45% by weight of the composition.
  • the inventors of the present invention have further observed that the solubility properties of lapatinib are improved by nanosizing thus leading to better bioavailability and dose reduction of the drug.
  • Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs.
  • the present invention thus provides a pharmaceutical composition comprising lapatinib in the form of nanoparticles.
  • nanosize refers to lapatinib particles having an average particle size of less than about 2000 nm, preferably less than about 1000 nm.
  • the particles may have an average particle size of less than about 700 nm, optionally less than about 500 nm, optionally less than about 250 nm, optionally less than about 150 nm.
  • the lapatinib particles may have a particle size distribution with a D90 not less than about700 nm, preferably less than 300 nm, optionally less than 100 nm.
  • the present invention thus provides a pharmaceutical composition comprising lapatinib wherein lapatinib is in the nanosize range.
  • particle refers to an individual particle of lapatinib, or particles of lapatinib, or lapatinib granules and/or mixtures thereof.
  • the particles of the present invention may comprise lapatinib and the one or more pharmaceutically acceptable excipients.
  • the nanosize particles of the present invention can be obtained by any process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, Particle replication in non-wetting templates (PRINT), thermal condensation, ultrasonication, spray drying or the like.
  • Such nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.
  • the pharmaceutical composition comprising lapatinib according to the present invention may be administered orally through unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like; liquid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, spot-on
  • the pharmaceutical composition comprising lapatinib according to the present invention may be administered in a solid oral dosage form such as tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles.
  • the solid oral dosage forms comprise nanosized lapatinib.
  • the pharmaceutical composition comprising lapatinib, according to the present invention is presented in a tablet dosage form.
  • the tablet dosage forms comprise nanosized lapatinib.
  • the methods and uses of the invention preferably comprise administering a total daily dose of less than 1250 mg of lapatinib, such as from 100 mg lapatinib to 1200 mg lapatinib to a patient in need thereof.
  • lapatinib is administered with a total daily dose of from 100 mg to 1100 mg, from 200 mg to 1100 mg, from 400 mg to 1000 mg, or from 600 mg to 800 mg.
  • the pharmaceutical compositions of the invention are administered at least once a day to a patient in need thereof.
  • Suitable excipients may be used for formulating the pharmaceutical composition of the invention, preferably as a tablet dosage form.
  • Suitable excipients comprise, but are not limited to, surface stabilizers, viscosity modifying agents, polymers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents coloring agents, carriers, fillers, anti-adherents, solvents, taste-marking agents, preservatives, antioxidants, viscosity modifying agents, texture enhancers, surface stabilisers, channeling agents, or combinations thereof.
  • Suitable surface stabilizers mean surfactants that are capable of stabilizing the increased surface charge of the nanosized drug.
  • Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical compositions of the present invention.
  • surfactants may comprise of one or more, but not limited to, Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride.
  • CTAB Cetyl trimethyl ammonium bromide
  • Polyethoxylated alcohols Polyoxyethylene sorbitan
  • Octoxynol N, N-dimethyldodecy
  • Carboxylates Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, ⁇ , ⁇ , ⁇ , ⁇ tetrakis substituted ethylenediamines 2- al
  • the amount of surface stabilizers in the pharmaceutical composition comprising lapatinib preferably range from about 2 % to about 10 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable viscosity modifying agents are excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition and thus preventing physical interaction of nanoparticles under the operating conditions employed.
  • viscosity modifying agents may comprise one or more, but not limited to derivatives of sugars, such as lactose, lactose monohydrate, saccharose, hydrolyzed starch (maltodextrin) or combinations thereof.
  • the amount of viscosity modifying agents in the pharmaceutical composition comprising lapatinib preferably range from about 4 % to about 20 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable polymers according to the present invention may comprise one or more hydrophilic polymers, but not limited to cellulose derivatives like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and copolymers, and combinations thereof.
  • hydrophilic polymers but not limited to cellulose derivatives like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyeth
  • the amount of polymers in the pharmaceutical composition comprising lapatinib preferably range from about 2 % to about 15 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable disintegrants or super disintegrants comprise agar-agar, calcium carbonate, microcrystalline cellulose, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, alginic acid, alginates such as sodium alginate other algins, other celluloses, gums, ion-exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, polyvinyl pyrollidone, cross-linked PVP, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, docusate sodium, guar gum, low- substituted HPC, polacrilin potassium, poloxamer, povidone, sodium glycine carbonate, sodium lauryl sulfate or combinations thereof.
  • the amount of disintegrant in the pharmaceutical compositions preferably ranges from about 5% w/w to about 30% w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable glidants, anti-adherents and lubricants according to the present invention include, but are not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, mineral oil, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerin, sorbitol, mannitol, other glycols, sodium lauryl s
  • the amount of glidants, anti-adherants and lubricants in the pharmaceutical composition comprising lapatinib preferably ranges from about 0.25 % to about 5 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable channeling agents according to the present invention include, but are not limited to sodium chloride, sugars, polyols and the like or mixtures thereof.
  • the amount of channeling agents in the pharmaceutical composition comprising lapatinib preferably range from about 0.5 % to about 10% of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable binders may also present in the pharmaceutical compositions of the present invention, which may comprise one or more of, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or combinations thereof, or any other suitable binder.
  • polyvinyl pyrrolidone also known as povidone
  • polyethylene glycol(s) polyethylene glycol(s)
  • acacia alginic acid
  • agar calcium carragenan
  • cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium
  • the amount of binder in the pharmaceutical compositions preferably ranges from about 5% w/w to about 20% w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable carriers, diluents or fillers for use, in the pharmaceutical composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, ⁇ -lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A
  • the amount of carriers, diluents or fillers in the pharmaceutical compositions preferably ranges from about 15% w/w to about 60 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Suitable anti-caking additives include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof.
  • Suitable anti-microbial agents or preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, thimersol, thymo, or combinations thereof.
  • Suitable sweetening agent or taste-masking agents include, but are not limited to, essential oils, water soluble extracts, sugar (natural or synthetic), monosaccharides, oligosaccharides, aldose, ketose, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, acesulfame, thaumatin, dihydrochalcone, alitame, miraculin, monellin, stevside sodium cyclamate, eugenylformate aldehyde flavorings or combinations thereof.
  • Suitable flavors include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder,
  • Suitable antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, or combinations thereof.
  • Suitable texture enhancers include, but are not limited to, pectin, polyethylene oxide, and carrageenan, or combinations thereof.
  • a process for preparing a pharmaceutical composition as described herein comprises admixing one or more pharmaceutically acceptable excipients with lapatinib, wherein the lapatinib is preferably in a nanosized form.
  • the process may comprise homogenizing lapatinib and at least one excipient to produce a homogenized dispersion of the lapatinib in the excipient.
  • the process further comprises processing said homogenized dispersion to produce lapatinib particles.
  • the processing may comprise milling said homogenized dispersion to produce a slurry of lapatinib particles.
  • the lapatinib particles may be dried and blended.
  • the dispersion comprises lapatinib, at least one surfactant, at least one polymer and at least one carrier, diluent or filler and purified water.
  • the lapatinib particles may be adsorbed by spraying the slurry onto a combination of at least one channeling agent, at least one anti-adherent and at least one disintegrant or super-disintegrant in a fluidized bed granulator.
  • the lapatinib particles may be compressed into unit dosage forms.
  • the lapatinib particles are lubricated before being compressed into unit dosage forms.
  • the unit dosage forms may be coated.
  • the lapatinib particles may have an average particle size of less than about 2000 nm.
  • the pharmaceutical composition of the present invention may be prepared by a process which comprises (a) preparing a dispersion of lapatinib with docusate sodium, hydroxyl propyl methylcellulose or hypromellose, sodium lauryl sulphate and lactose in purified water; (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on sodium chloride, magnesium stearate, silicified microcrystalline cellulose and sodium starch glycolate mixture in a fluidized bed granulator; (d) drying and blending the granules obtained in step (c).
  • the granules may be lubricated and finally compressed into tablets.
  • the tablets may further be film coated to form film coated tablets.
  • the pharmaceutical composition, according to the present invention may also optionally be coated. Examples of coatings comprise but are not limited to seal coating, enteric coating, film coating or a combination thereof.
  • pharmaceutical composition may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadry colour mix systems), Aqueous Acrylic Enteric System (such as Acryl-EZE ® ) and Kollicoat ® Protect.
  • colour mix systems such as Opadry colour mix systems
  • Aqueous Acrylic Enteric System such as Acryl-EZE ®
  • Kollicoat ® Protect Kollicoat ® Protect.
  • the pharmaceutical composition may be film coated.
  • the amount of film coat in the pharmaceutical compositions comprising lapatinib preferably ranges from about 2 % to about 15 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • the seal coat may comprise film forming polymeric materials, such as but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, carboxymethyl cellulose, hypromellose, acacia, and gelatin to increase adherence and coherence of the seal coat.
  • film forming polymeric materials such as but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, carboxymethyl cellulose, hypromellose, acacia, and gelatin to increase adherence and coherence of the seal coat.
  • the amount of seal coating system in the pharmaceutical compositions preferably ranges from about 1 % w/w to about 3 % w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
  • Pharmaceutically acceptable opacifiers may also be used in the pharmaceutical compositions of the present invention.
  • Pharmaceutically acceptable opacifiers may comprise one or more, but not limited to titanium dioxide.
  • the amount of opacificer in the pharmaceutical composition comprising lapatinib preferably ranges from about 1 % to about 4 % of the total weight of the composition, wherein the lapatinib is preferably in a nanosized form.
  • the pharmaceutical compositions of the invention comprise one or more surfactants, binders, disintegrants, lubricants, and optionally one or more channeling agents.
  • the pharmaceutical compositions of the invention comprise lapatinib nanoparticles in an amount of from 30% to 45% w/w, one or more surfactants present in an amount of from about 2% to about 10 % w/w, one or more binders in an amount of from about 5% to about 20% w/w, one or more disintegrants present in an amount of from about 5% to about 30% w/w, and optionally one or more channeling agents present in an amount of from about 0.5% to about 10% w/w.
  • the pharmaceutical composition of the present invention may further comprise at least one additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydroorotate dehydrogenase inhibitor, AKT inhibitor compounds, tyrosine kinase inhibitor, inhibitor of CDK4, PI3K beta inhibitor, MAPK pathway inhibitor, interleukin-2, c-Met antagonists, Hsp90 inhibitors, Wnt pathway inhibitors, pyruvate dehydrogenase kinase inhibitors, ERK pathway inhibitors, anti-ErbB3 antibody, MDM2 inhibitor, or combinations thereof wherein the lapatinib is preferably in a nanosized form.
  • additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MA
  • the pharmaceutical composition of the present invention may further comprise at least one additional active ingredient such as, but not limited to, capecitabine or letrozole.
  • the present invention further provides a method of treating advanced or metastatic breast cancer, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lapatinib to a patient in need thereof wherein the lapatinib is preferably in a nanosized form.
  • the present invention also provides the use of a pharmaceutical composition comprising lapatinib according to the present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer wherein the lapatinib is preferably in a nanosized form.
  • the present invention also provides a pharmaceutical composition comprising lapatinib according to the present invention for use in the treatment of advanced or metastatic breast cancer wherein the lapatinib is preferably in a nanosized form.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate
  • step (5) The lubricated granules obtained in step (5) were compressed and coated with Opadry orange.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) Blending and Lubrication: 4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate
  • step (5) The lubricated granules obtained in step (5) were compressed and coated with Opadry orange.
  • Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blended granules obtained in step (5) were lubricated with magnesium stearate
  • Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) Blending and Lubrication:
  • step (4) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blended granules obtained in step (5) were lubricated with magnesium stearate
  • step (6) The lubricated granules obtained in step (6) were compressed and coated with Opadry orange.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • step (5) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.
  • Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) Granulation: 4) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (4) The granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blend obtained in step (5) was lubricated with magnesium stearate.
  • step (6) The lubricated granules obtained in step (6) were compressed to produce dispersible tablets.
  • Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
  • step (3) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (4) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
  • step (5) The blended granules obtained in step (5) were lubricated with magnesium stearate.
  • step (2) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
  • step (3) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride
  • step (4) The blended granules obtained in step (4) were lubricated with magnesium stearate.

Abstract

A pharmaceutical composition comprises a tyrosine kinase inhibitor and one or more pharmaceutically acceptable excipients, a process for preparing such pharmaceutical compositions and use of the said pharmaceutical compositions for the treatment of cancer more specifically advanced or metastatic breast cancer.

Description

PHARMACEUTICAL COMPOSITION COMPRISING LAPATINIB
FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor, a process for preparing such pharmaceutical composition and use of the said pharmaceutical composition for the treatment of cancer more specifically advanced or metastatic breast cancer.
BACKGROUND AND PRIOR ART
Metastatic (also known as secondary or advanced or Stage IV) breast cancer occurs when breast cancer cells spread from the first (primary) tumour in the breast through the lymphatic or blood system to other parts of the body. The most common parts of the body that breast cancer spreads to are the bones, liver, lungs and brain. A diagnosis of metastatic breast cancer means that the cancer cannot be cured, although it can be controlled, sometimes for years.
Metastatic cancer may be treated with systemic therapy (chemotherapy, biological therapy, targeted therapy or hormonal therapy), local therapy (surgery or radiation therapy) or a combination of these treatments.
Although the outcomes of breast cancer have improved greatly over the past 20 years, dealing with recurrent and metastatic disease remains a significant and challenging medical problem, particularly in view of the high prevalence of the disease.
Several drugs have been approved for the treatment of breast cancer over the years; one amongst them being lapatinib.
Lapatinib is human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HERl/EGFR/ERBBl) tyrosine kinases inhibitor. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding.
Lapatinib is indicated in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (human epidermal growth factor receptors 1 and 2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Further lapatinib is used in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
Lapatinib is currently available under the brand name TYKERB® sold by Glaxosmithkline.
Lapatinib is present as the monohydrate of the ditosylate salt, with chemical name N-(3- chloro- 4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2- furanyl]-4-quinazolinamine bis(4- methylbenzenesulfonate) monohydrate.
Lapatinib ditosylate monohydrate is structurally represented as
Figure imgf000003_0001
WO2010099150 discloses a tablet composition of lapatinib wherein the tablet core comprises lapatinib and wherein the tablet composition is produced by a process which comprises the steps of granulating a mixture comprising said active ingredient and a starch, essentially in the absence of a cellulose, thereby producing granules of said mixture, ii) blending the granules produced in step with one or more extra-granular excipients to produce a granular blend, and iii) pressing the granular blend produced to form a tablet.
WO2010023187 discloses a composition of lapatinib wherein lapatinib is present in an amount of more than 60% by weight based on the total weight of the composition.
WO2006113649 discloses an oral composition of lapatinib and a binder, disintegrant, lubricant. The recommended dose of lapatinib is 1250 mg daily. Tablets comprising 250 mg lapatinib are sold under the trade name TYKERB®. Thus, the required dosage is comprised in five TYKERB® tablets that have to be administered orally once a day.
One of the issues with lapatinib is that its pharmacokinetic properties are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a "food effect". In particular, the bioavailability or systemic exposure of lapatinib increases with food. Lapatinib AUC values were approximately 3 and 4 times higher (Cmax approximately 2.5 and 3 times higher when administered with a low fat (5% fat) or with a high fat (50% fat) meal respectively.
As such, patients receive specific instructions to administer TYKERB® at least one hour before or one hour after a meal.
This situation is unsatisfactory and inconvenient to the patients especially cancer patients since their medications usually consist of multiple drug regimen demanding the administration of large numbers of tablets or capsules often along with intravenous therapy.
Further, these cancer patients often suffer from nausea and lesions of the oral mucosa. Therefore the oral administration of lapatinib may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of lapatinib.
Hence, it would be desirable to reduce the dosing regimen as well as nullify the food effect of lapatinib. Further, the resulting composition of lapatinib should be stable as well as exhibit optimal dissolution properties.
However, these characteristics are often difficult to achieve with high concentrations of lapatinib.
Additionally, common side effects associated with lapatinib therapy involve loss of appetite, nausea, diarrhea and skin problems. Less common side effects involve heart and liver problems which could be a cause of serious concern even though they are rare.
Accordingly, there have been no prior arts disclosing the dosage and ease of administration of lapatinib thereby facilitating patient compliance. Hence, the currently commercialized dosage form and the recommended dose still do not address the unsolved tribulations of the lapatinib therapy. The inventors of the present invention have appreciated the above problems associated with prior art compositions comprising lapatinib and methods of treating patients with them. Attempts to address the prior art problems have lead the inventors of the present invention to develop a patient compliant pharmaceutical composition with technical advancement and economic significance.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition comprising lapatinib and one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib along with pharmaceutically acceptable excipients.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting improved surface area and solubility.
Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting improved surface area and solubility.
Yet another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting increased bioavailability.
Yet another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting increased bioavailability.
Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib exhibiting minimal food effect.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib exhibiting minimal food effect.
Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of lapatinib. Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of nanosized lapatinib.
Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib for once a day administration.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib for once a day administration.
Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising lapatinib.
Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising nanosized lapatinib.
Yet another object of the present invention is to provide a method of treatment of advanced or metastatic breast cancer which method comprises administering a pharmaceutical composition comprising lapatinib.
Yet another object of the present invention is to provide a method of treatment of advanced or metastatic breast cancer which method comprises administering a pharmaceutical composition comprising nanosized lapatinib.
Another object of the present invention is to provide the use of a pharmaceutical composition comprising lapatinib, in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
Another object of the present invention is to provide the use of a pharmaceutical composition comprising nanosized lapatinib, in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
Another object of the present invention is to provide a pharmaceutical composition comprising lapatinib for the use in treatment of advanced or metastatic breast cancer.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized lapatinib for the use in treatment of advanced or metastatic breast cancer. SUMMARY OF THE INVENTION:
According to an aspect of the present invention, there is provided a pharmaceutical composition comprising lapatinib and one or more pharmaceutically acceptable excipients.
According to one aspect of the present invention there is provided a pharmaceutical composition comprising nanosized lapatinib, wherein the particles have an average particle size of less than about 2000 nm.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising nanosized lapatinib along with at least one pharmaceutically acceptable excipient.
According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising lapatinib with at least one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention there is provided a process for preparing a pharmaceutical composition comprising nanosized lapatinib with at least one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention there is provided a method of treating advanced or metastatic breast cancer, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lapatinib according to the present invention to a patient in need thereof.
According to another aspect of the present invention there is provided a method of treating advanced or metastatic breast cancer, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized lapatinib according to the present invention to a patient in need thereof.
According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising lapatinib according to the present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer. According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising nanosized lapatinib according to present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
According to another aspect of the present invention there is provided the pharmaceutical composition comprising lapatinib according to the present invention for use in treating advanced or metastatic breast cancer.
According to another aspect of the present invention there is provided the pharmaceutical composition comprising nanosized lapatinib according to the present invention for use in treating advanced or metastatic breast cancer.
DETAILED DESCRIPTION OF THE INVENTION:
Lapatinib is commercially available as a conventional film coated tablet formulation for the treatment of metastatic or advanced breast cancer in combination with capecitabine and letrozole. The required dosage is comprised in five lapatinib tablets that have to be administered once a day. Further, cancer patients are usually on a multiple drug regimen demanding the administration of large numbers of tablets or capsules often along with intravenous therapy.
Patient compliance in such a regimen can be addressed by decreasing the number of tablets or capsules administered as well as the type of dosage forms that are administered, with due consideration to the bioavailability of the administered drug . The bioavailability of the drug cannot be compromised to meet patient compliance.
The inventors have appreciated that the above criteria could be met by formulating a composition with a reduced or low dose such that it exhibits similar or increased bioavailability. Hence, lapatinib as an active pharmaceutical agent used for treating breast cancer, would be, preferred in an oral composition with a low dose provided in such a dosage forms which exhibit desired therapeutic effect and at the same time would ensure patient compliance.
The present invention provides a pharmaceutical composition comprising lapatinib which would ensure patient compliance due to simplification of therapy, ease of administration, an acceptable dosing regimen, bioavailability and which nullifies the food effect. The low dose which would be lower than the usual or the conventional dose, required to produce equal or higher therapeutic effect, would also reduce the plausible side effects thereby leading to limit the risk caused to the patient.
The term "lapatinib" is used in broad sense to include not only "lapatinib" per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc. Preferably, lapatinib is present in the form of lapatinib ditosylate monohydrate.
The term "low dose" or "reduced dose" as used herein refers to a therapeutically effective dose of lapatinib, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect.
Preferably, the pharmaceutical composition of the invention, according to the present invention may be administered at least once a day to a patient in need thereof. More preferably the pharmaceutical composition of the invention is administered once a day such that the total daily dose administered to a patient is a dose which is less than the conventionally administered daily dose. Preferably, the composition of the invention comprises less than 1250 mg of lapatinib. More preferably, the composition of the invention comprises from about 100 mg to about 1200 mg of lapatinib. Most preferably, the composition of the invention comprises from about 200 mg to about 1100 mg lapatinib. Optionally, the composition of the invention comprises from about 400 mg to about 1000 mg of lapatinib or from about 600 mg to about 800 mg of lapatinib. The conventional dose of TYKERB®, the current trade name for lapatinib, is 1250 mg per day. Lapatinib is preferably present in pharmaceutical compositions of the invention in an amount of from about 15% to about 55% by weight of the composition. More preferably, lapatinib is present in the compositions in an amount of from about 25% to about 50% by weight of the composition. Most preferably, the lapatinib is present in an amount of from about 30% to about 45% by weight of the composition. The inventors of the present invention have further observed that the solubility properties of lapatinib are improved by nanosizing thus leading to better bioavailability and dose reduction of the drug.
Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al, discusses the various methods to develop nanoformulations in "Nanonization strategies for poorly water-soluble drugs," Drug Discovery Today, Volume 00, Number 00, March 2010]. The present invention thus provides a pharmaceutical composition comprising lapatinib in the form of nanoparticles.
The term "nanosize" as used herein refers to lapatinib particles having an average particle size of less than about 2000 nm, preferably less than about 1000 nm.
The particles may have an average particle size of less than about 700 nm, optionally less than about 500 nm, optionally less than about 250 nm, optionally less than about 150 nm.
The lapatinib particles may have a particle size distribution with a D90 not less than about700 nm, preferably less than 300 nm, optionally less than 100 nm.
The present invention thus provides a pharmaceutical composition comprising lapatinib wherein lapatinib is in the nanosize range.
The term "particle" as used herein refers to an individual particle of lapatinib, or particles of lapatinib, or lapatinib granules and/or mixtures thereof. In addition, the particles of the present invention may comprise lapatinib and the one or more pharmaceutically acceptable excipients.
The nanosize particles of the present invention can be obtained by any process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, Particle replication in non-wetting templates (PRINT), thermal condensation, ultrasonication, spray drying or the like. Such nanoparticles obtained by any of these processes may further be formulated into desired dosage forms. The pharmaceutical composition comprising lapatinib according to the present invention may be administered orally through unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like; liquid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, spot-on), injection preparations etc. may also be envisaged under the ambit of the invention. Preferably, the unit dosage forms comprise nanosized lapatinib.
Preferably, the pharmaceutical composition comprising lapatinib according to the present invention may be administered in a solid oral dosage form such as tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles. Preferably, the solid oral dosage forms comprise nanosized lapatinib.
Suitably, the pharmaceutical composition comprising lapatinib, according to the present invention is presented in a tablet dosage form. Preferably, the tablet dosage forms comprise nanosized lapatinib.
The methods and uses of the invention preferably comprise administering a total daily dose of less than 1250 mg of lapatinib, such as from 100 mg lapatinib to 1200 mg lapatinib to a patient in need thereof. Optionally, lapatinib is administered with a total daily dose of from 100 mg to 1100 mg, from 200 mg to 1100 mg, from 400 mg to 1000 mg, or from 600 mg to 800 mg.
Preferably, the pharmaceutical compositions of the invention, are administered at least once a day to a patient in need thereof. Suitable excipients may be used for formulating the pharmaceutical composition of the invention, preferably as a tablet dosage form. Suitable excipients comprise, but are not limited to, surface stabilizers, viscosity modifying agents, polymers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents coloring agents, carriers, fillers, anti-adherents, solvents, taste-marking agents, preservatives, antioxidants, viscosity modifying agents, texture enhancers, surface stabilisers, channeling agents, or combinations thereof.
Suitable surface stabilizers, according to the present invention mean surfactants that are capable of stabilizing the increased surface charge of the nanosized drug. Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical compositions of the present invention.
According to the present invention, surfactants may comprise of one or more, but not limited to, Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, Ν,Ν,Ν,Ν tetrakis substituted ethylenediamines 2- alkyl 1- hydroxy ethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 - iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt, Phosal 53 MCT, Polyoxyethylene (20) sorbitan trioleate (Tween 85), Oleoyl macrogolglycerides (Labrafil M1944CS), Linoleoyl macrogolglycerides (Labrafil M2125CS), PG monolaurate (Lauroglycol 90), D-alpha-tocopheryl PEG 1000 succinate (Vitamin E TPGS), Polyoxyl 35 castor oil (Cremophor EL, Cremophor ELP), Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40, Cremophor RH 60), Lauroyl macrogolglycerides (Gelucire 44/14, Gelucire 50/13), Lauroyl macrogol-32 glycerides, Lauroyl polyoxyl-32 glycerides, Lauroyl polyoxylglycerides, Caprylocaproyl macrogol glycerides (Labrasol), Polyoxyethylene (20) sorbitan monooleate, (Polysorbate 80/ Tween 80), Polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/ Tween 20), polyglycerol (polyglyceryl oleate: Plural™ Oleique CC497) propylene glycol (propylene glycol monocaprylate: Capryol™ 90, propylene glycol monolaurate: Lauroglycol 90), polyoxyethylene glycols (PEG-8 stearate: Mirj 45, PEG- 40 stearate: Mirj® 52, PEG-15 hydroxystearate: Solutol® HS15), sorbitan or monoanhydrosorbitol (sorbitan monooleate: Span® 80, sucrose (sucrose monopalmitate: Surfhope® D-1616), Lutrol E 300, Transcutol HP, Transcutol P, Soyabean oil, Labrafac PG, Milyol 840, Pluronic L44, Pluronic L64, Polaxamer 188, and the like or combinations thereof.
The amount of surface stabilizers in the pharmaceutical composition comprising lapatinib preferably range from about 2 % to about 10 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable viscosity modifying agents are excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition and thus preventing physical interaction of nanoparticles under the operating conditions employed.
According to the present invention, viscosity modifying agents, may comprise one or more, but not limited to derivatives of sugars, such as lactose, lactose monohydrate, saccharose, hydrolyzed starch (maltodextrin) or combinations thereof.
The amount of viscosity modifying agents in the pharmaceutical composition comprising lapatinib preferably range from about 4 % to about 20 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable polymers according to the present invention, may comprise one or more hydrophilic polymers, but not limited to cellulose derivatives like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and copolymers, and combinations thereof.
The amount of polymers in the pharmaceutical composition comprising lapatinib preferably range from about 2 % to about 15 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable disintegrants or super disintegrants comprise agar-agar, calcium carbonate, microcrystalline cellulose, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, alginic acid, alginates such as sodium alginate other algins, other celluloses, gums, ion-exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, polyvinyl pyrollidone, cross-linked PVP, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, docusate sodium, guar gum, low- substituted HPC, polacrilin potassium, poloxamer, povidone, sodium glycine carbonate, sodium lauryl sulfate or combinations thereof.
The amount of disintegrant in the pharmaceutical compositions preferably ranges from about 5% w/w to about 30% w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable glidants, anti-adherents and lubricants according to the present invention include, but are not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, mineral oil, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerin, sorbitol, mannitol, other glycols, sodium lauryl sulfate, talc, long chain fatty acids and their salts, ethyl oleate, ethyl laurate, agar, syloid silica gel (a coagulated aerosol of synthetic silica (Evonik Degussa Co., Piano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, Mass. USA), or combinations thereof.
The amount of glidants, anti-adherants and lubricants in the pharmaceutical composition comprising lapatinib preferably ranges from about 0.25 % to about 5 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable channeling agents according to the present invention, include, but are not limited to sodium chloride, sugars, polyols and the like or mixtures thereof.
The amount of channeling agents in the pharmaceutical composition comprising lapatinib preferably range from about 0.5 % to about 10% of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable binders may also present in the pharmaceutical compositions of the present invention, which may comprise one or more of, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or combinations thereof thereof, or any other suitable binder.
The amount of binder in the pharmaceutical compositions preferably ranges from about 5% w/w to about 20% w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable carriers, diluents or fillers for use, in the pharmaceutical composition of the present invention may comprise one or more, but not limited to lactose (for example, spray-dried lactose, a-lactose, β-lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethylene, carboxymethyl hydroxyethyl cellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) or combinations thereof.
The amount of carriers, diluents or fillers in the pharmaceutical compositions preferably ranges from about 15% w/w to about 60 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
Suitable anti-caking additives include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof.
Suitable anti-microbial agents or preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, thimersol, thymo, or combinations thereof.
Suitable sweetening agent or taste-masking agents include, but are not limited to, essential oils, water soluble extracts, sugar (natural or synthetic), monosaccharides, oligosaccharides, aldose, ketose, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, acesulfame, thaumatin, dihydrochalcone, alitame, miraculin, monellin, stevside sodium cyclamate, eugenylformate aldehyde flavorings or combinations thereof.
Suitable flavors include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana and ginger or combinations thereof.
Suitable antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, or combinations thereof.
Suitable texture enhancers include, but are not limited to, pectin, polyethylene oxide, and carrageenan, or combinations thereof.
There is also provided a process for preparing a pharmaceutical composition as described herein which process comprises admixing one or more pharmaceutically acceptable excipients with lapatinib, wherein the lapatinib is preferably in a nanosized form.
The process may comprise homogenizing lapatinib and at least one excipient to produce a homogenized dispersion of the lapatinib in the excipient. Optionally, the process further comprises processing said homogenized dispersion to produce lapatinib particles. The processing may comprise milling said homogenized dispersion to produce a slurry of lapatinib particles. The lapatinib particles may be dried and blended.
Optionally, the dispersion comprises lapatinib, at least one surfactant, at least one polymer and at least one carrier, diluent or filler and purified water.
The lapatinib particles may be adsorbed by spraying the slurry onto a combination of at least one channeling agent, at least one anti-adherent and at least one disintegrant or super-disintegrant in a fluidized bed granulator.
The lapatinib particles may be compressed into unit dosage forms. Optionally, the lapatinib particles are lubricated before being compressed into unit dosage forms. The unit dosage forms may be coated. The lapatinib particles may have an average particle size of less than about 2000 nm.
The pharmaceutical composition of the present invention, may be prepared by a process which comprises (a) preparing a dispersion of lapatinib with docusate sodium, hydroxyl propyl methylcellulose or hypromellose, sodium lauryl sulphate and lactose in purified water; (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on sodium chloride, magnesium stearate, silicified microcrystalline cellulose and sodium starch glycolate mixture in a fluidized bed granulator; (d) drying and blending the granules obtained in step (c). The granules may be lubricated and finally compressed into tablets. The tablets may further be film coated to form film coated tablets. The pharmaceutical composition, according to the present invention, may also optionally be coated. Examples of coatings comprise but are not limited to seal coating, enteric coating, film coating or a combination thereof.
According to an embodiment of the present invention, pharmaceutical composition may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadry colour mix systems), Aqueous Acrylic Enteric System (such as Acryl-EZE®) and Kollicoat® Protect.
Preferably, the pharmaceutical composition, according to the present invention, may be film coated.
The amount of film coat in the pharmaceutical compositions comprising lapatinib preferably ranges from about 2 % to about 15 % of the total weight of the composition wherein the lapatinib is preferably in a nanosized form.
The seal coat may comprise film forming polymeric materials, such as but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, carboxymethyl cellulose, hypromellose, acacia, and gelatin to increase adherence and coherence of the seal coat.
The amount of seal coating system in the pharmaceutical compositions preferably ranges from about 1 % w/w to about 3 % w/w, of the total weight of the composition wherein the lapatinib is preferably in a nanosized form. Pharmaceutically acceptable opacifiers may also be used in the pharmaceutical compositions of the present invention. Pharmaceutically acceptable opacifiers may comprise one or more, but not limited to titanium dioxide.
The amount of opacificer in the pharmaceutical composition comprising lapatinib preferably ranges from about 1 % to about 4 % of the total weight of the composition, wherein the lapatinib is preferably in a nanosized form.
Preferably, the pharmaceutical compositions of the invention comprise one or more surfactants, binders, disintegrants, lubricants, and optionally one or more channeling agents.
More preferably, the pharmaceutical compositions of the invention comprise lapatinib nanoparticles in an amount of from 30% to 45% w/w, one or more surfactants present in an amount of from about 2% to about 10 % w/w, one or more binders in an amount of from about 5% to about 20% w/w, one or more disintegrants present in an amount of from about 5% to about 30% w/w, and optionally one or more channeling agents present in an amount of from about 0.5% to about 10% w/w.
The pharmaceutical composition of the present invention, may further comprise at least one additional active ingredient such as, but not limited to, MEK inhibitor, topoisomerase inhibitor, EGFR inhibitor, anti-CTLA4 antibody, DLL4 antagonist, anti-HMW-MAA antibody, peginterferon alfa-2a, dihydroorotate dehydrogenase inhibitor, AKT inhibitor compounds, tyrosine kinase inhibitor, inhibitor of CDK4, PI3K beta inhibitor, MAPK pathway inhibitor, interleukin-2, c-Met antagonists, Hsp90 inhibitors, Wnt pathway inhibitors, pyruvate dehydrogenase kinase inhibitors, ERK pathway inhibitors, anti-ErbB3 antibody, MDM2 inhibitor, or combinations thereof wherein the lapatinib is preferably in a nanosized form.
The pharmaceutical composition of the present invention, may further comprise at least one additional active ingredient such as, but not limited to, capecitabine or letrozole.
The present invention further provides a method of treating advanced or metastatic breast cancer, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lapatinib to a patient in need thereof wherein the lapatinib is preferably in a nanosized form. The present invention also provides the use of a pharmaceutical composition comprising lapatinib according to the present invention in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer wherein the lapatinib is preferably in a nanosized form.
The present invention also provides a pharmaceutical composition comprising lapatinib according to the present invention for use in the treatment of advanced or metastatic breast cancer wherein the lapatinib is preferably in a nanosized form.
The following examples are for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.
Example 1:
Figure imgf000020_0001
13. Opadry orange 15.0-30.0
14. Purified Water q.s.
Total weight 515.0-1030.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose and sodium lauryl sulphate were dissolved in water.
2) Lapatinib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate
D) Compression and Coating:
6) The lubricated granules obtained in step (5) were compressed and coated with Opadry orange.
Example 2:
Figure imgf000021_0001
3. Hydroxypropyl methylcellulose 37.5
4. Docusate Sodium 3.75
5. Lactose Monohydrate 37.5
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 75.0
8. Sodium Starch Glycolate 37.5
Blending and Lubrication
9. Sodium Chloride 22.5
10. Sodium Starch Glycolate 15.0
11. Silicified Microcrystalline Cellulose 52.4
12. Magnesium Stearate 6
Total Weight 500
Coating
13. Opadry orange 15.0
14. Purified Water q.s.
Total weight 515.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, and sodium lauryl sulphate were dissolved in water.
2) Lapatinib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication: 4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate
D) Compression and Coating:
6) The lubricated granules obtained in step (5) were compressed and coated with Opadry orange.
Example 3:
Figure imgf000023_0001
Total weight 565.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Cremophor ELP was dissolved in the solution obtained in step (1).
3) Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate
D) Compression and Coating:
7) The lubricated granules obtained in step (6) were compressed and coated with Opadry orange. Example 4:
Figure imgf000024_0001
4. Docusate Sodium 3.75
5. Lactose Monohydrate 37.5
6. Labrasol 50.0
7. Purified water q.s
Dry Mix
8. Lactose Monohydrate 75.0
9. Sodium Starch Glycolate 37.5
Blending and Lubrication
10. Sodium Chloride 22.5
11. Sodium Starch Glycolate 15.0
12. Silicified Microcrystalline Cellulose 52.4
13. Magnesium Stearate 6
Total Weight 550.0
Coating
14. Opadry orange 15.0
15. Purified Water q.s.
Total weight 565.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Labrasol was dissolved in the solution obtained in step (1).
3) Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules. C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate
D) Compression and Coating:
7) The lubricated granules obtained in step (6) were compressed and coated with Opadry orange.
Example 5
Figure imgf000026_0001
Process: A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Lapatinib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending & Lubrication:
4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression:
6) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets.
Example 6
Figure imgf000027_0001
8. Sodium Starch Glycolate 37.5
Blending and Lubrication
9. Sodium Chloride 22.5
10. Sodium Starch Glycolate 15.0
11. Silicified Microcrystalline Cellulose 52.4
12. Magnesium Stearate 6
Total Weight 500
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Lapatinib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression:
6) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets. Example 7
Sr. No. Ingredients Quantity (mg/tab)
Binder Slurry
1. Lapatinib Ditosylate Monohydrate 202.5
2. Sodium Lauryl Sulphate 10.35
3. Hydroxypropyl methylcellulose 37.5
4. Docusate Sodium 3.75
5. Lactose Monohydrate 37.5
6. Cremophor ELP 50.0
7. Purified water q.s
Dry Mix
8. Lactose Monohydrate 75.0
9. Sodium Starch Glycolate 37.5
Blending and Lubrication
10. Sodium Chloride 22.5
11. Sodium Starch Glycolate 15.0
12. Silicified Microcrystalline Cellulose 52.4
13. Magnesium Stearate 6
Total Weight 550.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methylcellulose, and sodium lauryl sulphate were dissolved in water.
2) Cremophor ELP was dissolved in the solution obtained in step (1).
3) Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation: 4) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
5) The granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
6) The blend obtained in step (5) was lubricated with magnesium stearate.
D) Compression:
7) The lubricated granules obtained in step (6) were compressed to produce dispersible tablets.
Example 8
Figure imgf000030_0001
Total Weight 550.0
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Labrasol was dissolved in the solution obtained in step (1).
3) Lapatinib was dispersed in the solution obtained in step (2) and then milled to form a slurry.
B) Granulation:
4) The drug slurry obtained in step (3) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
5) The dried granules obtained in step (4) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride.
6) The blended granules obtained in step (5) were lubricated with magnesium stearate.
D) Compression:
7) The lubricated granules obtained in step (6) were compressed to produce dispersible tablets. Example 9
Figure imgf000031_0001
4. Docusate Sodium 15.0
5. Lactose Monohydrate 150.0
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 300.0
8. Sodium Starch Glycolate 150.0
Blending and Lubrication
9. Sodium Chloride 90.0
10. Sodium Starch Glycolate 60.0
11. Silicified Microcrystalline Cellulose 209.6
12. Magnesium Stearate 24.0
Total Weight 2000
Process:
A) Drug Slurry Preparation:
1) Docusate sodium, hydroxypropyl methyl cellulose, and sodium lauryl sulphate were dissolved in water.
2) Lapatinib was dispersed in the solution obtained in step (1) and then milled to form a slurry.
B) Granulation:
3) The drug slurry obtained in step (2) was sprayed on lactose and sodium starch glycolate to obtain granules.
C) Blending and Lubrication:
4) The dried granules obtained in step (3) were blended with sodium starch glycolate, silicified microcrystalline cellulose and sodium chloride
5) The blended granules obtained in step (4) were lubricated with magnesium stearate.
D) Compression: 6) The lubricated granules obtained in step (5) were compressed to produce dispersible tablets.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

Claims

Claims
1. A pharmaceutical composition comprising lapatinib and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1 comprising lapatinib in the form of nanoparticles.
3. The pharmaceutical composition according to claim 2, wherein the nanoparticles have an average particle size of less than about 2000 nanometers.
4. The pharmaceutical composition according to claim 2, wherein the nanoparticles have an average particle size of less than about 1000 nanometers.
5. The pharmaceutical composition according to any preceding claim comprising lapatinib in the form of a pharmaceutically acceptable derivative thereof.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable derivative is selected from the list consisting of a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug or a combination thereof.
7. The pharmaceutical composition according to claim 6, wherein lapatinib is in the form of lapatinib ditosylate monohydrate.
8. The pharmaceutical composition according to any preceding claim, wherein the one or more pharmaceutically acceptable excipients comprise disintegrants or super disintegrants; carriers, diluents; fillers, plasticizers; binders; glidants; anti-adherents; lubricants; solvents, sweetening agents; taste-masking agents; flavoring agents; anti-caking agents; anti-microbial agents; preservatives; antifoaming agents; emulsifiers; surfactants; antioxidants; viscosity modifying agents; texture enhancers; surface stabilizers; buffering agents; coloring agents; channeling agents; or any combination thereof.
9. The pharmaceutical composition according to claim 8, wherein the composition comprises one or more surfactants optionally in an amount of from about 2% to about 10% of the total weight of the composition.
10. The pharmaceutical composition according to claim 8 or 9, wherein the composition comprises one or more viscosity modifying agents, optionally in an amount of from about 4% to about 20% of the total weight of the composition.
11. The pharmaceutical composition according to claim 8, 9 or 10, wherein the composition comprises at least one polymer, optionally in an amount of from about 2% to about 15% of the total weight of the composition.
12. The pharmaceutical composition according to any preceding claim, wherein the composition is in an oral dosage form.
13. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is for once a day administration.
14. The pharmaceutical composition according to claim 12 or 13, wherein the oral dosage form is in the form of a tablet, a coated tablet, powder, powder for reconstitution, pellets, beads, a mini-tablet, a multilayer tablet, a bilayered tablet, a tablet-in-tablet, a pill, a micro-pellet, a small tablet unit, capsules, MUPS (multiple unit pellet system), a disintegrating tablet, a dispersible tablet, granules, microspheres, multiparticulates, a capsule (optionally filled with powder, powder for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles, microspheres and multiparticulates), a sachet (optionally filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, sprinkles microspheres and multiparticulates) or sprinkles.
15. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises less than 1250 mg of lapatinib.
16. The pharmaceutical composition according to any preceding claim, further comprising at least one additional active ingredient selected from capecitabine, letrozole, an MEK inhibitor, a topoisomerase inhibitor, an EGFR inhibitor, an anti-CTLA4 antibody, an DLL4 antagonist, an anti-HMW-MAA antibody, peginterferon alfa-2a, a dihydroorotate dehydrogenase inhibitor, an AKT inhibitor compound, a tyrosine kinase inhibitor, an inhibitor of CDK4, a PI3K beta inhibitor, a MAPK pathway inhibitor, an interleukin-2, a c-Met antagonist, an Hsp90 inhibitor, a Wnt pathway inhibitor, a pyruvate dehydrogenase kinase inhibitor, an ERK pathway inhibitor, an anti-ErbB3 antibody, an MDM2 inhibitor, or combinations thereof.
17. The pharmaceutical composition according to claim 16, wherein the additional active pharmaceutical ingredient is capecitabine or letrozole.
18. A process for preparing a pharmaceutical composition according to any preceding claim which process comprises admixing one or more pharmaceutically acceptable excipients with lapatinib.
19. The pharmaceutical composition according to claim 1 to 17, for use in treating advanced or metastatic breast cancer.
20. A method of treating advanced or metastatic breast cancer, wherein the method comprises administering a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 17 to a patient in need thereof.
21. Use of a pharmaceutical composition according to any one of claims 1 to 17, in the manufacture of a medicament for the treatment of advanced or metastatic breast cancer.
22. A pharmaceutical composition substantially as described herein with reference to the examples.
23. A process for the preparation of a pharmaceutical composition as substantially described herein with reference to the examples.
PCT/GB2015/050885 2014-03-24 2015-03-24 Pharmaceutical composition comprising lapatinib WO2015145145A1 (en)

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WO2021033144A1 (en) * 2019-08-20 2021-02-25 Intas Pharmaceuticals Ltd. Oral suspension of capecitabine
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