WO2005074893A1 - Stable amorphous forms of montelukast sodium - Google Patents

Stable amorphous forms of montelukast sodium Download PDF

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Publication number
WO2005074893A1
WO2005074893A1 PCT/IL2005/000134 IL2005000134W WO2005074893A1 WO 2005074893 A1 WO2005074893 A1 WO 2005074893A1 IL 2005000134 W IL2005000134 W IL 2005000134W WO 2005074893 A1 WO2005074893 A1 WO 2005074893A1
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WO
WIPO (PCT)
Prior art keywords
amoφhous
montelukast sodium
condition
solvent
precipitate
Prior art date
Application number
PCT/IL2005/000134
Other languages
French (fr)
Inventor
Mohammed Alnabari
Yana Sery
Itai Adin
Oded Arad
Joseph Kaspi
Original Assignee
Chemagis Ltd.
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 Chemagis Ltd. filed Critical Chemagis Ltd.
Priority to CA002554927A priority Critical patent/CA2554927A1/en
Priority to BRPI0506610-7A priority patent/BRPI0506610A/en
Priority to JP2006552007A priority patent/JP2007520546A/en
Priority to EP05703177A priority patent/EP1711166A1/en
Priority to AU2005210236A priority patent/AU2005210236B2/en
Priority to NZ548873A priority patent/NZ548873A/en
Publication of WO2005074893A1 publication Critical patent/WO2005074893A1/en
Priority to IL177123A priority patent/IL177123A0/en

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    • 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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to stable amorphous forms of montelukast sodium and, more particularly, to stable amorphous forms of montelukast sodium which are suitable for use in the preparation of solid dosage formulations, to processes of preparing same, to compositions containing the same and to methods of treatment using the same.
  • Montelukast sodium is freely soluble in ethanol, methanol and water but is practically insoluble in acetonitrile.
  • Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti- asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent.
  • Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma.
  • Montelukast sodium formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis.
  • Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.
  • Singulair® the form of montelukast sodium used in preparing Singulair® is hygroscopic and therefore require special care in handling and storage, which adversely affect the efficiency of the production process.
  • Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480,717.
  • the synthesis of montelukast sodium involves coupling methyl l-(mercaptomethyl)cyclopropaneacetate with (S)- l-(3-(2-(7-chloro-2-quinolinyl)ethenyl( ⁇ henyl)-3(-2-(l-hydroxy-l- methylethyl)phenyl)propyl-methanesulfonate, followed by hydrolysis of the resulting methyl ester so as to form a free acid, which is followed by conversion of the free acid to a corresponding sodium salt.
  • the sodium salt is prepared in an aqueous solution and the water is removed by freeze-drying.
  • the montelukast sodium is crystallized from a toluene/acetonitrile solution to obtain crystalline montelukast sodium.
  • This publication further notes that the compounds disclosed in EP 480,717 are hydrated amorphous montelukast sodium, and are therefore not ideal for use in the formulation of pharmaceutical compositions.
  • International Patent Application PCT/US03/03700 published as WO 03/066598, discloses an anhydrous amorphous form of montelukast sodium.
  • amo ⁇ hous montelukast sodium is prepared, according to the teachings of WO 03/066598, by providing a solution of montelukast free acid in an aromatic solvent; converting the tree acid to an alkali salt using methanolic sodium hydroxide; adding a hydrocarbon solvent, and isolating the thus obtained amo ⁇ hous montelukast sodium.
  • Preparing amo ⁇ hous montelukast sodium by flocculation from aromatic and hydrocarbon solvents is disadvantageous, particularly when compared to aqueous solutions, due to the toxicity, cost and typical hazardousness of such organic solvents.
  • any failure to predict the bioavailability of a drug may result in administration of either too small or too large undesired doses, which may be dangerous to patients and in extreme cases, lethal.
  • Other examples are known, where different forms behave differently during physical processing like milling and pressing.
  • Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amo ⁇ hous form of the substance.
  • the solid-state experts are in a constant search for forms that can withstand physical stress and still retain their original properties. Different forms of a pharmaceutically useful compound therefore provide opportunities to improve the performance characteristics of a pharmaceutical product.
  • Different forms enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of an active pharmaceutical ingredient with a desired characteristic.
  • crystalline montelukast sodium and anhydrous amo ⁇ hous montelukast sodium are taught in WO 95/18107 and WO 03/066598, respectively.
  • formulating crystalline forms of substances into pharmaceutical compositions is limited by the instability of the crystalline form during the formulation process (e.g., when high pressure is applied), solubility characteristics of the substance, and other characteristics.
  • the preparation of the anhydrous amo ⁇ hous montelukast sodium taught in WO 03/066598 involves solvents such as aromatic hydrocarbons, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, which are all considered disadvantageous when used in the preparation of medicaments, since they are relatively toxic, cost-inefficient and environmental unfriendly.
  • solvents such as aromatic hydrocarbons, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons
  • novel amo ⁇ hous forms of montelukast sodium that are suitable for pharmaceutical use are presented.
  • stable, non-hygroscopic, amo ⁇ hous montelukast sodium Further according to the teachings of the present invention there is also provided a co-precipitate of amo ⁇ hous montelukast sodium and at least one pharmaceutically acceptable excipient.
  • the at least one pharmaceutically acceptable excipient comprises lactose.
  • the ratio between the amo ⁇ hous montelukast sodium and lactose ranges between about 1:0.1 and about 1:10, preferably the ratio ranges between about 1 :0.5 and 1 :2, and even more preferably the ratio is about 1:1.
  • the amo ⁇ hous montelukast sodium of the present invention and the co- precipitate including same are non-hygroscopic.
  • a weight gain of the amo ⁇ hous montelukast sodium or the co- precipitate described herein is less than 2 weight percents of its total weight, preferably less than 0.5 weight percents.
  • amo ⁇ hous montelukast sodium of the present invention and the co- precipitate including same are stable.
  • the amo ⁇ hous montelukast sodium retains an amo ⁇ hous character subsequent to storage at a temperature of at least 25 °C for a time period of at least 2 months and even subsequent to storage at a temperature of about 40 °C for a time period of about 3 months.
  • the amo ⁇ hous montelukast sodium retains an amo ⁇ hous character subsequent to application of a pressure greater than 5000 Kg/cm 3 for a period of about one minute and even subsequent to application of pressure of about 10000 Kg/cm 3 for a period of about one minute.
  • amo ⁇ hous montelukast sodium of the present invention and the co- precipitate including same have properties advantageous for use in preparing pharmaceutical compositions therewith.
  • the amo ⁇ hous montelukast sodium, as well as the co-precipitate including same have a bulk density that ranges between about 0.10 gram cm 3 and about 0.40 gram/cm 3 g/cm 3 , preferably greater than 0.10 g/cm 3 or even greater than 0.20 g/cm 3 .
  • the amo ⁇ hous montelukast sodium of the present invention has a powder X-ray diffraction pattern substantially as depicted in Figure 2.
  • an exemplary co-precipitate which comprises the amo ⁇ hous montelukast sodium and lactose has a powder X-ray diffraction pattern substantially as depicted in Figures 3, 4 and 5.
  • a process of preparing the amo ⁇ hous montelukast sodium of the present invention described above the process comprises dissolving montelukast sodium in a solvent, to thereby provide a solution of montelukast sodium in the solvent and removing the solvent from the solution by spray drying.
  • the solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof.
  • the water miscible organic solvent is selected from the group consisting of acetone, a C ⁇ -C 3 alcohol, and any combination thereof, preferably ethanol.
  • the solvent is water, ethanol or a mixture of water and ethanol.
  • a process of preparing the co-precipitate of the present invention comprising dissolving montelukast sodium and at least one pharmaceutically acceptable excipient in a solvent, to thereby provide a solution of montelukast sodium in the solvent and removing the solvent from the solution, thereby obtaining the co- precipitate of amo ⁇ hous montelukast sodium and the at least one excipient.
  • the at least one pharmaceutically acceptable excipient is lactose.
  • the at least one pharmaceutically acceptable excipient is lactose monohydrate.
  • the ratio between the amorphous montelukast and lactose ranges between about 1:0.1 and about 1:10, preferably the ratio ranges between about 1:0.5 and 1:2, and even more preferably the ratio is about 1:1.
  • removing the solvent is effected by freeze drying the solution.
  • removing the solvent is effected by spray drying the solution.
  • the solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof.
  • the water miscible organic solvent is selected from the group consisting of acetone, a C ⁇ -C 3 alcohol, and any combination thereof, preferably ethanol.
  • the solvent is water, ethanol or a mixture of water and ethanol.
  • pharmaceutical compositions comprising the amo ⁇ hous montelukast sodium of the present invention and/or the co-precipitate according to the present invention, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated in a solid dosage form, including but not limited to a tablet, a capsule, a peel, a dragee, a powder and granules.
  • the pharmaceutical composition of the present invention is packaged in a packaging material and identified in print, in or on said packaging material, for use for a need selected from the group consisting of curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition in which treatment with montelukast sodium is beneficial.
  • Exemplary conditions include but are not limited to allergic rhinitis and asthma.
  • a method of treating a medical condition in which administration of montelukast sodium is beneficial comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the pharmaceutical compositions of the present invention.
  • exemplary conditions include but are not limited to allergic rhinitis and asthma.
  • administration of the pharmaceutical composition is preferably administered orally.
  • the pharmaceutical composition is formulated in a solid dosage form.
  • the terms "comprising" and “including” or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do , not preclude the addition of one or more additional features, integers, steps, components or groups thereof.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • Implementation of the methods of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof.
  • active ingredient refers to a pharmaceutical agent including any natural or synthetic chemical substance that subsequent to its application has, at the very least, at least one desired pharmaceutical or therapeutic effect.
  • terapéuticaally effective amount denotes that dose of an active ingredient or a composition comprising the active ingredient that will provide the therapeutic effect for which the active ingredient is indicated.
  • the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.
  • the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • FIG. 1 presents an X-ray powder diffractogram of exemplary amo ⁇ hous montelukast sodium prepared by freeze-drying according to the process described in European Patent No. EP 480,717
  • FIG. 2 presents an X-ray powder diffractogram of exemplary amo ⁇ hous montelukast sodium according to the present invention, prepared by spray-drying and pressing at 10,000 Kg/cm 3 for 1 minute;
  • FIG. 1 presents an X-ray powder diffractogram of exemplary amo ⁇ hous montelukast sodium prepared by freeze-drying according to the process described in European Patent No. EP 480,717
  • FIG. 2 presents an X-ray powder diffractogram of exemplary amo ⁇ hous montelukast sodium according to the present invention, prepared by spray-drying and pressing at 10,000 Kg/cm 3 for 1 minute
  • FIG. 1 presents an X-ray powder diffractogram of exemplary amo ⁇ hous montelukast sodium prepared by freeze-drying
  • FIG. 3 presents an X-ray powder diffractogram of an exemplary co-precipitate of amo ⁇ hous montelukast sodium and lactose according to the present invention, prepared by spray drying and stored at a temperature of 40 °C for three months;
  • FIG. 4 presents an X-ray powder diffractogram of an exemplary co-precipitate of amo ⁇ hous montelukast sodium and lactose according to the present invention prepared by freeze-drying and pressing at 10,000 Kg/cm 3 for 1 minute; and FIG.
  • FIG. 5 presents an X-ray powder diffractogram of an exemplary co-precipitate of amo ⁇ hous montelukast sodium and lactose according to the present invention, prepared by freeze-drying and pressing at 10,000 Kg/cm 3 for 1 minute.
  • the amo ⁇ hous montelukast sodium and the co-precipitates including same described herein preferably contain less than about 10 % crystalline montelukast sodium, and more preferably are essentially free of crystalline montelukast sodium.
  • the phrase "essentially free of crystalline montelukast sodium" means that no crystalline montelukast sodium can be detected within the limits of a powder X-ray Diffractometer comparable to the instrumentation described hereinbelow in the Experimental section.
  • the teachings of the present invention relate to two general types of substances.
  • the first substance is stable, non-hygroscopic, amo ⁇ hous montelukast sodium.
  • the second substance is a co-precipitate of amo ⁇ hous montelukast sodium and at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient refers to an inert substance which is added so as to provide a pharmaceutical composition with a desired characteristic.
  • excipients typically used in pharmaceutical compositions include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, ⁇ ce starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the pharmaceutically acceptable excipient in the co-precipitate of the present invention is preferably selected so as to improve the mechanical characteristics of montelukast sodium in terms of, e.g., mechanical stability, physical stability, bulk density and the like.
  • An example of such an excipient is lactose. Lactose is known as an additive which upon being added to a solution of an amo ⁇ hous substance, leads to the production of free-flowing powders. As is well known in the art, free- flowing powders are highly suitable for formulation processes.
  • an exceptionally preferred co-precipitate according to the present invention is a co-precipitate of amo ⁇ hous montelukast sodium with lactose.
  • the ratio between the amo ⁇ hous montelukast sodium and lactose preferably ranges between about 1:0.1 and about 1:10, more preferably between about 1:0.5 and 1:2 and more preferably is about 1:1.
  • previously disclosed amo ⁇ hous forms of montelukast sodium are hygroscopic and/or include potentially toxic organic solvents, making such forms unsuitable for use in the preparation of pharmaceutical compositions.
  • the present inventors have now su ⁇ risingly uncovered amo ⁇ hous montelukast sodium that is stable, not hygroscopic and, in addition, has a relatively high bulk density, and hence is exceptionally suitable for preparing pharmaceutical compositions.
  • the present inventors have also uncovered a co-precipitate of amo ⁇ hous montelukast sodium and one or more pharmaceutically acceptable excipient(s), especially a co-precipitate of amo ⁇ hous montelukast sodium and lactose, which is exceptionally suitable for preparing pharmaceutical compositions by being stable, non-hygroscopic and having relatively high bulk density.
  • the term “stable” regarding the substances of the present invention is meant to define a characteristic of the substance by which the substance maintains chemical and physical features during storage or other challenging conditions, particularly those used in formulating procedures.
  • the substances of the present invention were found to be highly stable, maintaining their amo ⁇ hous character during e.g., storage and application of high pressure.
  • non-hygroscopic regarding the substances of the present invention is meant to define a characteristic of the substance by which the tendency of the substance to absorb water is negligible.
  • the amo ⁇ hous montelukast sodium and the co-precipitates including same according to the present invention are su ⁇ risingly non-hygroscopic.
  • the change in the total weight of exemplary substances according to the present invention was found to be about 0.36 weight percents.
  • the amo ⁇ hous montelukast sodium according to the present invention is characterized by such non-hygroscopicity that upon exposure to an atmosphere of about 30 % humidity for a period of one hour, the weight gain thereof is preferably less than 2 weight percents, more preferably than 1.5 weight percents, more preferably less than 1 weight percents, and even more preferably less than 0.5 weight percents.
  • the water content of an exemplary co- precipitate of amo ⁇ hous montelukast sodium according to the present invention changed from about 3.75 weight percents to about 4.11 weight percents upon exposure to an atmosphere of about 30 % humidity for a period of one hour.
  • This lack of hygroscopicity of the amo ⁇ hous montelukast sodium iid the co- precipitate thereof renders these substances exceptionally suitable for use in preparing pharmaceutical compositions.
  • the amo ⁇ hous montelukast sodium and the co-precipitate thereof according to the present invention are further characterized by high stability.
  • the substances of the present invention retain an amo ⁇ hous character while being stored for more than two months at a temperature higher than room temperature (e.g., of at least 25 °C). More specifically, it is shown that the substances of the present invention retain an amo ⁇ hous character subsequent to storage at a temperature of about 40 °C for a time period of about 3 months. This stability of the amo ⁇ hous montelukast sodium and the co-precipitates thereof renders these substances exceptionally suitable for use in preparing pharmaceutical compositions.
  • An additional advantage of the substances of the present invention is that these substances retain an amo ⁇ hous character under conditions typically used when preparing compressed solid dosage forms such as tablets.
  • amo ⁇ hous montelukast sodium and an exemplary co-precipitate thereof according to the present invention retained the amo ⁇ hous character subsequent to application of a high pressure, e.g., of about 10,000 kg/cm 3 , for a period of about one minute, as is widely employed in solid dosage formulations.
  • a high pressure e.g., of about 10,000 kg/cm 3
  • the substances of the present invention are particularly advantageously characterized by a relatively high bulk density.
  • the amo ⁇ hous montelukast sodium and the co-precipitates thereof according to the present invention have a bulk density greater than 0.1 gram/cm , such that preferably the amo ⁇ hous montelukast sodium and the co-precipitates thereof according to the present invention have a bulk density that ranges from 0.1 gram/cm to 0.4 gram/cm , and, more preferably, greater than about 0.2 gram/cm 3 .
  • Such a relatively high bulk density of the amo ⁇ hous montelukast sodium and the co-precipitates thereof according to the present invention renders these substances exceptionally suitable for use in preparing pharmaceutical compositions.
  • the amo ⁇ hous montelukast sodium of the present invention is generally prepared by dissolving montelukast sodium in a solvent to thereby provide a solution of the montelukast sodium in the solvent and then removing the solvent from the solution by spray drying.
  • the co-precipitate of the present invention is generally prepared by dissolving montelukast sodium and one or more pharmaceutically acceptable excipients in a solvent to thereby provide a solution of the montelukast sodium and the excipient in the solvent and then removing the solvent from the solution, preferably by spray drying or freeze-drying.
  • a preferred pharmaceutically acceptable excipient is lactose, preferably added to the solvent as lactose monohydrate.
  • the weight ratio between the amo ⁇ hous montelukast and lactose ranges between about 1:0.1 and about 1:10, preferably being about 1:1.
  • a first preferred method of removing the solvent suitable for preparing the co- precipitate according to the present invention is by freeze-drying. In freeze drying the solution comprises water as a solvent. The solution is frozen using conditions that avoid precipitation and or crystallization of substances in the solution. The frozen solution is then exposed to a reduced pressure so that the water sublimates from the frozen solution leaving an amo ⁇ hous form of the substances to be gathered.
  • a second preferred method of removing the solvent, suitable for preparing both amo ⁇ hous montelukast and a co-precipitate of the present invention is by spray drying.
  • spray drying a solution is sprayed from a nozzle into or with a large volume of a gas such as air. Generally, the solution, the nozzle and/or the gas are heated. The spraying from the nozzle generates droplets of solution containing substances in the solution. The combination of gas and heat causes the solvents in the droplets to evaporate, leaving an amo ⁇ hous form of the substances to be gathered.
  • suitable solvents include but are not limited to water, water miscible organic solvents and combinations thereof.
  • suitable water miscible organic solvents include but are not limited to acetone, a C ⁇ -C 3 alcohol (preferably ethanol), and any combination thereof.
  • the solvent is water.
  • the solvent is ethanol.
  • the solvent is a mixture of water and ethanol, preferably in a 1:1 ratio.
  • the temperature of the nozzle is greater than about 75 °C, preferably between about 100 °C and about 180 °C, more preferably between about 110 °C and about 170 °C and even more preferably between about 120 °C and about 160 °C. Additional preferred conditions for spray drying are described in the Examples section that follows.
  • Pharmaceutical Compositions As noted above, the substances of the present invention are exceptionally suitable for use in pharmaceutical compositions of the present invention.
  • the substances of the present invention are generally useful for the preparation of pharmaceutical compositions where montelukast sodium is an active ingredient.
  • the pu ⁇ ose of a pharmaceutical composition is to facilitate administration of a compound to a subject.
  • the term "active ingredient" refers to a compound which is accountable for a biological effect of a pharmaceutical composition.
  • a pharmaceutical composition according to the present invention includes at least one of the substances of the present invention (that is amo ⁇ hous montelukast sodium as described above or a co-precipitate as described above), as an active ingredient, together with a pharmaceutically acceptable carrier.
  • physiologically acceptable carrier and “pharmaceutically acceptable carrier”, which may be used interchangeably, refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a pharmaceutically acceptable carrier generally includes, in addition to the carrier or diluent, such components as antibacterial agents, antioxidant agents, binding agents, buffering agents, bulking agents, coloring agents, diluents, disintegrants, emulsifying agents, excipients, flavoring agents, glidants, lubricants, skin penetration enhancers, sweetening agents, viscosity modifying agents and any combination thereof, which provide the composition with desired characteristics.
  • a pharmaceutical composition according to the present invention can include, in addition to one or more of the substances of the present invention, an additional form of montelukast sodium, and/or an additional active ingredient other than montelukast sodium.
  • a pharmaceutical composition of the present invention can be formulated in various forms.
  • an aerosol a bolus, a capsule, a cream, a delayed release capsule, a dispersion, a dissolvable powder, a dragee, drops, a gel capsule, granules, an injection, an inhalable form, a liposome, an ointment, a patch, a pill, a powder, a suppository, a suspension, a syrup, a tablet, a tincture, a topical cream and a troche.
  • an aerosol a bolus, a capsule, a cream, a delayed release capsule, a dispersion, a dissolvable powder, a dragee, drops, a gel capsule, granules, an injection, an inhalable form, a liposome, an ointment, a patch, a pill, a powder, a suppository, a suspension, a syrup, a tablet, a tincture, a topical cream and a troche.
  • a pharmaceutical composition according to the present invention include solid dosage form for oral administration such as, but not limited to, tablets (including chewable tablets), capsules, peels, dragees, powders and granules.
  • the pharmaceutical compositions according to the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions suitable for use in context of the present invention include compositions where the active ingredients are contained in an amount effective to achieve the intended pu ⁇ ose. More specifically, a therapeutically effective amount means an amount of active ingredient effective to cure a condition, treat a condition, prevent a condition, treat symptoms of a condition, cure symptoms of a condition, ameliorate symptoms of a condition, treat effects of a condition, ameliorate effects of a condition, and prevent results of a condition.
  • the pharmaceutical compositions according to the present invention are particularly useful with regard to conditions in which treatment by Montelukast sodium is beneficial.
  • the pharmaceutical composition described above is packages in a packaging material and identified in print, in or on the packaging material for treating a medical condition as described herein.
  • Methods of treatment A pharmaceutical composition of the present invention is useful in implementing the method of treating a medical condition in which administration of montelukast sodium is beneficial.
  • the method is effected by administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present invention, as described hereinabove.
  • the administering is effected orally.
  • the pharmaceutical composition is formulated in a solid dosage form, as is detailed hereinabove.
  • Medical conditions that are treatable by the compositions of the present invention include, without limitation: pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases; allergies and allergic reactions such as allergic rhinitis, contact, allergic conjunctivitis, and the like; inflammation such as arthritis or inflammatory bowel disease; pain; skin disorders such as psoriasis, atopic eczema, and the like; conditions related to cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like; renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology; migraine or cluster headache; ocular conditions including inflammatory diseases such as uveitis; hepatitis resulting from chemical, immunological or infectious stimuli; trauma or shock states such as bum injuries, endotoxemia and the like
  • Additional conditions include, erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion, dysmenorrhea' ischemia, noxious agent-induced damage of necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatodxix agents such as CC14 and D- galactosamine; ischaemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.
  • EXAMPLES Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.
  • EXPERIMENTAL METHODS The novel forms of montelukast sodium of the present invention have been characterized by powder X-ray diffraction, which produces a finge ⁇ rint of the particular form. Measurements of 2 ⁇ values typically are accurate to within ⁇ 0.2 degrees 2 ⁇ .
  • X-ray diffraction data were acquired using a PHILIPS X-ray diffractometer model PW1050-70.
  • the pressed residue was kept in open air having 30 % humidity for 1 hour, so as to evaluate the change in the water content thereof and hence its hygroscopicity.
  • the water content of the residue changed from 3.75 % to 4.11 %, showing a low degree of hygroscopicity.

Abstract

An amorphous form of montelukast sodium and a montelukast sodium lactose co-precipitate, processes for producing same, pharmaceutical compositions containing same and methods of treatment utilizing same are disclosed.

Description

STABLE AMORPHOUS FORMS OF MONTELUKAST SODIUM
FIELD AND BACKGROUND OF THE INVENTION The present invention relates to stable amorphous forms of montelukast sodium and, more particularly, to stable amorphous forms of montelukast sodium which are suitable for use in the preparation of solid dosage formulations, to processes of preparing same, to compositions containing the same and to methods of treatment using the same. (R-(E)-l-(((l-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-(2-(l-hydroxy- l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium salt, also known by the name montelukast sodium, is represented by Formula I below:
Figure imgf000002_0001
Formula I
Montelukast sodium is freely soluble in ethanol, methanol and water but is practically insoluble in acetonitrile. Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti- asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma. Montelukast sodium, formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®. However, the form of montelukast sodium used in preparing Singulair® is hygroscopic and therefore require special care in handling and storage, which adversely affect the efficiency of the production process. Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480,717. The synthesis of montelukast sodium, as taught in EP 480,717, involves coupling methyl l-(mercaptomethyl)cyclopropaneacetate with (S)- l-(3-(2-(7-chloro-2-quinolinyl)ethenyl(ρhenyl)-3(-2-(l-hydroxy-l- methylethyl)phenyl)propyl-methanesulfonate, followed by hydrolysis of the resulting methyl ester so as to form a free acid, which is followed by conversion of the free acid to a corresponding sodium salt. The sodium salt is prepared in an aqueous solution and the water is removed by freeze-drying. International Patent Application published as WO 95/18107 teaches a method for the preparation of crystalline montelukast sodium, which involves the preparation of the dilithium dianion of l-(mercaptomethyι) cyclopropaneacetic acid as an intermediate, followed by condensation thereof with 2-(2-(3-(S)-(3-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol, to yield montelukast acid. The resulting montelukast acid is converted, via the corresponding dicyclohexyl amine salt, to montelukast sodium. The montelukast sodium is crystallized from a toluene/acetonitrile solution to obtain crystalline montelukast sodium. This publication further notes that the compounds disclosed in EP 480,717 are hydrated amorphous montelukast sodium, and are therefore not ideal for use in the formulation of pharmaceutical compositions. International Patent Application PCT/US03/03700, published as WO 03/066598, discloses an anhydrous amorphous form of montelukast sodium. The amoφhous montelukast sodium is prepared, according to the teachings of WO 03/066598, by providing a solution of montelukast free acid in an aromatic solvent; converting the tree acid to an alkali salt using methanolic sodium hydroxide; adding a hydrocarbon solvent, and isolating the thus obtained amoφhous montelukast sodium. Preparing amoφhous montelukast sodium by flocculation from aromatic and hydrocarbon solvents is disadvantageous, particularly when compared to aqueous solutions, due to the toxicity, cost and typical hazardousness of such organic solvents. In recent years, solid-state properties of drugs received a great focus in the pharmaceutical industry, as a major contributing factor to both bioavailability and formulation characteristics. The ability of some substances to exist in more than one form, whether crystalline or amoφhous, was accredited as one of the most important solid-state property of drugs. While different chemical forms have the same chemical composition, they differ in the packing and geometrical arrangement thereof, and exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, dissolution, and the like. General background and theory of forms is found for example in "Effects of Polymoφhism and Solid-State Solvation on Solubility and Dissolution Rate", in Polymoφhism in Pharmaceutical Solids, edited by Harry G. Brittain, Drugs and the Pharmaceutical Sciences, Volume 95, MARCEL DEKKER, Inc.; "Effects of Pharmaceutical Processing on Drug Polymoφhs and Solvates", in Polymoφhism in Pharmaceutical Solids, edited by Harry G. Brittain; Drugs and the Pharmaceutical Sciences, Volume 95, MARCEL DEKKER, Inc.; "Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing process",
Morris et al, Advanced drug delivery reviews, 48, 2001; and Theory and Origin of
Polymoφhism in "Polymoφhism in Pharmaceutical Solids" (1999) ISBN: 8247-0237. In some cases, different forms of the same drug can exhibit very different solubility, and therefore different dissolution rates (release profile) in-vivo. It is known, for example, that amoφhous forms of some drugs exhibit dissolution characteristics and bioavailability patterns different from corresponding crystalline forms [Konne T., Chem. Pharm. Bull., 38, 2003 1990]. For some therapeutic indications one bioavailability pattern may be favored over another. This phenomenon may be used to create better drugs that dissolve either rapidly or very slowly, according to the specific needs ot each formulation. However, any failure to predict the bioavailability of a drug may result in administration of either too small or too large undesired doses, which may be dangerous to patients and in extreme cases, lethal. Other examples are known, where different forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amoφhous form of the substance. The solid-state experts are in a constant search for forms that can withstand physical stress and still retain their original properties. Different forms of a pharmaceutically useful compound therefore provide opportunities to improve the performance characteristics of a pharmaceutical product. Different forms enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of an active pharmaceutical ingredient with a desired characteristic. It is well known that new forms of known useful compounds are of utility. Consequently, there is an ongoing search for new forms of known compounds used in pharmaceutical compositions, which may provide for improved performance thereof. Hence, the pπor art teaches hydrated amoφhous montelukast sodium, (European Patent No. EP 480,717), which is highly hygroscopic and therefore its usage in solid formulations is inefficient. The prior art further teaches other forms of montelukast sodium, which were aimed at overcoming the limitations associated with the hydrated amoφhous montelukast sodium disclosed in EP 480,717. These include, for example, crystalline montelukast sodium and anhydrous amoφhous montelukast sodium (as taught in WO 95/18107 and WO 03/066598, respectively). As discussed hereinabove, formulating crystalline forms of substances into pharmaceutical compositions is limited by the instability of the crystalline form during the formulation process (e.g., when high pressure is applied), solubility characteristics of the substance, and other characteristics. As is further discussed hereinabove, the preparation of the anhydrous amoφhous montelukast sodium taught in WO 03/066598 involves solvents such as aromatic hydrocarbons, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons, which are all considered disadvantageous when used in the preparation of medicaments, since they are relatively toxic, cost-inefficient and environmental unfriendly. There is thus a widely recognized need for, and it would be highly advantageous to have, novel forms of montelukast sodium and improved processes for the preparation thereof, devoid of the above limitations. SUMMARY OF THE INVENTION Thus, the present invention provides novel amoφhous forms of montelukast sodium, and processes for the preparation thereof. The general techniques that may lead to the discovery of amoφhous form of a certain compound are well known to those who are skilled in the art. Those who are skilled in the art appreciate that in a search for amoφhous forms of a certain compound, any one of these techniques is expected to fail. The search is an empirical exercise that involves series of trial and error experiments with different techniques and conditions. For these reasons, it is impossible to predict the experimental conditions that will produce an amoφhous form of montelukast sodium, what the properties of such a form are and whether such a form will be suitable for use in the preparation of a pharmaceutical preparation. It is, however, possible to provide methods that have successfully and selectively produced montelukast sodium after conducting a series of trial and error experiments. Herein novel amoφhous forms of montelukast sodium that are suitable for pharmaceutical use are presented. According to the teachings of the present invention there is provided stable, non-hygroscopic, amoφhous montelukast sodium. Further according to the teachings of the present invention there is also provided a co-precipitate of amoφhous montelukast sodium and at least one pharmaceutically acceptable excipient. In an embodiment of this aspect of the present invention, the at least one pharmaceutically acceptable excipient comprises lactose. In another embodiment, the ratio between the amoφhous montelukast sodium and lactose ranges between about 1:0.1 and about 1:10, preferably the ratio ranges between about 1 :0.5 and 1 :2, and even more preferably the ratio is about 1:1. The amoφhous montelukast sodium of the present invention and the co- precipitate including same are non-hygroscopic. In an embodiment of the present invention, upon exposure to an atmosphere of about 30 % humidity for a period of about one hour, a weight gain of the amoφhous montelukast sodium or the co- precipitate described herein is less than 2 weight percents of its total weight, preferably less than 0.5 weight percents. The amoφhous montelukast sodium of the present invention and the co- precipitate including same are stable. In an embodiment of the present invention the amoφhous montelukast sodium retains an amoφhous character subsequent to storage at a temperature of at least 25 °C for a time period of at least 2 months and even subsequent to storage at a temperature of about 40 °C for a time period of about 3 months. In an embodiment of the present invention the amoφhous montelukast sodium retains an amoφhous character subsequent to application of a pressure greater than 5000 Kg/cm3 for a period of about one minute and even subsequent to application of pressure of about 10000 Kg/cm3 for a period of about one minute. Both the amoφhous montelukast sodium of the present invention and the co- precipitate including same have properties advantageous for use in preparing pharmaceutical compositions therewith. In an embodiment of the present invention, the amoφhous montelukast sodium, as well as the co-precipitate including same, have a bulk density that ranges between about 0.10 gram cm3 and about 0.40 gram/cm3 g/cm3, preferably greater than 0.10 g/cm3 or even greater than 0.20 g/cm3. In an embodiment of the present the amoφhous montelukast sodium of the present invention has a powder X-ray diffraction pattern substantially as depicted in Figure 2. In another embodiment of the present invention an exemplary co-precipitate which comprises the amoφhous montelukast sodium and lactose has a powder X-ray diffraction pattern substantially as depicted in Figures 3, 4 and 5. According to the teachings of the present invention there is also provided a process of preparing the amoφhous montelukast sodium of the present invention described above, the process comprises dissolving montelukast sodium in a solvent, to thereby provide a solution of montelukast sodium in the solvent and removing the solvent from the solution by spray drying. In an embodiment of this aspect of the present invention, the solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof. In another embodiment of this aspect of the present invention, the water miscible organic solvent is selected from the group consisting of acetone, a Cι-C3 alcohol, and any combination thereof, preferably ethanol. In preferred embodiments of this aspect of the present invention, the solvent is water, ethanol or a mixture of water and ethanol. According to the teachings of the present invention there is also provided a process of preparing the co-precipitate of the present invention, the process comprising dissolving montelukast sodium and at least one pharmaceutically acceptable excipient in a solvent, to thereby provide a solution of montelukast sodium in the solvent and removing the solvent from the solution, thereby obtaining the co- precipitate of amoφhous montelukast sodium and the at least one excipient. In an embodiment of this aspect of the present invention, the at least one pharmaceutically acceptable excipient is lactose. In another embodiment of this aspect of the present invention, the at least one pharmaceutically acceptable excipient is lactose monohydrate. In an embodiment of the co-precipitate of the present invention, the ratio between the amorphous montelukast and lactose ranges between about 1:0.1 and about 1:10, preferably the ratio ranges between about 1:0.5 and 1:2, and even more preferably the ratio is about 1:1. In an embodiment of this aspect of the present invention, removing the solvent is effected by freeze drying the solution. In an embodiment of this aspect of the present invention, removing the solvent is effected by spray drying the solution. In an embodiment of the present invention, the solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof. In an embodiment of the present invention, the water miscible organic solvent is selected from the group consisting of acetone, a Cι-C3 alcohol, and any combination thereof, preferably ethanol. In preferred embodiments of the present invention, the solvent is water, ethanol or a mixture of water and ethanol. According to the teachings of the present invention there are also provided pharmaceutical compositions, comprising the amoφhous montelukast sodium of the present invention and/or the co-precipitate according to the present invention, and a pharmaceutically acceptable carrier. In an embodiment of this aspect of the present invention, the pharmaceutical composition is formulated in a solid dosage form, including but not limited to a tablet, a capsule, a peel, a dragee, a powder and granules. In another embodiment of this aspect of the present invention, the pharmaceutical composition of the present invention is packaged in a packaging material and identified in print, in or on said packaging material, for use for a need selected from the group consisting of curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition in which treatment with montelukast sodium is beneficial. Exemplary conditions include but are not limited to allergic rhinitis and asthma. According to the teachings of the present invention there is provided a method of treating a medical condition in which administration of montelukast sodium is beneficial, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the pharmaceutical compositions of the present invention. Exemplary conditions include but are not limited to allergic rhinitis and asthma. In an embodiment of the present invention, administration of the pharmaceutical composition is preferably administered orally. Preferably, the pharmaceutical composition is formulated in a solid dosage form. As used herein, the terms "comprising" and "including" or grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do , not preclude the addition of one or more additional features, integers, steps, components or groups thereof. These terms encompass the terms "consisting of and "consisting essentially of. The phrase "consisting essentially of or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition, device or method. The term "method" or "process" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. Implementation of the methods of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof. The term "active ingredient" refers to a pharmaceutical agent including any natural or synthetic chemical substance that subsequent to its application has, at the very least, at least one desired pharmaceutical or therapeutic effect. The term "therapeutically effective amount" or "pharmaceutically effective amount" denotes that dose of an active ingredient or a composition comprising the active ingredient that will provide the therapeutic effect for which the active ingredient is indicated. As used herein, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof. Throughout this disclosure, various aspects of this invention can be presented in a range format, it should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. BRIEF DESCRIPTION OF THE FIGURES The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for puφoses of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings: FIG. 1 presents an X-ray powder diffractogram of exemplary amoφhous montelukast sodium prepared by freeze-drying according to the process described in European Patent No. EP 480,717; FIG. 2 presents an X-ray powder diffractogram of exemplary amoφhous montelukast sodium according to the present invention, prepared by spray-drying and pressing at 10,000 Kg/cm3 for 1 minute; FIG. 3 presents an X-ray powder diffractogram of an exemplary co-precipitate of amoφhous montelukast sodium and lactose according to the present invention, prepared by spray drying and stored at a temperature of 40 °C for three months; FIG. 4 presents an X-ray powder diffractogram of an exemplary co-precipitate of amoφhous montelukast sodium and lactose according to the present invention prepared by freeze-drying and pressing at 10,000 Kg/cm3 for 1 minute; and FIG. 5 presents an X-ray powder diffractogram of an exemplary co-precipitate of amoφhous montelukast sodium and lactose according to the present invention, prepared by freeze-drying and pressing at 10,000 Kg/cm3 for 1 minute.
DESCRIPTION OF THE EMBODIMENTS The amoφhous form of montelukast sodium of the present invention as well as processes of preparing same, pharmaceutical compositions including same and methods of treatment using same are described hereinbelow. The co-precipitates of amoφhous montelukast sodium of the present invention as well as processes preparing same, pharmaceutical compositions including same and methods of treatment using same are further described hereinbelow. The principles, uses and implementations of the teachings of the present invention may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art is able to implement the teachings of the present invention without undue effort or experimentation. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth herein. The invention can be implemented with other embodiments and can be practiced or carried out in various ways. It is also understood that the phraseology and terminology employed herein is for descriptive puφose and should not be regarded as limiting. Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include techniques from the fields of analytical chemistry, biology, chemistry, engineering and synthetic chemistry. Such techniques are thoroughly explained in the literature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. In addition, the descriptions, materials, methods and examples are illustrative only and not intended to be limiting. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned are incoφorated by reference in their entirety as if fully set forth herein. In case of conflict, the specification herein, including definitions, will control. As used herein, the term "amoφhous" describes a solid devoid of long-range crystalline order. The term "co-precipitate" describes a mixture of two or more solid substances (herein amoφhous montelukast sodium and one or more pharmaceutically acceptable excipients) obtained by co-precipitation thereof from a solution. The amoφhous montelukast sodium and the co-precipitates including same described herein preferably contain less than about 10 % crystalline montelukast sodium, and more preferably are essentially free of crystalline montelukast sodium. Herein, the phrase "essentially free of crystalline montelukast sodium" means that no crystalline montelukast sodium can be detected within the limits of a powder X-ray Diffractometer comparable to the instrumentation described hereinbelow in the Experimental section. The teachings of the present invention relate to two general types of substances. The first substance is stable, non-hygroscopic, amoφhous montelukast sodium. The second substance is a co-precipitate of amoφhous montelukast sodium and at least one pharmaceutically acceptable excipient. As used herein, the phrase "pharmaceutically acceptable excipient" refers to an inert substance which is added so as to provide a pharmaceutical composition with a desired characteristic. Examples, without limitation, of acceptable excipients typically used in pharmaceutical compositions include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, πce starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). While the present invention is aimed at providing montelukast sodium that can be efficiently used in various formulations and particularly in solid dosage formulations, the pharmaceutically acceptable excipient in the co-precipitate of the present invention is preferably selected so as to improve the mechanical characteristics of montelukast sodium in terms of, e.g., mechanical stability, physical stability, bulk density and the like. An example of such an excipient is lactose. Lactose is known as an additive which upon being added to a solution of an amoφhous substance, leads to the production of free-flowing powders. As is well known in the art, free- flowing powders are highly suitable for formulation processes. Thus, an exceptionally preferred co-precipitate according to the present invention is a co-precipitate of amoφhous montelukast sodium with lactose. The ratio between the amoφhous montelukast sodium and lactose preferably ranges between about 1:0.1 and about 1:10, more preferably between about 1:0.5 and 1:2 and more preferably is about 1:1. As noted in the background section hereinabove, previously disclosed amoφhous forms of montelukast sodium are hygroscopic and/or include potentially toxic organic solvents, making such forms unsuitable for use in the preparation of pharmaceutical compositions. It has now been suφrisingly found that preparing amoφhous montelukast sodium by a process that involves spray drying from an aqueous solution provides a product with desired characteristics (e.g., stability, relatively high bulk density, and non-hygroscopicity). Further, it has been suφrisingly found that preparing a co- precipitate of amoφhous montelukast sodium with an excipient, from an aqueous solution, provides a product with such desired characteristics, whether prepared by spray drying or freeze drying. Thus, the present inventors have now suφrisingly uncovered amoφhous montelukast sodium that is stable, not hygroscopic and, in addition, has a relatively high bulk density, and hence is exceptionally suitable for preparing pharmaceutical compositions. The present inventors have also uncovered a co-precipitate of amoφhous montelukast sodium and one or more pharmaceutically acceptable excipient(s), especially a co-precipitate of amoφhous montelukast sodium and lactose, which is exceptionally suitable for preparing pharmaceutical compositions by being stable, non-hygroscopic and having relatively high bulk density. As used herein, the term "stable" regarding the substances of the present invention is meant to define a characteristic of the substance by which the substance maintains chemical and physical features during storage or other challenging conditions, particularly those used in formulating procedures. As is detailed hereinafter, the substances of the present invention were found to be highly stable, maintaining their amoφhous character during e.g., storage and application of high pressure. The term "non-hygroscopic" regarding the substances of the present invention is meant to define a characteristic of the substance by which the tendency of the substance to absorb water is negligible. The amoφhous montelukast sodium and the co-precipitates including same according to the present invention are suφrisingly non-hygroscopic. As is demonstrated in the Examples section that follows, upon exposure to an atmosphere of about 30 % humidity for a period of one hour, the change in the total weight of exemplary substances according to the present invention was found to be about 0.36 weight percents. Hence, the amoφhous montelukast sodium according to the present invention is characterized by such non-hygroscopicity that upon exposure to an atmosphere of about 30 % humidity for a period of one hour, the weight gain thereof is preferably less than 2 weight percents, more preferably than 1.5 weight percents, more preferably less than 1 weight percents, and even more preferably less than 0.5 weight percents. In one embodiment, the water content of an exemplary co- precipitate of amoφhous montelukast sodium according to the present invention changed from about 3.75 weight percents to about 4.11 weight percents upon exposure to an atmosphere of about 30 % humidity for a period of one hour. This lack of hygroscopicity of the amoφhous montelukast sodium iid the co- precipitate thereof renders these substances exceptionally suitable for use in preparing pharmaceutical compositions. The amoφhous montelukast sodium and the co-precipitate thereof according to the present invention are further characterized by high stability. As is further demonstrated in the Examples section that follows, it is shown that the substances of the present invention retain an amoφhous character while being stored for more than two months at a temperature higher than room temperature (e.g., of at least 25 °C). More specifically, it is shown that the substances of the present invention retain an amoφhous character subsequent to storage at a temperature of about 40 °C for a time period of about 3 months. This stability of the amoφhous montelukast sodium and the co-precipitates thereof renders these substances exceptionally suitable for use in preparing pharmaceutical compositions. An additional advantage of the substances of the present invention is that these substances retain an amoφhous character under conditions typically used when preparing compressed solid dosage forms such as tablets. As is demonstrated in the Examples section that follows and the accompanying drawings, the amoφhous montelukast sodium and an exemplary co-precipitate thereof according to the present invention retained the amoφhous character subsequent to application of a high pressure, e.g., of about 10,000 kg/cm3, for a period of about one minute, as is widely employed in solid dosage formulations. The substances of the present invention are particularly advantageously characterized by a relatively high bulk density. Specifically, the amoφhous montelukast sodium and the co-precipitates thereof according to the present invention have a bulk density greater than 0.1 gram/cm , such that preferably the amoφhous montelukast sodium and the co-precipitates thereof according to the present invention have a bulk density that ranges from 0.1 gram/cm to 0.4 gram/cm , and, more preferably, greater than about 0.2 gram/cm3. Such a relatively high bulk density of the amoφhous montelukast sodium and the co-precipitates thereof according to the present invention renders these substances exceptionally suitable for use in preparing pharmaceutical compositions. As is clear to one skilled in the art, such bulk densities allow efficient mixing of the substance with solid carriers and other materials during formulation of a solid dosage form of a pharmaceutical composition. For comparison, the bulk density of an amoφhous montelukast sodium prepared according to the prior art procedure described in European Patent No. EP 480,717 was found to be 0.061 gram/cm3 (see, Reference Example 1 in the Examples section that follows), a bulk density that is too low for convenient use in the preparation of pharmaceutical compositions. The advantageous characteristics of the amoφhous montelukast sodium and the co-precipitate including the amoφhous montelukast sodium and an excipient render these substances highly superior to the presently known forms of montelukast sodium. Processes of preparing amorphous montelukast sodium and co-precipitates containing same: The amoφhous montelukast sodium of the present invention is generally prepared by dissolving montelukast sodium in a solvent to thereby provide a solution of the montelukast sodium in the solvent and then removing the solvent from the solution by spray drying. The co-precipitate of the present invention is generally prepared by dissolving montelukast sodium and one or more pharmaceutically acceptable excipients in a solvent to thereby provide a solution of the montelukast sodium and the excipient in the solvent and then removing the solvent from the solution, preferably by spray drying or freeze-drying. As noted above, a preferred pharmaceutically acceptable excipient is lactose, preferably added to the solvent as lactose monohydrate. Depending on the embodiment, the weight ratio between the amoφhous montelukast and lactose ranges between about 1:0.1 and about 1:10, preferably being about 1:1. A first preferred method of removing the solvent suitable for preparing the co- precipitate according to the present invention is by freeze-drying. In freeze drying the solution comprises water as a solvent. The solution is frozen using conditions that avoid precipitation and or crystallization of substances in the solution. The frozen solution is then exposed to a reduced pressure so that the water sublimates from the frozen solution leaving an amoφhous form of the substances to be gathered. The prior art method of preparing amoφhous montelukast sodium using freeze-drying leads to a product having unsuitable physical properties. A second preferred method of removing the solvent, suitable for preparing both amoφhous montelukast and a co-precipitate of the present invention is by spray drying. In spray drying, a solution is sprayed from a nozzle into or with a large volume of a gas such as air. Generally, the solution, the nozzle and/or the gas are heated. The spraying from the nozzle generates droplets of solution containing substances in the solution. The combination of gas and heat causes the solvents in the droplets to evaporate, leaving an amoφhous form of the substances to be gathered. Unpredictably and in contrast to the prior art amoφhous montelukast sodium prepared by freeze-drying, the amoφhous montelukast sodium of the present invention prepared by spray drying has a significantly higher bulk density than does the prior art amoφhous montelukast sodium prepared by freeze-drying. In embodiments of this aspect of the present invention, suitable solvents include but are not limited to water, water miscible organic solvents and combinations thereof. Suitable water miscible organic solvents include but are not limited to acetone, a Cι-C3 alcohol (preferably ethanol), and any combination thereof. In a preferred embodiment, the solvent is water. In another preferred embodiment the solvent is ethanol. In still another preferred embodiment of the present invention, the solvent is a mixture of water and ethanol, preferably in a 1:1 ratio. In embodiments of this aspect of the present invention, when spray drying is used in a process of preparing a substance of the present invention, the temperature of the nozzle is greater than about 75 °C, preferably between about 100 °C and about 180 °C, more preferably between about 110 °C and about 170 °C and even more preferably between about 120 °C and about 160 °C. Additional preferred conditions for spray drying are described in the Examples section that follows. Pharmaceutical Compositions: As noted above, the substances of the present invention are exceptionally suitable for use in pharmaceutical compositions of the present invention. Similar to prior art Montelukast sodium forms, the substances of the present invention are generally useful for the preparation of pharmaceutical compositions where montelukast sodium is an active ingredient. The puφose of a pharmaceutical composition is to facilitate administration of a compound to a subject. The term "active ingredient" refers to a compound which is accountable for a biological effect of a pharmaceutical composition. Generally a pharmaceutical composition according to the present invention includes at least one of the substances of the present invention (that is amoφhous montelukast sodium as described above or a co-precipitate as described above), as an active ingredient, together with a pharmaceutically acceptable carrier. The terms "physiologically acceptable carrier" and "pharmaceutically acceptable carrier", which may be used interchangeably, refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A pharmaceutically acceptable carrier generally includes, in addition to the carrier or diluent, such components as antibacterial agents, antioxidant agents, binding agents, buffering agents, bulking agents, coloring agents, diluents, disintegrants, emulsifying agents, excipients, flavoring agents, glidants, lubricants, skin penetration enhancers, sweetening agents, viscosity modifying agents and any combination thereof, which provide the composition with desired characteristics. A pharmaceutical composition according to the present invention can include, in addition to one or more of the substances of the present invention, an additional form of montelukast sodium, and/or an additional active ingredient other than montelukast sodium. A pharmaceutical composition of the present invention can be formulated in various forms. These include, without limitations, an aerosol, a bolus, a capsule, a cream, a delayed release capsule, a dispersion, a dissolvable powder, a dragee, drops, a gel capsule, granules, an injection, an inhalable form, a liposome, an ointment, a patch, a pill, a powder, a suppository, a suspension, a syrup, a tablet, a tincture, a topical cream and a troche. Since at present montelukast sodium is preferably administered orally, preferred forms of a pharmaceutical composition according to the present invention include solid dosage form for oral administration such as, but not limited to, tablets (including chewable tablets), capsules, peels, dragees, powders and granules. The pharmaceutical compositions according to the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Techniques for formulation and administration of compounds as medicaments may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incoφorated herein by reference. Pharmaceutical compositions suitable for use in context of the present invention include compositions where the active ingredients are contained in an amount effective to achieve the intended puφose. More specifically, a therapeutically effective amount means an amount of active ingredient effective to cure a condition, treat a condition, prevent a condition, treat symptoms of a condition, cure symptoms of a condition, ameliorate symptoms of a condition, treat effects of a condition, ameliorate effects of a condition, and prevent results of a condition. The pharmaceutical compositions according to the present invention are particularly useful with regard to conditions in which treatment by Montelukast sodium is beneficial. Such conditions include, but are not limited to, allergic rhinitis, asthma, and any of the conditions listed hereinunder. Hence, according to a preferred embodiment of the present invention, the pharmaceutical composition described above is packages in a packaging material and identified in print, in or on the packaging material for treating a medical condition as described herein. Methods of treatment: A pharmaceutical composition of the present invention is useful in implementing the method of treating a medical condition in which administration of montelukast sodium is beneficial. The method is effected by administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present invention, as described hereinabove. Preferably, the administering is effected orally. Further preferably, the pharmaceutical composition is formulated in a solid dosage form, as is detailed hereinabove. Medical conditions that are treatable by the compositions of the present invention include, without limitation: pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases; allergies and allergic reactions such as allergic rhinitis, contact, allergic conjunctivitis, and the like; inflammation such as arthritis or inflammatory bowel disease; pain; skin disorders such as psoriasis, atopic eczema, and the like; conditions related to cardiovascular disorders such as angina, myocardial ischemia, hypertension, platelet aggregation and the like; renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology; migraine or cluster headache; ocular conditions including inflammatory diseases such as uveitis; hepatitis resulting from chemical, immunological or infectious stimuli; trauma or shock states such as bum injuries, endotoxemia and the like; allograft rejection; prevention of side effects associated with therapeutic administration of cytokines such as interleukin II and tumor necrosis factor; chronic lung diseases such as cystic fibrosis, bronchitis and other small and large-airway diseases; cholecystitis; and glomerular nephritis. Additional conditions include, erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion, dysmenorrhea' ischemia, noxious agent-induced damage of necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatodxix agents such as CC14 and D- galactosamine; ischaemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.
Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.
EXAMPLES Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion. EXPERIMENTAL METHODS The novel forms of montelukast sodium of the present invention have been characterized by powder X-ray diffraction, which produces a fingeφrint of the particular form. Measurements of 2Θ values typically are accurate to within ± 0.2 degrees 2Θ. X-ray diffraction data were acquired using a PHILIPS X-ray diffractometer model PW1050-70. System description: Kαl = 1.54178 A, voltage 40 kV, current 28 mA, diversion slit = 1°, receiving slit = 0.2 mm, scattering slit = 1° with a Graphite monochromator. Experiment parameters: pattern measured between 2Θ = 4° and 2Θ = 30° with 0.05° increments; count time was 0.5 second per increment. Mini spray dryer of Buchi 190 was used for spray drying. Freeze-drying was performed with Virtis Advantage instrument. Water content was measured using a Karl Fischer Titrator (Mettler Toledo Model DL-53) according to standard procedures. REFERENCE EXAMPLE 1 AMORPHOUS MONTELUKAST SODIUM Amoφhous montelukast sodium was prepared according to the process disclosed in European Patent No. EP 480,717. Thus, montelukast sodium (5.0 grams) was dissolved in water (200 ml) and filtered. The solution was then freeze dried (lyophilized), producing a residue with a bulk density of 0.061 gram/cm3. The X-ray analysis of the residue is presented in Figure 1.
EXAMPLE 1 AMORPHOUS MONTELUKAST SODIUM Montelukast sodium (5.0 grams) was stirred in ethanol (100 ml) in a round bottom flask until complete dissolution was achieved. The solution was then spray- dried, producing a residue with a bulk density of 0.269 gram/cm3. Spray drying parameters were: outlet temperature of approximately 85 °C, airflow 30 m3/h and solution feed rate of approximately 6 ml/minute. The X-ray analysis of the residue gave a featureless diffractogram with a broad peak centered at 20 about 22°, showing the residue was amoφhous. The residue was pressed at 10,000 Kg/cm for 1 minute. The X-ray analysis of the pressed residue obtained by pressing the residue at 10,000 Kg/cm3 for 1 minute gave a featureless diffractogram with a broad peak centered at 2Θ about.22°, as shown in Figure 2, indicating that the residue remained amoφhous.
EXAMPLE 2 AMORPHOUS MONTELUKAST SODIUM AND LACTOSE Montelukast sodium (2.5 grams) and lactose monohydrate (2.5 grams) were stirred in a 1:1 water/ethanol mixture (100 ml) in a round bottom flask until complete dissolution was achieved. The solution was then spray-dried, producing a residue which is a co-precipitate of the Montelukast sodium and the lactose. Spray drying parameters were: outlet temperature of approximately 85 °C, airflow 30 m3/h and solution feed rate of approximately 5.8 ml/minute. The X-ray analysis of the residue gave a featureless diffractogram showing the residue was amoφhous. The residue was stored for 3 months at a temperature of 40 ± 2 °C. The X-ray analysis of the stored residue gave a featureless diffractogram, as shown in Figure 3, indicating that the residue remained amoφhous.
EXAMPLE 3 AMORPHOUS MONTELUKAST SODIUM LACTOSE Montelukast sodium (5.0 grams) and lactose monohydrate (0.5 gram) were dissolved in water (200 ml) and filtered. The solution was then lyophilized, producing a residue which is a co-precipitate of the Montelukast sodium and the lactose. The X-ray analysis of the residue gave a featureless diffractogram showing the residue was amoφhous. The residue was then pressed at 10,000 Kg/cm3 for 1 minute. The X-ray analysis of the pressed residue gave a featureless diffractogram, as shown in Figure 4, indicating that the residue remained amoφhous. The pressed residue was kept in open air having 30 % humidity for 1 hour, so as to evaluate the change in the water content thereof and hence its hygroscopicity. The water content of the residue changed from 3.75 % to 4.11 %, showing a low degree of hygroscopicity.
EXAMPLE 4 AMORPHOUS MONTELUKAST SODIUM LACTOSE Montelukast sodium (4.0 grams) and lactose monohydrate (12 grams) were dissolved in water (500 ml) and filtered. The solution was then lyophilized, producing a residue, which includes a co-precipitate of montelukast sodium and lactose, with a bulk density of 0.21 gram/cm3. The X-ray analysis of the residue gave a featureless diffractogram showing the residue was amoφhόus. The residue was then pressed at 10,000 Kg/cm3 for 1 minute. The X-ray analysis of the pressed residue gave a featureless diffractogram, as shown in Figure 6, indicating that the residue remained amoφhous. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, the present invention is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
All publications, patents and patent applications mentioned in this specification are herein incoφorated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incoφorated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:
1. A stable, non-hygroscopic, amoφhous montelukast sodium.
2. The amoφhous montelukast sodium of claim 1, wherein upon exposure to an atmosphere ol about iϋ % humidity for a period of about one hour, a weight gain thereof is less than 2 weight percents of its total weight.
3. The amoφhous montelukast sodium of claim 2, wherein said weight gain is less than 0.5 weight percents.
4. The amoφhous montelukast sodium of claim 1, which retains an amoφhous character subsequent to storage at a temperature of at least 25 °C for a time period of at least 2 months.
5. The amoφhous montelukast sodium of claim 4, which retains an amoφhous character subsequent to storage at a temperature of about 40 °C for a time period of about 3 months.
6. The amoφhous montelukast sodium of claim 1, having a bulk density greater than 0.10 g/cm3
7. The amoφhous montelukast sodium of claim 1, having a bulk density greater than 0.20 g/cm3.
8. The amoφhous montelukast sodium of claim 1, having a bulk density that ranges between about 0.10 gram/cm3 and about 0.40 gram/cm3 g/cm3.
9. The amoφhous montelukast sodium of claim 1, which retains an amoφhous character subsequent to application of a pressure greater than 5000 Kg/cm for a peπod of about one minute.
10. The amoφhous montelukast sodium of claim 9, which retains an amoφhous character subsequent to application of pressure of about 10000 Kg/cm3 for a period of about one minute.
11. The amoφhous montelukast sodium of claim 1 , having a powder X-ray diffraction pattern substantially as depicted in Figure 2.
12. A process of preparing the amoφhous montelukast sodium of claim 1, the process comprising: dissolving montelukast sodium in a solvent, to thereby provide a solution of montelukast sodium in said solvent; removing said solvent from said solution by spray drying, thereby obtaining the amoφhous montelukast sodium.
13. The process of claim 12, wherein said solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof.
14. The process of claim 13, wherein said water miscible organic solvent is selected from the group consisting of acetone, a Cι-C3 alcohol, and any combination thereof.
15. The process of claim 13, wherein said water-miscible solvent is ethanol.
16. The process of claim 12, wherein said solvent is water.
17. The process of claim 12, wherein said solvent is ethanol.
18. The process of claim 12, wherein said solvent is a mixture of water and ethanol.
19. A pharmaceutical composition comprising the amoφhous montelukast sodium of claim 1 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19, formulated in a solid dosage form.
21. The pharmaceutical composition of claim 20, wherein said solid dosage form is selected from the group consisting of a tablet, a capsule, a peel, a dragee, a powder and granules.
22. The pharmaceutically composition of claim 19, packaged in a packaging material and identified in print, in or on said packaging material, for use for a need selected from the group consisting of curing a condition, treating a condition, preventmg a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition in which treatment with montelukast sodium is beneficial.
23. The pharmaceutically composition of claim 22, wherein said condition is selected from the group consisting of allergic rhinitis and asthma.
24. A method of treating a medical condition in which administration of montelukast sodium is beneficial, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 19.
25. The method of claim 24, wherein said medical condition is selected from the group consisting of allergic rhinitis and asthma.
26. The method of claim 24, wherein said administering is effected orally.
27. The method of claim 26, wherein said pharmaceutical composition is formulated in a solid dosage form.
28. An amoφhous co-precipitate of montelukast sodium and at least one pharmaceutically acceptable excipient.
29. The co-precipitate of claim 28, wherein said at least one pharmaceutically acceptable excipient comprises lactose.
30. The co-precipitate of claim 29, wherein a ratio between the amoφhous montelukast and lactose ranges between about 1 :0.1 and about 1:10.
31. The co-precipitate of claim 30, wherein said ratio ranges between about 1:0.5 and 1:2.
32. The co-precipitate of claim 30, wherein said ratio is about 1:1.
33. The co-precipitate of claim 28, wherein upon exposure to an atmosphere of about 30 % humidity for a period of one hour, a weight gain thereof is less than 2 weight percents of its total weight.
34. The co-precipitate of claim 33, wherein said weight gain is less than 0.5 %.
35. The co-precipitate of claim 28, which retains an amoφhous character subsequent to storage at a temperature of at least 25 °C for a time period of at least 2 months.
36. The co-precipitate of claim 35, which retains an amoφhous character subsequent to storage at a temperature of about 40 °C for a time period of about 3 months.
37. The co-precipitate of claim 28, having a bulk density greater than 0.10 gram/cm .
38. The co-precipitate of claim 28, having a bulk density greater than t
0.20 gram/cm
39. The co-precipitate of claim 28, having a bulk density that ranges between about 0.10 gram/cm and about 0.35 gram/cm .
40. The co-precipitate of claim 28, which retains an amoφhous character subsequent to application of pressure of greater than 5,000 kg/cm3 for a period of about one minute.
41. The co-precipitate of claim 40, which retains an amoφhous character subsequent to application of pressure of about 10,000 Kg/cm for a period of about one minute.
42. The co-precipitate of claim 28, having a powder X-ray diffraction pattern substantially as depicted in Figure 3, Figure 4 or Figure 5.
43. A process of preparing the co-precipitate of claim 28, the process comprising: dissolving montelukast sodium and at least one pharmaceutically acceptable excipient in a solvent, to thereby provide a solution of montelukast sodium in said solvent; removing said solvent from said solution, thereby obtaining the co-precipitate of amoφhous montelukast sodium and said at least one excipient .
44. The process of claim 43, wherein said at least one pharmaceutically acceptable excipient is lactose.
45. The process of claim 44, wherein said at least one pharmaceutically acceptable excipient is lactose monohydrate.
46. The process of claim 44, wherein a weight ratio between the amoφhous montelukast and lactose ranges between about 1:0.1 and about 1:10.
47. The process of claim 44, wherein said weight ratio ranges between about 1:0.5 and 1:2.
48. The process of claim 44, wherein said ratio is about 1:1.
49. The process of claim 43, wherein said removing said solvent is effected by freeze drying said solution.
50. The process of claim 43, wherein said removing of said solvent is effected by spray drying said solution.
51. The process claim 43, wherein said solvent is selected from the group consisting of water, a water miscible organic solvent and a combination thereof.
52. The process of claim 51 , wherein said water miscible organic solvent is selected from the group consisting of acetone, a C1-C3 alcohol, and any combination thereof.
5ό. The process of claim 51, wherein said water-miscible solvent is ethanol.
54. The process of claim 43, wherein said solvent is water.
55. The process of claim 43, wherein said solvent is ethanol.
56. The process of claim 43, wherein said solvent is a mixture of water and ethanol.
57. A pharmaceutical composition comprising the co-precipitate of claim 28 and a pharmaceutically acceptable carrier.
58. The pharmaceutical composition of claim 57, formulated in a solid dosage form.
59. The pharmaceutical composition of claim 58, wherein said solid dosage form is selected from the group consisting of a tablet, a capsule, a peel, a dragee, a powder and granules.
60. The pharmaceutically composition of claim 57, packaged in a packaging maieπai and identified in print, in or on said packaging material, for use for a need selected from the group consisting of curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition in which treatment with montelukast sodium is beneficial.
61. The pharmaceutically composition of claim 60, wherein said condition is selected from the group consisting of allergic rhinitis and asthma.
62. A method of treating a medical condition in which administration of montelukast sodium is beneficial, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 57.
63. The method of claim 62, wherein said medical condition is selected from the group consisting of allergic rhinitis and asthma.
64. The method of claim 62, wherein said administering is effected orally.
65. The method of claim 64, wherein said pharmaceutical composition is formulated in a solid dosage form.
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