US20090042821A1 - Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials - Google Patents

Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials Download PDF

Info

Publication number
US20090042821A1
US20090042821A1 US11/914,867 US91486706A US2009042821A1 US 20090042821 A1 US20090042821 A1 US 20090042821A1 US 91486706 A US91486706 A US 91486706A US 2009042821 A1 US2009042821 A1 US 2009042821A1
Authority
US
United States
Prior art keywords
dosage form
solid dosage
form according
excipients
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US11/914,867
Inventor
Arno Appavoo Enose
Harish Kumar Madan
Sumit Madan
Anupam Trehan
Puneet Tyagi
Vinod Kumar Arora
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Assigned to RANBAXY LABORATORIES LIMITED reassignment RANBAXY LABORATORIES LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TYAGI, PUNEET, ARORA, VINOD KUMAR, TREHAN, ANUPAM, ENOSE, ARNO APPAVOO, MADAN, HARISH KUMAR, MADAN, SUMIT
Publication of US20090042821A1 publication Critical patent/US20090042821A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/02—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the field of the invention relates to stable dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation.
  • Malaria the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death especially amongst children and pregnant women. According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
  • the clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.
  • Quinine an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940's, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as ‘Chinchonism syndrome’ characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug-resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.
  • trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs.
  • the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day.
  • the foregoing dose may be administered as a single dose or may be divided into multiple doses.
  • a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure continued up to 1-2 weeks post-exposure.
  • trioxolanes there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.
  • a stable antimalarial oral solid dosage form comprising Spiro or dispiro 1,2,4-trioxolanes can be prepared by controlling the water content below a certain critical limit. Further the bitter taste can be masked by applying a film coating layer to the solid dosage form.
  • a stable oral solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I,
  • R 1 and R 2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R 1 and R 2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and one or more pharmaceutically acceptable excipients, wherein not more than 5% w/w total related substances are formed on storage at 40 ⁇ 2° C. and 75 ⁇ 5% relative humidity over a period of 6 months.
  • Embodiments of the oral solid dosage form may include one or more of the following features.
  • the dosage form may include one or more of other antimalarial drugs.
  • the other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin, their salts and derivatives thereof.
  • piperaquine, lumefantrine and DB 289 may be used.
  • the pharmaceutically acceptable excipients may include one or more of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents.
  • a stable oral solid dosage form of a therapeutically effective amount of a compound having the structure of Formula I which is formulated using a dry or non-aqueous process.
  • the solid dosage form may be in the form of a tablet and the tablet may be coated.
  • a process for the preparation of a stable oral solid dosage form includes blending a compound having the structure of Formula I and one or more intragranular excipients; granulating the blend to form granules; blending the granules with one or more extragranular excipients; and compressing the blend into tablet or filling into capsule.
  • Embodiments of the process may include one or more of the following features.
  • the granulation may be wet granulation and the wet granulation may include a non-aqueous granulating liquid selected from ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution.
  • the granulation may be dry granulation and the dry granulation may be compaction or slugging.
  • the dry granulation may be compaction for example, dry roller compaction.
  • the tablet may be coated with one or more film coating layers.
  • a process for the preparation of a stable oral solid dosage form includes blending a compound having the structure of Formula I, and one or more pharmaceutically acceptable excipients; directly compressing the blend into tablet or filling into capsule; and optionally applying one or more film coating layers to the tablet.
  • a process for the preparation of a stable oral solid dosage form includes granulating a blend of one or more excipients; drying the excipient granules; blending excipient granules with a compound having the structure of Formula I, or with granules comprising a compound having the structure of Formula I; compressing the blend into tablet or filling into capsule; and optionally applying one or more film coating layers to the tablet.
  • Embodiments of the process may include one or more of the following features.
  • the granulation may be wet granulation and the wet granulation may include a granulating liquid selected from water, ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution.
  • the granulation may be dry granulation and the dry granulation may be compaction or slugging.
  • the dry granulation may be compaction for example, dry roller compaction.
  • a method of prophylaxis or treatment of malaria includes administering a solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I; and one or more pharmaceutically acceptable excipients, wherein not more than 5% w/w total related substances are formed on storage at 40 ⁇ 2° C. and 75 ⁇ 5% relative humidity over a period of 6 months.
  • Embodiments of the oral solid dosage form may include one or more of the following features.
  • the dosage form may include one or more other antimalarial drugs.
  • the other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin, their salts and derivatives thereof.
  • piperaquine, lumefantrine and DB 289 may be used.
  • a method of prophylaxis or treatment of malaria includes administering a solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I, which is formulated using a dry or non-aqueous process.
  • a stable oral solid dosage form includes a therapeutically effective amount of a compound having the structure of Formula I; at least one other antimalarial drug selected from lumefantrine, piperaquine, or DB 289; and one or more pharmaceutically acceptable excipients.
  • Embodiments of the oral dosage form may include one or more of the following features.
  • the water content of the dosage form may not be more than 6.5% w/w.
  • a stable oral solid dosage form includes cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl] -1′,2′,4′-trioxaspiro[4.5]decane hydrogen maleate; piperaquine; and one or more pharmaceutically acceptable excipients.
  • stable refers to chemical stability of active compound in solid dosage forms against decomposition occurring during shelf life due to hydrolysis, wherein not more than 5% w/w total related substances are formed on storage at 40 ⁇ 2° C. and 75 ⁇ 5% relative humidity over a period of 6 months.
  • solid dosage form as used herein includes tablets or coated tablets, capsules, pellets, pills, granules, powders, and the like.
  • a particularly suitable solid dosage form is that of tablets.
  • the present invention provides stable oral solid dosage forms of active compound, by using excipients having low water content and manufactured using dry or non-aqueous formulation processes.
  • active compound as used herein includes spiro or dispiro 1,2,4-trioxolane compound of Formula I
  • R 1 and R 2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R 1 and R 2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms.
  • R 1 is hydrogen, for example, compounds having the structure of Formula II.
  • Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168; U.S. Pat. Nos. 6,486,199 and 6,825,230 and are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.
  • Active compound includes free form of the compounds referred to herein as well as their pharmaceutically acceptable salts, solvates, esters, enantiomers, diastereomers, polymorphs, metabolites, prodrugs and analogues.
  • active compound is cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane hydrogen maleate.
  • the stable oral solid dosage forms of the present invention may further comprise one or more pharmaceutically acceptable excipients, which include all physiologically inert excipients used in the art for the preparation of solid dosage forms. Examples include binders, diluents, glidants/ lubricants disintegrants, surfactants, coloring agents, and the like.
  • the excipients may be used either intragranularly or extragranularly, or both.
  • the weight ratio of active compound and excipients in the dosage forms may vary from about 1.5:1 to about 1:30.
  • binder examples include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth, sodium alginate, and the like.
  • disintegrants include clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, soy polysaccharides, and the like.
  • lubricants or ‘glidants’ include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
  • the ‘coloring agents’ include any FDA approved colors for oral use.
  • the solid dosage forms may further be coated with one or more functional and/or non-functional layers comprising film-forming polymers, and other coating additives.
  • film-forming polymers examples include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit® RL and RS; and the like.
  • commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
  • the ‘coating additives’ include plasticizers, glidants or flow regulators, opacifiers and lubricants.
  • Solid dosage forms of active compound may be prepared by densifying active compound and one or more excipients, and processing into solid dosage forms. Densification may be carried out using any conventional method known in the art. In particular, granulation or extrusion-spheronization may be used.
  • stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound and intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
  • stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
  • stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of a suitable size; blending the granules with extragranular portion of a lubricant in a double cone blender; and finally filling into capsules of a suitable size.
  • stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluent, and disintegrant; wet granulating the blend with a non aqueous granulating fluid or a solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of lubricant, in a double cone blender; and finally filling into capsules of a suitable size.
  • Active compound and intragranular portion of microcrystalline cellulose were sieved through sieve BSS# 44 and mixed together in a double cone blender to form a uniform blend.
  • step 3 The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS # 22 to form granules.
  • Example 2 The tablets prepared as per Example 1 were subjected to stability studies at 25° C./RH 60%, 30° C./RH 65% and 40° C./RH 75% over a period of 6 months. The results are summarized in Table 2. The results of in vitro drug release analyzed at predetermined time periods are given in Table 3.
  • the tablets prepared by the process of the present invention in which water is absent shows acceptable shelf stability.
  • Active compound, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sifted through sieve BSS# 44.
  • step 3 To the blend of step 2, sifted magnesium stearate was added and mixed for about 5 minutes.
  • step 3 The blend obtained in step 3 was directly compressed using suitable size capsule shape punches to obtain compressed tablets.
  • Example 3 % w/w
  • Example 4 % w/w Intragranular Maleate salt of a compound of 7.68 13.8 Formula II (active compound) Piperquine phosphate 61.80 55.5 Microcrystalline Cellulose 20.39 21.05 Magnesium stearate 0.44 0.39 Crospovidone 2.21 1.99 Extragranular Microcrystalline Cellulose 4.42 3.99 Crospovidone 2.21 1.99 Magnesium stearate 1.05 1.09 Coating Opadry ® O2B53782 orange 2.5 2.5 Water q.s q.s Total weight (mg) 1332.5 738 Water content ⁇ 6.55% w/w ⁇ 6.55% w/w/w
  • Active compound, piperaquine phosphate and intragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and mixed together in a double cone blender to form a uniform blend.
  • step 2 To the blend of step 1, intragranular portion of sifted magnesium stearate was added and blended for about 5 minutes.
  • step 3 The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS # 18 to form granules.
  • step 5 The blend of step 5 was compressed using suitable size punches to obtain compressed tablets.
  • step 6 The tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight built of up to 2.5% w/w.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The field of the invention relates to stable dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation. The water content of the dosage form is not more than 6.5% w/w.

Description

    FIELD OF THE INVENTION
  • The field of the invention relates to stable dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation.
    • BACKGROUND OF THE INVENTION
  • Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death especially amongst children and pregnant women. According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
  • Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiaewhich serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector's gut; sporozoites are produced and are migrated to the vector's salivary glands.
  • The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.
  • Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940's, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as ‘Chinchonism syndrome’ characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug-resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.
  • Malarial treatment further progressed with the discovery of Artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick, S. R. et al., Microbiol. Rev. 1996, 60, 301-315; Vroman J. A. et al., Curr. Pharm. Design, 1999, 5, 101-138; Dhingra V. K. et al., 2000, 66, 279-300), and a number of its precursors, metabolites and semi synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, C., dv. Drug Res. 1997, 29, 271-325; Cumming, J. N. et al., Adv. Pharmacol. 1997, 37, 254-297) and to identify novel antimalarial peroxides (Dong, Y. and Vennerstrom, J. L., Expert Opin. Ther. Patents 2001, 11, 1753-1760).
  • Although the clinically useful semi synthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche, D. L. et al., Antimicrob. Agents. Chemother. 1994, 38, 1813-1819) and metabolic instability (White, N. J., Trans. R. Soc. Trop. Med. Hyg., 1994, 88, 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, N. J., Trans. R. Soc. Trop. Med. Hyg., 1994, 88, 41-43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, 199-205).
  • Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties. Following that, many synthetic antimalarial 1,2,4-trioxanes (Jefford, C., Adv. Drug Res. 1997, 29, 271-325; Cumming, J. N. et al., Adv. Pharmacol. 1997, 37, 254-297), 1,2,4,5-tetraoxanes (Vennerstrom, J. L. et al., J. Med. Chem., 2000, 43, 2753-2758), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, in U.S. Patent Application No. 2004/0186168; U.S. Pat. Nos. 6,486,199 and 6,825,230. The present invention relates to solid dosage forms of the various spiro or dispiro 1,2,4-trioxolanes antimalarial compounds disclosed in these patents/ applications and are incorporated herein by reference.
  • Active compounds representing various Spiro and dispiro 1,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure continued up to 1-2 weeks post-exposure.
  • However, in spite of many advantages of trioxolanes, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.
  • We have now discovered that a stable antimalarial oral solid dosage form comprising Spiro or dispiro 1,2,4-trioxolanes can be prepared by controlling the water content below a certain critical limit. Further the bitter taste can be masked by applying a film coating layer to the solid dosage form.
    • SUMMARY OF THE INVENTION
  • In one general aspect there is provided a stable oral solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I,
  • Figure US20090042821A1-20090212-C00001
  • and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein:
  • R1 and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R1 and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and one or more pharmaceutically acceptable excipients, wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months.
  • Embodiments of the oral solid dosage form may include one or more of the following features. For example, the dosage form may include one or more of other antimalarial drugs. The other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin, their salts and derivatives thereof. In particular, piperaquine, lumefantrine and DB 289 may be used.
  • The pharmaceutically acceptable excipients may include one or more of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents.
  • In another aspect there is provided a stable oral solid dosage form of a therapeutically effective amount of a compound having the structure of Formula I, which is formulated using a dry or non-aqueous process.
  • The solid dosage form may be in the form of a tablet and the tablet may be coated.
  • In another general aspect there is provided a process for the preparation of a stable oral solid dosage form. The process includes blending a compound having the structure of Formula I and one or more intragranular excipients; granulating the blend to form granules; blending the granules with one or more extragranular excipients; and compressing the blend into tablet or filling into capsule.
  • Embodiments of the process may include one or more of the following features. For example, the granulation may be wet granulation and the wet granulation may include a non-aqueous granulating liquid selected from ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution. The granulation may be dry granulation and the dry granulation may be compaction or slugging. In particular, the dry granulation may be compaction for example, dry roller compaction.
  • The tablet may be coated with one or more film coating layers.
  • In another general aspect there is provided a process for the preparation of a stable oral solid dosage form. The process includes blending a compound having the structure of Formula I, and one or more pharmaceutically acceptable excipients; directly compressing the blend into tablet or filling into capsule; and optionally applying one or more film coating layers to the tablet.
  • In another general aspect there is provided a process for the preparation of a stable oral solid dosage form. The process includes granulating a blend of one or more excipients; drying the excipient granules; blending excipient granules with a compound having the structure of Formula I, or with granules comprising a compound having the structure of Formula I; compressing the blend into tablet or filling into capsule; and optionally applying one or more film coating layers to the tablet.
  • Embodiments of the process may include one or more of the following features. For example, the granulation may be wet granulation and the wet granulation may include a granulating liquid selected from water, ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution. The granulation may be dry granulation and the dry granulation may be compaction or slugging. In particular, the dry granulation may be compaction for example, dry roller compaction.
  • In another general aspect there is provided a method of prophylaxis or treatment of malaria. The method includes administering a solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I; and one or more pharmaceutically acceptable excipients, wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months.
  • Embodiments of the oral solid dosage form may include one or more of the following features. For example, the dosage form may include one or more other antimalarial drugs. The other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin, their salts and derivatives thereof. In particular, piperaquine, lumefantrine and DB 289 may be used.
  • In another aspect there is provided a method of prophylaxis or treatment of malaria. The method includes administering a solid dosage form that includes a therapeutically effective amount of a compound having the structure of Formula I, which is formulated using a dry or non-aqueous process.
  • In another aspect there is provided a stable oral solid dosage form. The dosage form includes a therapeutically effective amount of a compound having the structure of Formula I; at least one other antimalarial drug selected from lumefantrine, piperaquine, or DB 289; and one or more pharmaceutically acceptable excipients.
  • Embodiments of the oral dosage form may include one or more of the following features. For example, the water content of the dosage form may not be more than 6.5% w/w.
  • In another general aspect there is provided a stable oral solid dosage form. The dosage form includes cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl] -1′,2′,4′-trioxaspiro[4.5]decane hydrogen maleate; piperaquine; and one or more pharmaceutically acceptable excipients.
  • The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
    • DETAILED DESCRIPTION OF THE INVENTION
  • We have now discovered that stable solid oral dosage forms of Spiro or dispiro 1,2,4-trioxolane antimalarials can be prepared which do not degrade significantly and provide acceptable shelf life.
  • The term “stable” as used herein refers to chemical stability of active compound in solid dosage forms against decomposition occurring during shelf life due to hydrolysis, wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months.
  • The term “solid dosage form” as used herein includes tablets or coated tablets, capsules, pellets, pills, granules, powders, and the like. A particularly suitable solid dosage form is that of tablets.
  • The present invention provides stable oral solid dosage forms of active compound, by using excipients having low water content and manufactured using dry or non-aqueous formulation processes.
  • The term “active compound” as used herein includes spiro or dispiro 1,2,4-trioxolane compound of Formula I
  • Figure US20090042821A1-20090212-C00002
  • wherein R1 and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R1 and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms. In particular, it includes compounds of Formula I, wherein R1 is hydrogen, for example, compounds having the structure of Formula II.
  • Figure US20090042821A1-20090212-C00003
  • Active compound includes one or more of the various spiro and dispiro trioxolane derivatives disclosed in U.S. Application No. 2004/0186168; U.S. Pat. Nos. 6,486,199 and 6,825,230 and are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes derivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicity.
  • Active compound includes free form of the compounds referred to herein as well as their pharmaceutically acceptable salts, solvates, esters, enantiomers, diastereomers, polymorphs, metabolites, prodrugs and analogues. In particular, active compound is cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methylpropyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro[4.5]decane hydrogen maleate.
  • It has been observed through exhaustive experimentation that when active compound is formulated into dosage forms, including liquid as well as solid dosage forms, it gets degraded by hydrolysis. The degradation may be due to water associated with the excipients or added during the course of processing. Thus, liquid oral dosages forms such as aqueous syrups, suspensions or solutions having desired shelf life could not be successfully prepared. Further, preparation of solid oral dosage forms of active compound, using techniques involving use of water such as wet granulation, spray drying, or extrusion-spheronization processes resulted in dosage forms with wavering stability results. However, acceptable stability results were obtained when the solid dosage forms were formulated using appropriate excipients with low water content and a process in which water was absent such as dry granulation, direct compression or non-aqueous granulation. In case where excipients were granulated using water, the excipient granules were dried appropriately before blending with active compound as such or with active compound containing granules, and processed into solid dosage forms of acceptable stability.
  • The role of excipients and water content was evaluated by conducting compatibility studies of active compound with various excipients, in different proportions and evaluating the extent of degradation by forced degradation at 60° C. over the period of 2 weeks and at 50° C. for 4 weeks. The water content was analyzed using Karl Fischer method and the total related substances (% w/w) were determined by HPLC method. The results of the study are represented below in Table 1.
  • TABLE 1
    Compatibility studies of active compound with various excipients
    Total Related Substance (% w/w)
    After 4 After 2
    Drug: Water weeks/ weeks/
    Excipient Excipient (% w/w) Initial 50° C. 60° C.
    Croscarmellose sodium 1:0.5 0.59 0.09 0.34 0.35
    Cross povidone 1:0.5 3.49 0.13 0.40 0.68
    Sodium starch glycolate 1:0.5 1.43 0.13 0.43 0.89
    Hydroxypropyl 1:0.5 1.22 0.17 0.70 1.05
    methylcellulose 5 cps
    Polyvinyl pyrrolidone K 1:0.5 3.02 0.00 0.33 0.79
    30
    Sodium lauryl sodium 1:0.5 0.79 0.15 0.92 1.59
    Opadry ® 1:0.5 0.46 0.17 1.85 0.96
    Titanium dioxide 1:0.5 0.18 0.16 0.57 0.93
    Talc 1:0.1 0.12 0.15 0.63 0.90
    Mg. Stearate 1:0.1 0.46 0.13 0.65 0.86
    Aerosol 1:0.1 0.27 0.14 0.66 0.86
    Polyethylene glycol 400 1:0.1 0.88 0.14 0.66 0.68
    Microcrystalline cellulose 1:2 3.69 0.19 0.70 0.74
    Starch 1:2 4.73 0.08 0.60 0.74
    Dicalcium phosphate 1:2 2.01 0.07 0.77 1.32
    Pearlitol 1:2 0.02 0.14 0.72 0.77
    Micro crystalline cellulose 1:10 4.94 0.39 0.78 1.02
    Starch 1:10 — 0.07 0.60 4.13
    Dicalcium phosphate 1:10 2.14 0.17 0.61 6.07
    Pearlitol 1:10 0.52 0.14 0.46 0.70
  • The study clearly indicates the importance of use of excipients having low water or moisture content in stabilizing solid dosage forms of active compound. In the present invention, we have discovered that the use of excipients having water content less than 6.5% w/w surprisingly increases the stability of the active compound, and thus provides reasonably long shelf lives. Starch was found to be incompatible with active compound when used in higher amounts. Further, lactose was also found to be incompatible due to degradation by other mechanisms such as Maillard reaction, and dicalcium phosphate was not preferred due to increase in related substances at 60° C. Microcrystalline cellulose, however, gave the most satisfactory results.
  • The stable oral solid dosage forms of the present invention may further comprise one or more pharmaceutically acceptable excipients, which include all physiologically inert excipients used in the art for the preparation of solid dosage forms. Examples include binders, diluents, glidants/ lubricants disintegrants, surfactants, coloring agents, and the like. The excipients may be used either intragranularly or extragranularly, or both. The weight ratio of active compound and excipients in the dosage forms may vary from about 1.5:1 to about 1:30.
  • Examples of ‘binders’ include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth, sodium alginate, and the like.
  • Examples of ‘diluents’ include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, sucrose, sugar compressible, sugar confectioners, and the like.
  • Examples of ‘disintegrants’ include clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, soy polysaccharides, and the like.
  • Examples of ‘lubricants’ or ‘glidants’ include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
  • Examples of ‘surfactants’ include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in sweetener compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol—20 dioleate, polyethylene glycol 4-150 mono dilaurate, polyethylene glycol—20 glyceryl stearate; alcohol—oil transesterification products, for example polyethylene glycol—6 corn oil; polyglycerized fatty acids, for example polyglyceryl—6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol—20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol—20 cetyl ether, polyethylene glycol—10-100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene—polyoxypropylene block copolymers known as “poloxamer”; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.
  • The ‘coloring agents’ include any FDA approved colors for oral use.
  • The solid dosage forms may further be coated with one or more functional and/or non-functional layers comprising film-forming polymers, and other coating additives.
  • Examples of ‘film-forming polymers’ include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit® RL and RS; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
  • The ‘coating additives’ include plasticizers, glidants or flow regulators, opacifiers and lubricants.
  • The pharmaceutical acceptable excipients and/or film forming polymers and coating additives may be selected to provide immediate release profile or modified release profile.
  • Solid dosage forms of active compound may be prepared by densifying active compound and one or more excipients, and processing into solid dosage forms. Densification may be carried out using any conventional method known in the art. In particular, granulation or extrusion-spheronization may be used.
  • In one of the embodiments, stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound and intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
  • In another embodiment, stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
  • In another embodiment, stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compactor to form a compact mass; reducing the compact into granules of a suitable size; blending the granules with extragranular portion of a lubricant in a double cone blender; and finally filling into capsules of a suitable size.
  • In another embodiment, stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of a suitable size; blending the granules with extragranular portion of lubricant in a double cone blender; and finally filling into capsules of a suitable size.
  • In another embodiment, stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound, a diluent, a lubricant and a disintegrant; and directly compressing into tablets using suitable tooling.
  • In another embodiment, stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, a diluent, and a lubricant; and filling into capsules of a suitable size.
  • In another embodiment, stable oral tablet of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of a diluent, and disintegrant; wet granulating the blend with a non aqueous granulating fluid or a solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of a lubricant, disintegrant and diluent in a double cone blender; and finally compressing into tablets using suitable tooling.
  • In yet another embodiment, stable oral capsule of active compound may be prepared by a process comprising the steps of blending active compound, intragranular portion of diluent, and disintegrant; wet granulating the blend with a non aqueous granulating fluid or a solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of lubricant, in a double cone blender; and finally filling into capsules of a suitable size.
  • Examples of ‘non-aqueous granulating fluid’ include organic solvents such as methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, and the like.
  • In yet another embodiment, tablets prepared by any of the above described processes may further be coated with film forming polymers and one or more coating additives, using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor; or dip coating. Alternatively, coating can also be performed using a hot melt technique.
  • The coating layers over the tablet may be applied as a solution/dispersion of coating components in a suitable solvent. Examples of solvents used for preparing a solution/dispersion of the coating ingredients include methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water and the like, and mixtures thereof.
  • In still another embodiment, one or more of another antimalarial drug selected from piperaquine, lumefantrine, and DB 289 (pafuramidine maleate) may be added in the blend comprising active compound, in any of the embodiments above.
  • The invention described herein is further illustrated by the following examples, which should not be construed as limitation the scope of the invention.
    • EXAMPLE 1
  • Ingredients % w/w
    Intragranular
    Maleate salt of a compound of Formula II (active 43.2
    compound)
    Microcrystalline Cellulose 46.67
    Magnesium stearate 0.75
    Extragranular
    Microcrystalline Cellulose 5.63
    Croscarmellose sodium 3.0
    Magnesium stearate 0.75
    Coating
    Opadry ® OY SS 58910 white 2.5
    Water q.s
    Total weight 615
    Water content <6.55% w/w
    • Procedure:
  • 1. Active compound and intragranular portion of microcrystalline cellulose were sieved through sieve BSS# 44 and mixed together in a double cone blender to form a uniform blend.
  • 2. To the blend of step 1, intragranular portion of sifted magnesium stearate was added and blended for about 5 minutes.
  • 3. The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS # 22 to form granules.
  • 4. Extragranular portion of microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sieved through sieve BSS # 44 and blended with the granules of step 3.
  • 5. The blend of step 4 was compressed using suitable size punches to obtain compressed tablets.
  • 6. The tablets as obtained from step 5 were coated with Opadry® using conventional coating techniques.
  • The tablets prepared as per Example 1 were subjected to stability studies at 25° C./RH 60%, 30° C./RH 65% and 40° C./RH 75% over a period of 6 months. The results are summarized in Table 2. The results of in vitro drug release analyzed at predetermined time periods are given in Table 3.
  • TABLE 2
    Total related substances (% w/w)
    1 2 3 6
    Storage Condition Initial months months months months
    25° C. and 60% relative 0.11 — — 0.27 0.28
    humidity
    30° C. and 65% relative 0.11 0.37 0.27 0.29 0.34
    humidity
    40° C. and 75% relative 0.11 0.55 0.67 1.40 1.82
    humidity
    * % Total Related Substance should not be more than 5%
  • TABLE 3
    Percentage (%) of In vitro drug release in USP II apparatus
    (media: 2% tween 80 in water, 900 ml 75, rpm, in 45 min)
    1 2 3 6
    Storage Condition Initial months months months months
    25° C. and 60% relative 93 — — 101 95
    humidity
    30° C. and 65% relative 93 98 93 94 96
    humidity
    Temperature 40° C. and 93 98 96 92 94
    75% relative humidity
    *The in vitro drug release (% w/w) should not be less than 70% (Q) of the labeled amount dissolved in 45 minutes.
  • As evident from the above studies, the tablets prepared by the process of the present invention in which water is absent shows acceptable shelf stability.
    • EXAMPLE 2
  • Ingredients % w/w
    1 Maleate salt of a 44.33
    compound of Formula II
    (active compound)
    2 Microcrystalline Cellulose 51.17
    3 Magnesium stearate 1.5
    4 Croscarmellose sodium 3.0
    Total weight 600 mg
    Water content <6.5%
    • Procedure:
  • 1. Active compound, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sifted through sieve BSS# 44.
  • 2. Sifted active compound, microcrystalline cellulose, and croscarmellose sodium were mixed in a double cone blender for about 15 minutes to form a uniform blend.
  • 3. To the blend of step 2, sifted magnesium stearate was added and mixed for about 5 minutes.
  • 4. The blend obtained in step 3 was directly compressed using suitable size capsule shape punches to obtain compressed tablets.
    • EXAMPLES 3 AND 4
  • Ingredients Example 3 % w/w Example 4 % w/w
    Intragranular
    Maleate salt of a compound of 7.68 13.8
    Formula II (active compound)
    Piperquine phosphate 61.80 55.5
    Microcrystalline Cellulose 20.39 21.05
    Magnesium stearate 0.44 0.39
    Crospovidone 2.21 1.99
    Extragranular
    Microcrystalline Cellulose 4.42 3.99
    Crospovidone 2.21 1.99
    Magnesium stearate 1.05 1.09
    Coating
    Opadry ® O2B53782 orange 2.5 2.5
    Water q.s q.s
    Total weight (mg) 1332.5 738
    Water content <6.55% w/w <6.55% w/w
    • Procedure:
  • 1. Active compound, piperaquine phosphate and intragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and mixed together in a double cone blender to form a uniform blend.
  • 2. To the blend of step 1, intragranular portion of sifted magnesium stearate was added and blended for about 5 minutes.
  • 3. The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS # 18 to form granules.
  • 4. Extragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and blended with the granules of step 3.
  • 5. Extragranular portion of magnesium stearate were sieved through sieve BSS # 44 and blended with the blend of step 4, in a double cone blender for about 5 minutes.
  • 6. The blend of step 5 was compressed using suitable size punches to obtain compressed tablets.
  • 7. The tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight built of up to 2.5% w/w.
  • The tablets prepared as per the Example 3 & 4 were subjected to stability studies at 40° C./RH 75% over a period of 3 months, as represented in Table 4.
  • TABLE 4
    % total related substances (% w/w)
    1 2 3
    Ingredient Initial month months months
    Maleate salt of a Example 3 0.19 0.27 0.44 0.54
    compound of Formula II Example 4 0.25 0.32 0.45 0.54
    Piperaquine phosphate Example 3 1.16 1.1 1.11 1.16
    Example 4 1.15 1.03 1.13 1.16
    * % Total related substance should not be more than 5%
  • While several particular formulations have been described, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the invention. For example although the tablet dosage form has been prepared, other conventional solid dosage forms like capsule can also be prepared using the similar compositions. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims (20)

1. A stable oral solid dosage form comprising:
(a) a therapeutically effective amount of a compound having the structure of Formula I,
Figure US20090042821A1-20090212-C00004
and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein:
R1 and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R1 and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and
(b) one or more pharmaceutically acceptable excipients,
wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months.
2. The stable solid dosage form according to claim 1, wherein the compound has the structure of Formula II.
Figure US20090042821A1-20090212-C00005
3. The stable solid dosage form according to claim 1, wherein the dosage form further comprises one or more of other antimalarial drugs selected from quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, clindamycin, and DB 289.
4. A stable oral solid dosage form comprising:
(a) a therapeutically effective amount of a compound having the structure of Formula II,
Figure US20090042821A1-20090212-C00006
and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates;
(b) piperaquine; and
(c) one or more pharmaceutically acceptable excipients.
5. The stable solid dosage form according to claim 4, wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 3 months.
6. The stable solid dosage form according to claim 1 or 4, wherein the pharmaceutically acceptable excipients comprises one or more of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents.
7. The stable solid dosage form according to claim 7, wherein the diluent is microcrystalline cellulose.
8. The stable solid dosage form according to claim 7, wherein water content of the excipients is not more than 6.5% w/w.
9. The stable solid dosage form according to claim 1 or 4, wherein the dosage form comprises a tablet, capsule, pill, granule and powder.
10. The stable solid dosage form according to claim 9, wherein the tablet is coated with one or more functional and/or non-functional coating layers comprising film-forming polymers and coating additives.
11. The stable solid dosage form according to claim 10, wherein the coating additives comprises one or more of plasticizers, glidants or flow regulators, opacifiers and lubricants.
12. The stable solid dosage form according to claim 1 or 4, wherein the dosage form provides immediate release profile or modified release profile.
13. The stable oral solid dosage form according to claim 1 or 4, wherein the dosage form is prepared using a dry or non-aqueous process.
14. The stable solid dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:
(a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;
(b) granulating the blend by roller compaction;
(c) blending the granules with one or more extragranular excipients; and
(d) compressing the blend into tablets or filling into capsules.
15. The stable solid dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:
(a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;
(b) granulating the blend by slugging;
(c) blending the granules with one or more extragranular excipients; and
(d) compressing the blend into tablets or filling into capsules.
16. The stable solid dosage form according to claims 1, wherein the dosage form is prepared by a process comprising the steps of:
(a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more pharmaceutically acceptable excipients; and
(b) directly compressing the blend into tablets or filling into capsules.
17. The stable solid dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:
(a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;
(b) wet granulating the blend with a non-aqueous granulating fluid;
(c) drying and reducing the granules to a suitable size;
(d) blending the granules with one or more extragranular excipients; and
(e) compressing into tablets or filling into capsules.
18. The stable solid dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:
(a) granulating a blend of one or more excipients;
(b) drying the excipient granules;
(c) blending excipient granules with a compound of Formula I and, optionally, one or more other antimalarial drugs; and
(d) compressing the blend into tablets or filling into capsules.
19. A method of prophylaxis or treatment of malaria, the method comprising administering a stable oral solid dosage form comprising:
(a) a therapeutically effective amount of a compound having the structure of Formula I,
Figure US20090042821A1-20090212-C00007
and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein:
R1 and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R1 and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and
(b) one or more pharmaceutically acceptable excipients,
wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months.
20. The method of prophylaxis or treatment of malaria according to claim 19, wherein the dosage form further comprises one or more of other antimalarial drugs.
US11/914,867 2005-05-18 2006-05-18 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials Abandoned US20090042821A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IN1279DE2005 2005-05-18
IN1279/DEL/2005 2005-05-18
IN1192/DEL/2006 2006-05-12
IN1192DE2006 2006-05-12
PCT/IB2006/051588 WO2006123314A2 (en) 2005-05-18 2006-05-18 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/051588 A-371-Of-International WO2006123314A2 (en) 2005-05-18 2006-05-18 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/183,119 Continuation-In-Part US8664265B2 (en) 2005-05-18 2011-07-14 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Publications (1)

Publication Number Publication Date
US20090042821A1 true US20090042821A1 (en) 2009-02-12

Family

ID=37198895

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/914,867 Abandoned US20090042821A1 (en) 2005-05-18 2006-05-18 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials
US13/183,119 Active US8664265B2 (en) 2005-05-18 2011-07-14 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/183,119 Active US8664265B2 (en) 2005-05-18 2011-07-14 Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Country Status (9)

Country Link
US (2) US20090042821A1 (en)
EP (1) EP1898901B1 (en)
CN (1) CN101272777B (en)
CY (1) CY1118583T1 (en)
ES (1) ES2615458T3 (en)
HU (1) HUE033191T2 (en)
PL (1) PL1898901T3 (en)
PT (1) PT1898901T (en)
WO (1) WO2006123314A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130011483A1 (en) * 2010-03-31 2013-01-10 Supernus Pharmaceuticals, Inc. Formulations of mazindol

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8067620B2 (en) * 2005-05-04 2011-11-29 Medicines For Malaria Venture Mmv Dispiro 1,2,4-trioxolane antimalarials
CN101472582A (en) * 2006-05-17 2009-07-01 兰贝克赛实验室有限公司 Antimalarial therapy using a combination of synthetic artemisinin derivative and bisquinoline derivative
AU2012282077A1 (en) * 2011-07-14 2014-01-30 Sun Pharmaceutical Industries Limited Stable dosage forms of arterolane and piperaquine
AP2015008748A0 (en) * 2013-02-28 2015-09-30 Sun Pharmaceutical Ind Ltd Stable dispersible formulation of arterolane maleate and piperaquine and process of preparation thereof
AU2014234258B2 (en) * 2013-03-22 2019-02-14 Adare Pharmaceuticals S.R.L. Piperaquine microcapsules and compositions containing them
WO2015140709A1 (en) * 2014-03-19 2015-09-24 Novartis Ag Solid pharmaceutical dosage forms
CN109464442B (en) * 2018-11-19 2020-02-28 裴建梅 Sacubitril valsartan sodium pharmaceutical composition and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6486199B1 (en) * 2001-06-21 2002-11-26 Medicines For Malaria Venture Mmv International Centre Cointrin Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040039008A1 (en) * 2002-06-21 2004-02-26 Medicines For Malaria Ventures Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040186168A1 (en) * 2002-06-21 2004-09-23 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6486199B1 (en) * 2001-06-21 2002-11-26 Medicines For Malaria Venture Mmv International Centre Cointrin Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040039008A1 (en) * 2002-06-21 2004-02-26 Medicines For Malaria Ventures Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
US20040186168A1 (en) * 2002-06-21 2004-09-23 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
US6825230B2 (en) * 2002-06-21 2004-11-30 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trixolane antimalarials

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130011483A1 (en) * 2010-03-31 2013-01-10 Supernus Pharmaceuticals, Inc. Formulations of mazindol

Also Published As

Publication number Publication date
CN101272777A (en) 2008-09-24
CN101272777B (en) 2013-01-30
EP1898901B1 (en) 2016-11-23
CY1118583T1 (en) 2017-07-12
ES2615458T3 (en) 2017-06-07
US8664265B2 (en) 2014-03-04
WO2006123314A2 (en) 2006-11-23
WO2006123314A3 (en) 2008-04-10
US20120183607A1 (en) 2012-07-19
PL1898901T3 (en) 2017-07-31
EP1898901A2 (en) 2008-03-19
HUE033191T2 (en) 2017-11-28
PT1898901T (en) 2017-02-27

Similar Documents

Publication Publication Date Title
US8664265B2 (en) Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials
RU2328274C2 (en) Medicinal agent lamotrigin with regulated release
RU2376988C2 (en) Pharmaceutical composition of slow release, containing aplindor and its derivatives
US5814339A (en) Film coated tablet of paracetamol and domperidone
KR102072546B1 (en) Oral tablet formulation of lenalidomide
HU186078B (en) Process for producing pharmaceutical compositions for peroral application containing dipyridamol
JPH11501951A (en) Multiple unit boiling dosage forms containing proton pump inhibitors.
HUP0402104A2 (en) Delayed-release drug containing 3-(3-Dimethylamino-1-ethyl-2-methylpropyl)phenol
AU2012282077A1 (en) Stable dosage forms of arterolane and piperaquine
WO2010023690A2 (en) Prolonged release formulation of amisulpride
WO2022074681A1 (en) Pharmaceutical compositions with enhanced blend uniformity and content uniformity
EP2368543A1 (en) Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe
RU2694056C2 (en) Anti-tuberculosis stable pharmaceutical composition in form of dispersible tablet containing granulated isoniazid and granulated rifapentine, and method for preparing it
KR102539236B1 (en) Sustained-release pharmaceutical compositions containing ginkgo biloba extracts
MX2014007635A (en) Non-enteric pharmaceutical composition comprising crofelemer.
US20210220373A1 (en) Orally disintegrating pharmacutical composition comprising nefopam and process for preparing the same
OA16845A (en) Stable dosage forms of arterolane and piperaquine
WO2014132226A1 (en) Stable dispersible formulation of arterolane maleate and piperaquine and process of preparation thereof
EA013739B1 (en) Solid pharmaceutical composition comprising mirtazapine
KR20190129880A (en) Tableted pharmaceutical composition containing nalpurapine
KR20190064208A (en) Solid dispersion comprising Fimasartan
WO2005016315A1 (en) Pharmaceutical compositions of nateglinide and a high amount of a water-soluble filler
KR100212960B1 (en) Oral combinations
EP2698151A1 (en) Orally Disintegrating Formulation of Paliperidone
KR20180002437A (en) Pharmaceutical complex formulation comprising doxylamine and pyridoxine

Legal Events

Date Code Title Description
AS Assignment

Owner name: RANBAXY LABORATORIES LIMITED, INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ENOSE, ARNO APPAVOO;MADAN, HARISH KUMAR;MADAN, SUMIT;AND OTHERS;REEL/FRAME:021207/0159;SIGNING DATES FROM 20071121 TO 20071123

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION