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 PDFInfo
- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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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
- A61K9/20—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
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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
- A61K9/20—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
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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
- A61K9/20—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.
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PCT/IB2006/051588 WO2006123314A2 (fr) | 2005-05-18 | 2006-05-18 | Formes dosifiees stables de substances antipaludiques de spiro 1,2,4-trioxolane et de dispiro 1,2,4-trioxolane |
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PCT/IB2006/051588 A-371-Of-International WO2006123314A2 (fr) | 2005-05-18 | 2006-05-18 | Formes dosifiees stables de substances antipaludiques de spiro 1,2,4-trioxolane et de dispiro 1,2,4-trioxolane |
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US20130011483A1 (en) * | 2010-03-31 | 2013-01-10 | Supernus Pharmaceuticals, Inc. | Formulations of mazindol |
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US8067620B2 (en) * | 2005-05-04 | 2011-11-29 | Medicines For Malaria Venture Mmv | Dispiro 1,2,4-trioxolane antimalarials |
AP2525A (en) * | 2006-05-17 | 2012-12-05 | Ranbaxy Lab Ltd | Antimarial 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 |
JP6345762B2 (ja) * | 2013-03-22 | 2018-06-20 | アデーレ ファルマスーティカルズ エッセ・エッレ・エッレ | ピペラキンマイクロカプセル及びそれらを含有する組成物 |
WO2015140709A1 (fr) * | 2014-03-19 | 2015-09-24 | Novartis Ag | Formes posologiques pharmaceutiques solides |
CN109464442B (zh) * | 2018-11-19 | 2020-02-28 | 裴建梅 | 一种沙库巴曲缬沙坦钠药物组合物及其制备方法 |
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US20040186168A1 (en) * | 2002-06-21 | 2004-09-23 | Medicines For Malaria Venture Mmv | Spiro and dispiro 1,2,4-trioxolane antimalarials |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20130011483A1 (en) * | 2010-03-31 | 2013-01-10 | Supernus Pharmaceuticals, Inc. | Formulations of mazindol |
Also Published As
Publication number | Publication date |
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CY1118583T1 (el) | 2017-07-12 |
WO2006123314A2 (fr) | 2006-11-23 |
CN101272777B (zh) | 2013-01-30 |
HUE033191T2 (en) | 2017-11-28 |
US20120183607A1 (en) | 2012-07-19 |
PT1898901T (pt) | 2017-02-27 |
US8664265B2 (en) | 2014-03-04 |
PL1898901T3 (pl) | 2017-07-31 |
EP1898901B1 (fr) | 2016-11-23 |
WO2006123314A3 (fr) | 2008-04-10 |
CN101272777A (zh) | 2008-09-24 |
ES2615458T3 (es) | 2017-06-07 |
EP1898901A2 (fr) | 2008-03-19 |
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