Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

• the present invention relates to a new and stable Fludarabine phosphate pharmaceutical composition.
• inactive ingredients which may serve as binders, fillers, disintegrating agents, lubricants, and colorants or have other purposes.
• inactive ingredients are also known as "excipients". The following general criteria are essential for excipients:
• the inactive ingredients i.e., the totality of ingredients other than the active ingredient
• the carrier After the active ingredient is mixed with the carrier, the mix filled into gelatin capsules or compressed in tablets.
• the processes of preparing the mix and filling capsules, as well tabletting are well known to those skilled in the art of pharmaceutical formulation.
• One of the requirements for an acceptable pharmaceutical composition is that it must be stable, so as not to exhibit substantial decomposition of the active ingredient during the time between manufacture of the composition and use by the patient.
• Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products. Impurity profiling (i.e., the identity as well as the quantity of impurity in the pharmaceuticals), is now gaining critical attention from regulatory authorities. Fludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies.
• Fludarabine phosphate solid forms are known, there still exists a necessity for another stable Fludarabine phosphate final dosage forms.
• New solid formulation should enhance the stability and should be characterised with minimized formation of impurities.
• composition according to the present invention may be prepared in the oral formulation with the conventional pharmaceutical excipients, for example, a disintegrant, such as pregelatinised corn starch, microcrystalline cellulose, croscarmellose sodium, and sodium starch glycolate, a binder, such as colloidal silicon dioxide, a diluent, such as mannitol, a lubricant, such as magnesium stearate or stearic acid, etc.
• a disintegrant such as pregelatinised corn starch, microcrystalline cellulose, croscarmellose sodium, and sodium starch glycolate
• a binder such as colloidal silicon dioxide
• a diluent such as mannitol
• a lubricant such as magnesium stearate or stearic acid
• a composition is provided in which the Fludarabine is mixed into a carrier that omits ingredients which could cause instability.
• the carrier of pharmaceutical composition presented by invention is pregelatinised corn starch and sodium starch glycolate as disintegrant, mannitol as diluent and stearic acid as lubricant.
• Figure 1 shows changes of impurity content, such as 6-amino-9-(5-O-phosphono- b-D-arabinofuranosyl)-9A/-purin-2-ol in Fludarabine 10mg capsule, containing mannitol as a dilent, Fludarabine 10mg capsule containing lactose as a diluent and Fludara oral 10mg film-coated tablet conatining lactose as diluent samples after their degradation
• Example 1 Fludarabine phosphate (10 mg), lactose monohydrate (75 mg), colloidal silicon dioxide (0.5 mg), microcrystalline cellulose (60 mg), croscarmellose Na (3.0 mg) and magnesium stearate (1.5 mg) were mixed in a mortar. The blend was sieved through a screen and dried. The dried particles were used to prepare a granulation. The granules were filled into capsules so that each of them would contain 150 mg of the granules.
• Fludarabine phosphate (10 mg), mannitol (112 mg), stearic acid (1.5 mg), pregelantinised corn starch (16.5 mg) and sodium starch glycolate (10.0 mg) were mixed in a mortar.
• the blend was sieved through a screen and dried. The dried particles were used to prepare a granulation.
• the granules were filled into capsules so that each of them would contain 150 mg of the granules.
• Example 3 Fludarabine phosphate (10 mg), mannitol (112 mg), stearic acid (1.5 mg), pregelantinised corn starch (16.5 mg) and sodium starch glycolate (10.0 mg) were mixed in a mortar. The blend was sieved through a screen and dried. The dried particles were used to prepare a granulation. The granules were then compresses with a conventional tableting machine, thereafter were coated by conventional coating materials.
• Fludarabine 10mg capsule, containing mannitol as a diluent had pronounced effect, because amount of impurity, 6-amino-9-(5-O- phosphono- ⁇ -D-arabinofuranosyl)-9#-purin-2-ol, is significantly reduced by comparing with Fludarabine 10mg capsule containing lactose as a diluent or Fludara oral 10mg film-coated tablet conatining lactose as diluent thereby shell life of composition caintaining mannitol was increased.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2010
  • 2010-05-19 WO PCT/EP2010/056878 patent/WO2010133629A1/en active Application Filing
  • 2010-05-19 EA EA201190243A patent/EA201190243A1/ru unknown
  • 2010-05-19 EP EP10723037A patent/EP2432457A1/en not_active Withdrawn

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