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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • 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

Definitions

• the present invention is related to pharmaceutical formulations comprising olanzapine used in the treatment of schizophrenia group of psychotic disorders, to provide clinical improvement in maintenance treatment of patients who respond to the first-line treatment, in bipolar disorder, in the treatment of heavy and moderate manic periods and to prevent their recurrence.
• Said formulations are characterized in being in orodispersible tablet form.
• the molecule olanzapine which is shown with Formula I was first disclosed in the patent numbered EP045436. It was also disclosed in said document that the molecule is a potential neuroleptic having anxiolytic, relaxing, antiemetic properties; it is useful in treatment of psychotic cases such as schizophrenia, schizophrenia group disorders and acute mania; it is used in low doses in treatment of mild cases of anxiety.
• Olanzapine is in 2.5, 5, 7.5, 10, 15, 20 mg film tablet; 5, 10, 15, 20 mg orodispersible tablet; 2.5, 5, 10, 15, 20 mg tablet and 5, 10 mg bisect film tablet forms on the market.
• Dissolution and dispersion time of tablets obtained from pharmaceutical formulations formulated in orodispersible tablet form and comprising olanzapine in mouth when taken orally are quite important on absorption of olanzapine into the blood and its bioavailability.
• olanzapine is a non-water-soluble molecule. Therefore it is significant that the mechanical properties of the tablet forms obtained are at optimum levels during preparation of formulations comprising olanzapine in order for said tablet forms to dissolve easily and disperse fast.
• the tablets obtained from the orodispersible formulations comprising olanzapine do not have optimum tablet hardness and brittleness values, the tablets do not disperse in the mouth easily or break into small pieces fast.
• the orodispersible tablet formulations of olanzapine which comprise at least one low-density cellulose derivative as the binder have the required hardness and brittleness values and therefore provide an effective treatment by realizing the required active agent bioavailability as they can disperse easily and fast in the mouth.
• the first element of the present invention is orodispersible tablet formulations of olanzapine which comprise at least one low-density cellulose derivative as the binder.
• the present invention is related to orodispersible tablet formulations of olanzapine which comprise at least one low-density cellulose derivative as the binder.
• said orodispersible tablet formulation comprises the active agent olanzapine in the range of 0.1-25%, preferably in the range of 0.5-20%, more preferably in the range of 1-15%.
• the subject of the present invention is that said formulation comprises the active agent olanzapine in the range of 0.05-15 mg, preferably in the range of 0.1 -12 mg, more preferably in the range of 1-10 mg.
• the active agent olanzapine used in the formulations of the present invention can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
• the formulation comprises a low-density cellulose derivative in the range of 0.5-25%, preferably in the range of 2-20%, more preferably in the range of 5-15% as the binder.
• the low-density cellulose derivative that is used as the binder in the formulation of the present invention can be selected from a group comprising hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, ethyl methyl cellulose, hydroxy ethyl cellulose, hydroxy ethyl methyl cellulose, ethyl hydroxy ethyl cellulose and carboxymethyl cellulose and/or combinations thereof.
• the low-density cellulose derivative that is used as the binder in the formulation of the present invention can preferably be low-density hydroxy propyl cellulose.
• hydroxy propyl cellulose comprises hydroxy propoxyl group in the range of 1-30%, preferably in the range of 2-25%, more preferably in the range of 5-20%.
• a characteristic feature of the formulation of the present invention is that hydroxy propyl cellulose used as the binder comprises hydroxy propoxyl group in the range of 1-30%, preferably in the range of 2-25%, more preferably in the range of 5-20%.
• Dispersion characteristics of the orodispersible tablets comprising olanzapine are affected by particle size of the binder as well as selection of the binder.
• the inventors focused particularly on low-density hydroxypropyl cellulose and have observed that the tablets present optimum dispersion characteristics in the case that the particle size of this binder is in the range of 5-85 ⁇ , preferably in the range of 10-80 ⁇ , more preferably in the range of 20-70 ⁇ .
• the particle size of low-density hydroxy propyl cellulose used as binder in the formulation is in the range of 5-85 ⁇ , preferably in the range of 10-80 ⁇ , more preferably in the range of 20-70 ⁇ .
• the formulation comprises at least one pharmaceutically acceptable excipient in addition to olanzapine used as the active agent and low-density cellulose derivative substance.
• excipients that can be used in the formulation prepared according to the invention can be selected from a group comprising diluent, sweetener, flavouring agent and lubricant or combinations thereof.
• said formulation comprises at least one diluent in the range of 20-99%, preferably in the range of 30-95%, more preferably in the range of 40-90%.
• the diluent in the formulations of the present invention can be selected from a group comprising microcrystalline cellulose, lactose, sorbitol, silicon dioxide, dicalcium phosphate or a combination thereof.
• lactose more preferably lactose monohydrate can be used as the diluent in the formulations of the present invention.
• the sweetener in the formulations of the present invention can be selected from a group comprising acesulfame, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
• the flavouring agent in the formulations of the present invention can be selected from a group comprising levomenthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry or combinations thereof.
• the lubricant in the formulations of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
• the formulations prepared according to the present invention can comprise olanzapine in the range of 0.1 -25%, diluent in the range of 20-99%, binder in the range of 0.5-25%, sweetener in the range of 0.1-5%, flavoring agent in the range of 0.1-2.5% and lubricant in the range of 0.1-5% in proportion to total weight of unit dose.
• olanzapine is mixed with the diluent and the binder.
• the mixture granulated with a granulation solution comprising diluent is dried and sieved.
• the sweetener and the flavoring agent are added to the mixture.
• the mixture is lubricated with the lubricant and sent to tablet compression.
• the formulation of the present invention can be used in the treatment of schizophrenia group of psychotic disorders, to provide clinical improvement in maintenance treatment of patients who respond to the first-line treatment, in bipolar disorder, in the treatment of heavy and moderate manic periods and to prevent their recurrence.
• the formulation given above is prepared by wet granulation method. Olanzapine is mixed with the diluent and the binder. The mixture granulated with the granulation solution comprising diluent is dried and sieved. The sweetener and the flavoring agent are added to the mixture. Lastly, the mixture is lubricated with the lubricant and sent to tablet compression.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (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)
• Nutrition Science (AREA)
• Physiology (AREA)
• Zoology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (5)

• 2013
  • 2013-05-08 WO PCT/TR2013/000149 patent/WO2013172805A1/fr not_active Ceased

Patent Citations (5)

Non-Patent Citations (2)

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