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
  • A61K31/33—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
• • 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
  • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

• Olanzapine was described in patent EP 456 436, where pharmaceutical formulations of the compound were also mentioned in general.
• the patent lists a number of auxiliary substances that can be used for preparation of the pharmaceutical formulation.
• the tablet is prepared via granulation of a mixture of olanzapine, microcrystalline cellulose, magnesium stearate and starch using povidone as the binder. The granulate is further tabletted. Further information about the medical form of olanzapine is presented in patent EP 733 367 B. It is a coated tablet that contains lactose, hydroxypropyl cellulose, microcrystalline cellulose in the core and hydroxypropylmethyl cellulose (HPMC) in the isolation layer of the coating and a subsequent coating with a suspension.
• HPMC hydroxypropylmethyl cellulose
• the isolation layer is important according to the patent, which is supposed to prevent change of the tablet's color, which is a problem specifically for olanzapine.
• polyethyleneglycol is not suitable for the coating being supposed to prevent the color change.
• the tablet according to patent EP 733 367 B is prepared via a wet granulation technique, drying and tabletting.
• the patent suggests (page 4) that the applicant believes that an insufficiently homogenous mixture (non-uniformity of doses) is formed in direct tabletting and recommends wet granulation in a high-shear granulation device.
• the wet granulation method usually indeed provides better homogeneity and hence uniformity of the composition of individual tablets.
• the active agent is exposed to temperature stress under wet conditions. That can lead to a number of decomposition reactions and eventually to lower purity of the product.
• wet granulation can also result in a color change of the tablet, which is subsequently solved using a suitable coating.
• Another problem can include change of the crystalline form of the active agent, which can also often occur when the substance is heated under wet conditions.
• the change of the crystalline form can result in a change of biological availability of the active agent in the pharmaceutical formulation, which, in the worst case, eventually leads to loss of activity.
• the risk of conversion to another crystalline form is especially high. It seems to be desirable, therefore, to overcome the problem of insufficient dose uniformity during direct tabletting, so that this most gentle method can be used for olanzapine.
• Such a composition is solved by the present invention.
• a pharmaceutical composition containing olanzapine as the active agent, and further a filler and auxiliary substances, in the form of a tablet obtainable by direct tabletting, the essence of which is that the core of the tablet contains olanzapine in an amount of 0.5 to 20 w.% and a pharmaceutically acceptable filler in an amount of 35 to 99 w.% with the particle sizes ranging from 10 to 1000 ⁇ m, the core being optionally coated, in which case the coating contains 1 to 10 w.% of polyethyleneglycol after drying.
• the pharmaceutical preparation according to the invention preferably contains a pharmaceutically acceptable filler in an amount of 60 to 95 w.% and has a particle size of preferably from 50 to 400 ⁇ m.
• the content of the active agent olanzapine is preferably 2 up to 10%.
• the pharmaceutically acceptable filler is selected from the series of microcrystalline cellulose, lactose, the polyalcohols mannitol or sorbitol, calcium hydrogenphosphate and a combination of microcrystalline cellulose with a mono- or oligosaccharide or polyalcohol.
• the invention also solves a process for the preparation of a tablet containing the active agent olanzapine, comprising mixing a mixture of olanzapine and the filler in a homogenization device; optionally adding a substance modifying the flow properties of the tabletting blend and an anti-adhesive substance in the subsequent step and, after homogenization, the mixture is tabletted.
• Preparation of the tabletting blend is technologically simple; it is limited only to steps that are not energetically demanding or time-consuming.
• the preparation of the tabletting blend does not involve stress procedures such as introduction of a moistening agent into the mixture of the active agent and auxiliary substances and dry granulation via compacting the mixture of the active agent and auxiliary agents for preparation of the tabletting blend.
• Compression of the tabletting blend prepared by dry mixing allows for preparation of cores and/or tablets having satisfactory parameters and the presented method of preparation and selection of auxiliary substances according to the invention also ensure good stability of the preparation and the required physical properties of the pharmaceutical formulation.
• the technique of direct tabletting is not only simple, but primarily the most gentle of all the methods. Therefore, it represents further progress compared to the previously described techniques of wet granulation, which is associated with introduction of a moistening agent, and of dry granulation, which is associated with compacting and, therefore, using high pressures, which can subsequently cause problems concerning release of the drug into the patient's organism. Such problems can lead to the situation when a significant part of the drug is not utilized at all.
• Another problem of direct tabletting can include variation of the dosage sizes in the individual tablets; the problem therefore resides in uniformity of doses. As specified above, this problem was expected during preparation of an olanzapine tablet (EP 0 733 367 B). Accordingly, dry mixing does not have to be sufficiently effective. This was the reason why only wet granulation, most preferably in a high-shear granulation device, has been applied so far.
• the filler is important, or rather its share in the tablet's core and the size of the particles that form it.
• the most advantageous ratios between the active agent and the filler are 1 : 5 to 30, particularly between 1 : 10 to 25.
• the content of the active agent in the tablet's core ranges from 2 to 10 w.%.
• the filler from the series of microcrystalline cellulose, lactose, the polyalcohols mannitol or sorbitol, calcium hydrogenphosphate and a combination of microcrystalline cellulose with a mono- or oligosaccharide or polyalcohol.
• Microcrystalline cellulose turns to be a particularly advantageous filler for these purposes is. It has good flow properties.
• the tablets have acceptable strength and disintegration properties because microcrystalline cellulose in the pressing ensures preservation of capillary orifices, through which water, inhibiting the effect of bonding forces, gets in. They ensure very good stability of the preparation.
• quality of selected microcrystalline cellulose is essential.
• Particle size of commercially available cellulose for pharmaceutical use ranges from about 1 to 1000 ⁇ m. For direct tabletting of olanzapine, cellulose within the range from 10 to 1000 ⁇ m can be used; it is advantageous to use particles with sizes ranging from 90 to 360 ⁇ m, the size 180 ⁇ m appearing to be the most preferable one.
• the tabletting blend contains anti-adhesive substances, facilitating the tabletting process.
• Magnesium stearate is the most preferable substance for the described mixture, preferably in an amount of 0.1 to 10 %, especially preferably 0.5 to 4 %.
• the tablets according to the invention ensure reproducibility of the production process.
• the preparation of the tabletting blend is not energetically demanding or time-consuming.
• Mixing II substances for the final preparation are added - silicii dioxidum colloidale and magnesii stearas and the mixture is mixed in a homogenization device for 15 minutes.
• the tablets prepared via the method showed break resistance of at least 6ON, which indicates that they will not be damaged under common transportation conditions.
• the content of thus obtained tablets of olanzapine 10 mg conformed to the limit 9.5 - 10.5 mg.
• more than 85 % of the total content was released within 30 minutes. The result is in very good agreement with the already registered and marketed preparation Zyprexa of Eli Lilly.
• Olanzapine 20 mg, 15 mg, 7.5 mg, 5 mg, 2.5 mg was obtained by the same method.
• composition Olanzapine 20 mg tablets
• the tablet was produced by the method according to Example 1.

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

Applications Claiming Priority (2)

Publications (2)

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Cited By (4)

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• 2005
  • 2005-02-02 CZ CZ20050063A patent/CZ200563A3/cs not_active IP Right Cessation
• 2006
  • 2006-01-19 WO PCT/CZ2006/000002 patent/WO2006081779A2/en not_active Ceased

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