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
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
• • 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
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • 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
  • A61P25/24—Antidepressants

Definitions

• the present invention relates to novel formulations and to the use of the formulations in the treatment and/or prevention of certain disorders
• This compound has been approved for human use and is marketed, in the form of its hydrochloride salt, m many count ⁇ es around the world as an anti-depressant agent
• WO 95/16448 discloses that paroxetine is likely to develop a pink colour unless it is formulated into tablets using a formulation process in which water is absent, such as dry direct compression of paroxetine or dry granulation of paroxetine followed by compression into tablets
• dry was used to denote substantially dry as opposed to the wholesale addition of water which had been previously employed in the wet granulation process
• paroxetine hydrochlo ⁇ de anhydrate has a tendency to convert at least partially to the hemihydrate dunng the tabletting process Although not dangerous, this creates difficulties in establishing and maintaining a reference standard for regulatory and quality control purposes Accordingly, the present invention provides paroxetine hydrochloride. in a form other than the hemihydrate, which is formulated into tablets under conditions such there is no detectable conversion to hemihydrate during the tabletting process.
• the paroxetine hydrochloride may, for example be amorphous or in the form of a crystalline anhydrate.
• excipients which are essentially anhydrous. That is to say, they contain less than 2%, more especially less than 1.5%. preferably less than 1 % water.
• dibasic calcium phosphate anhydrous can be used to form oral swallow tablets with paroxetine hydrochloride anhydrate without undesired conversion to hemihydrate during the tabletting process.
• the tabletting process may for example comprise dry direct compression of paroxetine or dry granulation of paroxetine followed by compression into tablets.
• the tablets are then packaged with a desiccant in order to prevent conversion of anhydrate to hemihydrate on storage.
• the present invention also provides a process for the preparation of paroxetine hydrochloride anhydrate tablets free of detectable hemihydrate which is characterised by the use of conditions such there is no detectable conversion of the anhydrate to hemihydrate during the tabletting process.
• Such conditions can be achieved by the use of essentially anhydrous excipients.
• tabletting can also be carried out under conditions of low relative humiditv
• excipients with the necessary low moisture content suitable for direct compression include materials such as dibasic calcium phosphate anhydrous.
• anhydrous direct compression lactose monosaccharide sugars eg mannitol. disaccharide sugars eg lactitol. powdered cellulose, pregelatinised starch and similar materials.
• Dibasic calcium phosphate anhydrous is commercially available in a pharmaceutically acceptable grade, eg A-TAB (Rhone Poulenc).
• Anhydrous direct compression lactose is commercially available in a pharmaceutically acceptable grade. eg anhydrous direct tabletting (Quest International Inc).
• Direct compression lactilol is commercially available in a pharmaceutically acceptable grade, eg Finlac DC (Xyrofin).
• paroxetine hydrochloride anhydrate is mixed with dibasic calcium phosphate anhydrous, and/or anhydrous direct compression grade lactose(s), and/or microcrystalline cellulose (in particular A-TAB. lactose anhydrous direct tabletting, and Avicel PHI 12 dried to a moisture content of 0.8- 1.5%) in a suitable blender.
• Other pharmaceutically acceptable excipients may also be added such as disintegrants eg sodium starch glycolate, croscarmellose sodium, and colloidal silicon dioxide (in particular Explotab (dried to a moisture content of ⁇ 2%).
• Ac-Di-Sol. and Syloid 244. respectively lubricants such as magnesium stearate; and glidants such as colloidal silicon dioxide, and talc.
• the composition is then mixed and compressed using standard pharmaceutical procedures.
• the tablets can be film coated.
• Standard aqueous film coating is not appropiate for such a moisture sensitive product; however, the tablets can be coated with hydrophobic coating materials, such as glyceryl behenate. using a hot melt coating technique.
• tablet cores are coated with a 2% w/w of glyceryl behenate (in particular Compritol 888). 2% levels of glyceryl behenate do not adversely affect the dissolution of the dosage form in the gastric environment.
• Glyceryl behenate is commercially available in a pharmaceutically acceptable grade, eg Compritol 888 (Gattefosse).
• a modified aqueous film coating procedure using Opadry AMB (Aqueous Moisture Barrier) can also be utilised.
• tablet cores are coated with a 2% w/w of Opadry AMB.
• Opadry AMB is commercially available in a pharmaceutically acceptable grade, eg Opadry OY-B-31006 (Colorcon).
• Coated tablets are then packaged in standard pharmaceutical container/closure presentations, optionally with a desiccant.
• compositional ranges of key excipients on a w/w basis are provided :
• the amounts of lubricants are in the range 0.5 to 2.0%. most preferably 0.5 to 1.0%.
• the disintegrants are controlled in the range 0.5 to 8.0%. most preferably 2.0 to 4.0%.
• the amounts of anhydrous diluents are controlled in the range 50.0 to 95.0%. Mixtures of the principal diluents can be used to assist in flow and compression properties of the formulation.
• the amounts of film coat are controlled in the range 1.0 to 3.0%. most preferably 2.0%.
• the amount of paroxetine used is adjusted such that in a single unit dose there is a therapeutically effective amount of paroxetine.
• the unit dose contains from 10 to 100 mg paroxetine (as measured in terms of the free base). More preferable the amount of paroxetine in a unit dose is lOmg, 20mg. 30mg, 40mg or 50mg. The most preferred amount of paroxetine in a unit dose is 20mg.
• Paroxetine used in the formulation is in the form of the hydrochloride anhydrate which may be prepared according to the procedures outlined in WO 96/24595.
• Suitable procedures for preparing paroxetine include those mentioned in US Patents 4.009.196. 4.902.801. 4.861.893 and 5,039.803 and PCT/GB 93/00721.
• paroxetine has particular utility in the treatment of depression; paroxetine may also be used in the treatment of mixed anxiety and depression, obsessive compulsive disorders, panic, pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia and the depression arising from premenstrual tension and adolescence.
• the present invention therefore also provides a method of treating or preventing any of the above disorders which comprises administering an effective or prophylactic amount of an oral swallow tablet prepared in accordance with the present invention.

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• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Neurology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (13)

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Publications (2)

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Citations (4)

• 1998
  • 1998-05-13 GB GBGB9810181.9A patent/GB9810181D0/en not_active Ceased
• 1999
  • 1999-05-13 HU HU0102064A patent/HUP0102064A2/hu unknown
  • 1999-05-13 CA CA002331871A patent/CA2331871A1/en not_active Abandoned
  • 1999-05-13 EA EA200001174A patent/EA200001174A1/ru unknown
  • 1999-05-13 CN CN99808325A patent/CN1308521A/zh active Pending
  • 1999-05-13 JP JP2000547965A patent/JP2002514591A/ja active Pending
  • 1999-05-13 AU AU39409/99A patent/AU3940999A/en not_active Abandoned
  • 1999-05-13 ID IDW20002347A patent/ID28019A/id unknown
  • 1999-05-13 EP EP99922302A patent/EP1077682A2/en not_active Withdrawn
  • 1999-05-13 KR KR1020007012706A patent/KR20010043574A/ko not_active Application Discontinuation
  • 1999-05-13 PL PL99344573A patent/PL344573A1/xx unknown
  • 1999-05-13 TR TR2000/03350T patent/TR200003350T2/xx unknown
  • 1999-05-13 SK SK1714-2000A patent/SK17142000A3/sk unknown
  • 1999-05-13 BR BR9910401-6A patent/BR9910401A/pt not_active Application Discontinuation
  • 1999-05-13 WO PCT/GB1999/001520 patent/WO1999058113A2/en not_active Application Discontinuation
  • 1999-05-13 IL IL13959499A patent/IL139594A0/xx unknown
  • 1999-05-13 AP APAP/P/2000/002019A patent/AP2000002019A0/en unknown
• 2000
  • 2000-11-10 NO NO20005683A patent/NO20005683L/no not_active Application Discontinuation
  • 2000-11-13 ZA ZA200006562A patent/ZA200006562B/en unknown
  • 2000-11-30 BG BG105010A patent/BG105010A/xx unknown

Patent Citations (4)

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