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
  • 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
  • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • 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
  • A61K9/2009—Inorganic compounds
• • 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
  • A61K9/2013—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
  • 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
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs

Definitions

• the present Invention relates to a process for preparing tablets of pramipexoie dihydrochloride.
• the present invention relates to a process for preparing tablets of pramipexoie dihydrochloride wherein the tablets exhibit high storage stability properties.
• Pramipexoie is a known dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, e.g., bromocriptine or pergolide. It is also pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors.
• Pramipexoie was originally disclosed in U.S. Patent Nos.4,731,374, 4,843,086 and 4,886,812, all of which are incorporated herein by reference.
• Pramipexoie is designated chemically as (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole and has the molecular formula Ci 0 Hi 7 N 3 S and a relative molecular mass of 211.33.
• the chemical formula is as follows:
• Pramipexoie dihydrochloride monohydrate (molecular formula C I0 H 2I Cl 2 N 3 OS; relative molecular mass 302.27).
• Pramipexoie dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296° C to 301° C, with decomposition.
• Pramipexoie is a chiral compound with one chiral center.
• the pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.
• Pramipexoie dihydrochloride monohydrate is a highly soluble compound. Water solubility is more than 20 mg/mL and solubility in buffer media is generally above 10 mg/mL between pH 2 and pH 7.4. Pramipexole dfliydrochloride monohydrate is not hygroscopic, and has a highly crystalline nature. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive.
• Pramipexole IR tablets are indicated in the EU and US for the treatment of signs and symptoms of either early Parkinson's Disease or advanced Parkinson's Disease in combination with Levodopa.
• the product is known in the USA under the brand name MIRAPEX ® .
• the IR tablets are indicated to be taken 3 times a day.
• the present invention relates to a process for preparing tablets of pramipexole dihydrochloride monohydrate wherein the tablets exhibit high storage stability properties.
• pramipexole dihydrochloride means pramipexole dihydrochloride and the pharmaceutically acceptable solvates thereof in particular including the monohydrate of pramipexole dihydrochloride.
• the process comprises the steps of optionally sizing the intra- granular tableting ingredients to form substantially uniform sized particles of intra-granular tableting ingredients, forming a premix comprising the - optionally substantially uniform sized - intra-granular tableting ingredients, the pramipexole d ⁇ hydrochloride and the binder, granulating the premix and drying said granulated premix to an endpoint moisture content of from about 1.5% to about 2.5%, more preferably 1.0% to about 2.5% to form a dried premix, mixing the extra-granular tableting agents with the dried premix to form a final blend and compressing the final blend into tablets.
• step (f) mixing said granulated premix of step (e) with the extra-granular tableting agents and blending to form a final blend
• a process for preparing pramipexole dihydrochloride tablets comprising intra-granular tableting ingredients, pramipexole dihydrochloride, a binder and extra-granular tableting agents, wherein at least a portion of the process is performed in a closed system and comprises the steps of: (Step 1) loading mannitol, silica colloidal anhydrous and maize starch into a fluid bed granulator wherein the particles of the intra-granular tableting ingredients may optionally be sized prior to loading to form substantially uniform sized particles and mix the ingredients, preferably as a dry mixture,
• Step 2 dissolving the pramipexole dihydrochloride in water and povidone to form an aqueous pramipexole dihydrochloride solution and spraying the pramipexole dihydrochloride solution onto the particles of intra-granular tableting ingredients in the fluid bed granulator,
• Step 3 preparing a paste of suspend maize starch in purified water and adding the same to the fluid bed granulator to form a granulate (Fluid Bed Granulation), while preferably protecting the wet granulate from light.
• Step 4 drying the granulate, preferably while protecting the dried granulate from light.
• Step 5 preparing a raw granulate by a screening mill passing through the dried granulate
• Step 6 blending the raw granulate with magnesium stearate, silica colloidal anhydrous and maize starch by means of a diffusion mixer (final blend).
• Step 7 pressing the final blend into tablets of the final strengths (Tablets), e.g. about 210 mg.
• Step 8 optionally packaging.
• a further aspect of the invention includes a process for the manufacture of a pharmaceutical tablet formulation comprising pramipexole dihydrochloride, wherein the average amount of pramipexole dihydrochloride remaining in the tablet at 18 months under storage conditions of 25° C and a relative humidity of 60% is at least about 97%of the labeled amount.
• Another aspect of the invention includes a process for the manufacture a pharmaceutical tablet formulation comprising pramipexole dihydrochloride, wherein the average amount of pramipexole dihydrochloride remaining in the tablet at 24 months under storage conditions of 25° C and a relative humidity of 60% is at least about 95% of the labeled amount and further may be, preferably, at least about 97%.
• Another aspect of the invention includes a process for the manufacture a pharmaceutical tablet formulation comprising pramipexole dihydrochloride, wherein the average amount of pramipexole dihydrochloride remaining in the tablet at 36 months under storage conditions of 25° C and a relative humidity of 60% is at least about 95% of the labeled amount and further may be, preferably, at least about 97%.
• average amount is calculated by determining the amount of the designated product (either active ingredient or degradation product) present in a particular sample of product and then taking an average of the samples of product.
• the tablets are included as packaged products and packaging may include bottles, blister packs or the like.
• FIG. 1 is a flow chart showing a process for producing pramipexole dihydrochloride tablets according to one aspect of the invention.
• pramipexole dihydrochloride tablets can be prepared which exhibit high storage stability. This is valuable in the pharmaceutical arena as it enables pharmaceutical manufacturers to produce and store the pramipexole dihydrochloride tablets for long periods thereby reducing concern as to whether the product has exceeded its life and requires disposal. This, in turn, enables pharmacies, and ultimately consumers, to enjoy the benefits of reduced costs associated with the need to monitor the efficacy of a product and the need to replenish the market supply due to expiration of the product.
• the pramipexole dihydrochloride tablets of the invention comprise intra-granular tableting ingredients, pramipexole dihydrochloride, a binder and extra- granular tableting agents.
• the process of the invention comprises the steps of sizing the intra- granular tableting ingredients to form substantially uniform sized particles of intra-granular tableting ingredients (optional step), forming a mix comprising the optionally uniformly sized intra-granular tableting ingredients, the pramipexole dihydrochloride and the binder, granulating the mix and drying said granulated mix to an endpo ⁇ nt moisture content (Loss on Drying (LOD) at 95 - 105 0 C, preferably 105 0 C) of from about 1.0% to about 2.5% to form a dried mix, mixing the extra-granular tableting agents with the dried mix to form a final blend and compressing the final blend into tablets.
• the granulated mix is dried to an endpo ⁇ nt moisture content (Lo
• FIG. 1 A process for formulating the tablets which may result in commercial pramipexole products of high stability is set forth in Figure 1.
• the process shown in Figure 1 involves a process for preparing pramipexole dihydrochloride tablets comprising intra-granular tableting ingredients, pramipexole dihydrochloride, a binder and extra-granular tableting agents, wherein at least a portion of the process is performed in a closed system.
• the process comprises the steps of:
• step (g) mixing said granulated mix of step (f) with the extra-granular tableting agents and blending to form a final blend
• the intra-granular tableting ingredients include mannitol-D USP 1 colloidal silicon dioxide NF, povidone (K25) USP, corn starch NF and purified water USP.
• the mannitol-D used as starting material in the process of the present invention preferably is a mixture of the delta crystal modification and the beta crystal modification.
• the percentage in weight of the delta crystal modification exceeds the percentage in weight of the beta crystal modification.
• the percentage of the beta crystal modification is not more than 10%, with the remaining 90% being of the delta crystal modification.
• the beta content is between 1.0 and 10%, preferably 1,5 and 10%, more preferably 2.0 and 10% and even more preferably 2.5 and 10%
• the extra-granular tableting agents of the present invention include colloidal silicon dioxide NF, corn starch NF and magnesium stearate NF.
• Tablet strengths can be from 0.125 mg to 2,5 mg with typical strengths being 0.125 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.5 mg and 2.0 mg.
• the purified water is adapted to the equipment used and does not appear in the final product.
• the advantages to be realized from using the processes of the invention to produce the pramipexole dihydrochloride tablets of the invention include high storage stability properties.
• Such high storage stability properties include, but are not necessarily limited to, high shelf life.
• the pramipexole dihydrochloride tablets prepared according to the process of the present invention has an average amount of pramipexole dihydrochloride remaining in the tablet at 18 months under storage conditions of 25° C and a relative humidity of 60% of at least about 97% of the labeled amount.
• the commercial formulation stored tinder the same conditions average less than 95.8% of the labeled amount (average amount).
• the trend for the amount of active ingredient present in the stored tablets prepared according to the invention can be projected out to 24 and even 36 months where even at 36 months greater than 95 % of the labeled amount should remain. This of course is significant as it allows for long shelf life of the product and thus cost savings to consumers as the product does not have to be replaced by the manufacturer too frequently due to expiration of the unused product stored by the manufacturer, distributor and/or pharmacist,
• the starch paste was then added to 38,000 ml of purified water which had been heated to 95 0 C and stirred at a rate of from about 350 RPM (stirring can be from about 250 RPM to about 1250 RPM).
• An additional 21,000 ml of purified water (room temperature) was then added and stirred at 350 RPM.
• the temperature was allowed to cool to about 60 0 C (the temperature can be from about 55 0 C to about 65 D C at this stage).
• the starch solution was then sprayed onto the intra-granular ingredients and pramipexole dihydrochloride mixture in the fluid bed granulator.
• the material in the fluid bed granulator was then granulated and dried to a residual moisture content of 2.3% and sieved through a screening mill to form a pramipexole raw granulate.
• An extra-granular blend of magnesium stearate (3,000 g), colloidal silicon dioxide (1,200 g) and corn starch (18,000 g) was mixed with 187,800 g of the pramipexole raw granulate in a diffusion mixer for 30 minutes at 10 BlPM to form a final blend.
• the final blend was then compressed into tablets weighing 210 mg and containing 0.5 mg pramipexole dihydrochloride.

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• 2007
  • 2007-08-22 WO PCT/EP2007/058696 patent/WO2008023027A2/en active Application Filing
  • 2007-08-22 MX MX2009001884A patent/MX2009001884A/es not_active Application Discontinuation
  • 2007-08-22 AU AU2007287560A patent/AU2007287560A1/en not_active Abandoned
  • 2007-08-22 RU RU2009110253/15A patent/RU2009110253A/ru not_active Application Discontinuation
  • 2007-08-22 KR KR1020097006052A patent/KR20090045943A/ko not_active Application Discontinuation
  • 2007-08-22 EP EP07788511A patent/EP2056795A2/en not_active Withdrawn
  • 2007-08-22 JP JP2009525064A patent/JP2010501525A/ja active Pending
  • 2007-08-22 BR BRPI0715835-1A patent/BRPI0715835A2/pt not_active IP Right Cessation
  • 2007-08-22 CA CA002661616A patent/CA2661616A1/en not_active Abandoned
  • 2007-08-23 CL CL200702477A patent/CL2007002477A1/es unknown
  • 2007-08-23 TW TW096131278A patent/TW200816998A/zh unknown
  • 2007-08-24 AR ARP070103757A patent/AR062509A1/es unknown
• 2009
  • 2009-02-19 IL IL197130A patent/IL197130A0/en unknown

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