[go: up one dir, main page]

US20050226926A1 - Sustained-release tablet composition of pramipexole - Google Patents

Sustained-release tablet composition of pramipexole Download PDF

Info

Publication number
US20050226926A1
US20050226926A1 US10/626,166 US62616603A US2005226926A1 US 20050226926 A1 US20050226926 A1 US 20050226926A1 US 62616603 A US62616603 A US 62616603A US 2005226926 A1 US2005226926 A1 US 2005226926A1
Authority
US
United States
Prior art keywords
composition
tablet
starch
pramipexole
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/626,166
Other languages
English (en)
Inventor
Gregory Amidon
Loksidh Ganorkar
John Heimlich
Ernest Lee
Robert Noack
Joseph Reo
Connie Skoug
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Priority to US10/626,166 priority Critical patent/US20050226926A1/en
Assigned to PHARMACIA CORPORATION reassignment PHARMACIA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMIDON, GREGORY, GANORKAR, LOKSIDH D., HEIMLICH, JOHN M., LEE, ERNEST J., NOACK, ROBERT M, REO, JOSEPH P., SKOUG, CONNIE J.
Publication of US20050226926A1 publication Critical patent/US20050226926A1/en
Priority to US12/716,755 priority patent/US8399016B2/en
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PHARMACIA CORPORATION
Abandoned legal-status Critical Current

Links

Images

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
    • A61K9/2004—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
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • 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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to tablet formulations, and more particularly to a sustained-release tablet composition for oral delivery of a water-soluble drug or prodrug, exemplified by pramipexole dihydrochloride.
  • a well-known system for formulating such dosage forms involves a matrix comprising a hydrophilic polymer wherein the agent is dispersed; the agent is released over a period of time in the gastrointestinal tract upon dissolution or erosion of the matrix.
  • Sustained-release dosage forms comprising such a matrix system are conveniently prepared as compressed tablets, described herein as “matrix tablets”.
  • Drugs and prodrugs having relatively high solubility in water for example a solubility of about 10 mg/ml or greater, present challenges to the formulator wishing to provide a sustained-release dosage form, and the higher the solubility the greater are the challenges. These challenges are well illustrated in the cases of pramipexole dihydrochloride, which has a solubility in water of about 200 mg/ml.
  • Pramipexole (I) is a dopamine D 2 receptor agonist useful in treatment of Parkinson's disease.
  • Pramipexole as its dihydrochloride salt is commercially available in the United States as Mirapex® tablets of Pharmacia & Upjohn. These are immediate-release tablets in 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg and 1.5 mg strengths, designed for oral administration of a single tablet three times per day to provide a daily dose of 0.375 to 4.5 mg. See Physicians' Desk Reference 57th edition (2003), 2768-2772. Doses herein are expressed in amounts of pramipexole dihydrochloride monohydrate unless otherwise specified; 1.0 mg pramipexole dihydrochloride monohydrate is equivalent to about 0.7 mg pramipexole base.
  • a three times daily dosing regimen for immediate-release pramipexole dihydrochloride tablets is well tolerated, but patient compliance would be much improved if a once-daily regimen were possible.
  • Parkinson's disease the primary indication for the drug, Parkinson's disease, is an affliction that becomes more prevalent with advancing age and is often accompanied by decline in memory.
  • a once-daily regimen would be especially useful in enhancing compliance among elderly patients.
  • U.S. Pat. No. 6,197,339 discloses a sustained-release tablet comprising (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1) (sumanirole maleate) in a matrix comprising hydroxypropylmethylcellulose (HPMC) and starch.
  • HPMC hydroxypropylmethylcellulose
  • Starches disclosed to be suitable therein include pregelatinized starch.
  • U.S. Pat. No. 5,458,887 discloses a controlled-release tablet comprising an osmotic core that consists of a drug in admixture with a water-swellable component such as HPMC or polyethylene oxide, and a coating that comprises a water-resistant polymer and a minor amount of a water-soluble compound that acts as a pore-former. Upon formation of pores in the coating by dissolution of the water-soluble compound, the water-swellable agent is said to expand the core and provide a drug-rich surface in contact with gastrointestinal fluid.
  • a water-swellable component such as HPMC or polyethylene oxide
  • U.S. Pat. No. 5,656,296 discloses a dual control sustained-release formulation comprising a core that comprises a drug and a low melting point excipient, and a coating layer over the core that comprises a pH-independent water-insoluble polymer and a water-soluble film-forming polymer.
  • European Patent Application No. EP 0 933 079 discloses a starch said to be suitable for preparing tablets having high hardness yet being capable of rapid disintegration in an aqueous medium. Tensile strength of the finished tablets is calculated from the hardness.
  • sustained-release pharmaceutical composition in a form of an orally deliverable tablet comprising a water-soluble salt of pramipexole, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN cm ⁇ 2 at a solid fraction representative of the tablet.
  • the composition preferably exhibits sustained-release properties adequate to provide therapeutic effectiveness when administered orally not more than once daily to a subject in need thereof.
  • a method of treatment of a subject having a condition or disorder for which a dopamine D 2 receptor agonist is indicated comprising orally administering to the subject a sustained-release pharmaceutical composition in a form of a tablet comprising a water-soluble salt of pramipexole dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN cm ⁇ 2 at a solid fraction representative of the tablet.
  • water-soluble herein means having solubility of at least about 10 mg/ml.
  • “solubility” herein means solubility in water at 20-25° C. at any physiologically acceptable pH, for example at any pH in the range of about 4 to about 8.
  • solubility in water refers to the salt, not to the free base form of pramipexole.
  • Solid fraction is the ratio of absolute to apparent density of a compact of the starch.
  • a “compact” herein is a compressed tablet, prepared for example on a tablet press, consisting only of a sample of starch for which it is desired to measure tensile strength.
  • a “solid fraction representative of the tablet” is a solid fraction selected to be similar to the solid fraction of tablets prepared according to the invention. Typically a solid fraction of about 0.75 to about 0.85, illustratively 0.8, will be selected.
  • oral means suitable for oral, including peroral and intra-oral (e.g., sublingual or buccal) administration, but tablets of the present invention are adapted primarily for peroral administration, i.e., for swallowing, typically whole or broken, with the aid of water or other drinkable fluid.
  • a “subject” herein is an animal of any species, preferably mammalian, most preferably human.
  • Conditions and disorders in a subject for which a particular agent is said herein to be “indicated” are not restricted to conditions and disorders for which the agent has been expressly approved by a regulatory authority, but also include other conditions and disorders known or believed by a physician to be amenable to treatment with the agent.
  • Treatment herein embraces prophylactic treatment unless the context requires otherwise.
  • FIG. 1 is a graph showing relationship of tensile strength of pregelatinized starch lots, as determined by a test method of the invention using a 4 second dwell time (Example 1 herein) to triaxial tensile strength.
  • FIG. 2 is a graph showing relationship of tensile strength of pregelatinized starch lots, as determined by a test method of the invention using a 90 second dwell time (Example 1 herein) to triaxial tensile strength.
  • FIG. 3 is a graph showing correlation of tensile strength of pregelatinized starch lots with maximum hardness of tablets containing these lots.
  • FIG. 4 is a graph showing in vitro dissolution profiles of three different 0.375 mg sustained-release tablet formulations of pramipexole dihydrochloride monohydrate, as more fully described in Example 10.
  • FIG. 5 is a graph from a human PK study showing time course of mean plasma pramipexole concentration following oral administration of 0.375 mg pramipexole dihydrochloride, either as a 0.125 mg immediate-release tablets administered three times at 8-hour intervals or as a single 0.375 mg dose of each of three different sustained-release tablets, as more fully described in Example 10.
  • FIG. 6 shows in vitro/in vivo correlation for the 0.375 mg pramipexole dihydrochloride tablets of Example 5.
  • FIG. 7 shows in vitro/in vivo correlation for the 0.375 mg pramipexole dihydrochloride tablets of Example 6.
  • FIG. 8 shows in vitro/in vivo correlation for the 0.375 mg pramipexole dihydrochloride tablets of Example 9.
  • the invention provides a pharmaceutical composition in a form of an orally deliverable tablet comprising a water-soluble salt of pramipexole.
  • Preferred salts have solubility not less than about 50 mg/ml, more preferably not less than about 100 mg/ml.
  • pramipexole or a salt thereof herein embraces racemates, enantiomers, polymorphs, hydrates and solvates thereof.
  • Pramipexole (I) is used preferably in the form of its S-enantiomer, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole.
  • a preferred salt of pramipexole is the dihydrochloride salt, most preferably in the form of the monohydrate.
  • Pramipexole compositions of the invention are preferably suitable for administration no more than once daily. Such compositions are useful in treatment of any CNS condition or disorder for which pramipexole has therapeutic utility, but especially Parkinson's disease and complications associated therewith.
  • Pramipexole and its salts useful herein can be prepared by processes known per se, including processes disclosed in patents and other literature pertaining to pramipexole.
  • the amount of the pramipexole salt present in a composition of the invention is sufficient to provide a daily dose in one to a small plurality, for example one to about 4, of tablets to be administered at one time.
  • a daily dose is delivered in a single tablet.
  • pramipexole salt expressed as pramipexole dihydrochloride monohydrate equivalent, of about 0.1 to about 10 mg per tablet, or about 0.05% to about 5% by weight of the composition, will generally be suitable. Preferably an amount of about 0.2 to about 6 mg, more preferably an amount of about 0.3 to about 5 mg, per tablet is present. Specific dosage amounts per tablet contemplated herein include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0 and 4.5 mg pramipexole dihydrochloride monohydrate.
  • a composition of the present invention comprises a pramipexole salt as defmed above, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN cm ⁇ 2 at a solid fraction representative of the tablet, for example about 0.75 to about 0.85, illustratively 0.8.
  • Hydrophilic polymers useful herein are pharmaceutically acceptable polymeric materials having a sufficient number and distribution of hydrophilic substituents such as hydroxy and carboxy groups to impart hydrophilic properties to the polymer as a whole.
  • Suitable hydrophilic polymers include, without limitation, methylcellulose, HPMC (hypromellose), carmellose (carboxymethylcellulose) sodium and carbomer (polyacrylic acid). More than one such polymer can optionally be used.
  • HPMC is a preferred hydrophilic polymer.
  • Various types and grades of HPMC are available.
  • HPMC type 2208 preferably meeting specifications set forth in a standard pharmacopeia such as USP 24, is used.
  • HPMC type 2208 contains 19-24% by weight methoxy and 4-12% by weight hydroxypropoxy substituents.
  • Especially suitable HPMCs have nominal viscosity ranging from about 100 to about 10,000 mPa s; illustratively a suitable HPMC type 2208 is one having a nominal viscosity of about 4,000, with a measured viscosity of about 3,000 to about 5,600 mPa s.
  • Such an HPMC is available, for example, as Methocel® K4MP from Dow Chemical Co., and substantially equivalent products are available from other manufacturers.
  • the amount of hydrophilic polymer in the composition depends on the particular polymer selected, on the active pharmaceutical agent and on the desired sustained release profile. Typically, however, the hydrophilic polymer is included in an amount of about 20% to about 70%, preferably about 30% to about 60% and more preferably about 35% to about 50%, by weight of the composition. In the illustrative case of HPMC type 2208, a suitable amount will generally be found in the range from about 30% to about 60%, preferably about 35% to about 50%, for example about 40%, by weight of the composition.
  • hydrophilic polymer functions to provide extended or sustained release of the pramipexole, for example by gradual dissolution or erosion of the polymer in the gastrointestinal tract.
  • Starches useful herein include starches from any suitable botanical source, for example corn, wheat, rice, tapioca, potato, etc.
  • Preferred starches have a relatively high ratio of amylose to amylopectin, containing for example at least about 20%, more preferably at least about 25%, amylose.
  • pregelatinized starch which is a type of modified starch that has been processed to render the starch more flowable and directly compressible. Partially or wholly pregelatinized starches can be used.
  • starch in a composition of the invention is as a binding agent.
  • a starch meeting the tensile strength criterion defmed herein can be referred to as a “super binder”.
  • the amount of starch in the composition is typically higher than is conventionally present as a binder in tablet formulations. Suitable amounts will generally be found in the range of about 25% to about 75% by weight. Preferably the amount of starch is about 40% to about 70%, more preferably about 45% to about 65%, for example about 50%, by weight of the composition.
  • Tensile strength of a starch sample can be measured by any suitable test. Illustrative test procedures are described by Hiestand & Smith (1984), Powder Technology 38, 145-159, and by Hiestand & Smith (1991), International Journal of Pharmaceutics 67, 231-246, these articles being incorporated herein by reference.
  • Triaxial tensile strength test An example of a tensile strength test that can be used (herein referred to as a “triaxial tensile strength test”) requires preparation of a series of compacts of the starch sample, followed by determination of tensile strength of the compacts using a computerized multifunction tablet tester (MTT).
  • the compacts are prepared with various degrees of compression force to provide compacts having a range of solid fraction.
  • a sustained release tablet formulation typically has a solid fraction of about 0.8, it is useful to prepare compacts approximating such a solid fraction.
  • Absolute density of the starch sample can be determined using a helium-air pycnometer.
  • a computer-controlled triaxial tablet press is used to prepare the compacts. Voltage output from the punch and die load cells of the tablet press are first zeroed. The punch and die are lubricated with magnesium stearate powder and the die assembly is placed in the press. Compression and decompression parameters are selected on the computer. The desired amount of starch to be compacted is weighed and poured into the die cavity. The resulting powder bed is leveled with a spatula. The punch is inserted into the die and the computer-controlled compression/decompression cycle is started.
  • LVDT linear variable differential transformer
  • the punch and die rams are retracted.
  • the compact is removed from the die and inspected for defects, such as cracking or sticking. Cracking can be reduced by increasing decompression time. If the compact is free of defects, its length, width, thickness and weight are measured to enable calculation of apparent density. Solid fraction is calculated by dividing absolute density by apparent density.
  • a suitable software program is run.
  • the platen is screwed to the load cell of the MTT and the tensile strength assembly is slid into the MTT opposite the platen.
  • the load cell signal is monitored via the computer and the zero offset on the signal conditioner is adjusted to provide a positive baseline voltage as close as possible to zero.
  • a forward velocity is selected that will generate a time constant of approximately 15 seconds (usually the velocity selected will be about 0.8 to about 1.2 mm s ⁇ 1 ).
  • the compact to be tested is placed in the holder of the tensile strength assembly.
  • the motor is initiated via the computer, driving the platen toward the compact until the surface of the compact is detected, and stopping the platen a few millimeters from the compact.
  • the oscilloscope is triggered, to record the force applied to the compact, and the motor is restarted.
  • the platen is driven into the compact until a crack is detected, either by sight or by sound, and the motor is immediately reversed.
  • Peak force is recorded from the oscilloscope trace.
  • Tensile strength is calculated from the peak force using appropriate computer software.
  • compacts of the starch sample are prepared on a standard automated tablet press under a range of compression forces.
  • a Carver press e.g., Model 3888.1DT0000
  • suitable diameter e.g., 10/32 inch or about 0.7 cm for a 300 mg compact
  • compression forces about 4 to about 16 kN (about 900 to about 3600 lbf) for a dwell time of at least about 4 seconds
  • such compacts can be prepared at 1000, 1500, 2000 and 3000 lbf (4.45, 6.67, 8.90 and 13.34 kN).
  • a dwell time of 90 seconds has been found to give satisfactory results.
  • Weight, diameter and thickness of each compact are measured accurately (alternatively, diameter can be assumed to equal that of the tooling) to enable calculation of apparent density and hence solid fraction, absolute density having been measured as described above, for example by helium-air pycnometry.
  • Hardness of each compact thus prepared is then determined by any suitable tablet hardness test, for example using a Key HT 500 hardness tester. Hardness is a measure of the force required to cause crushing of the compact, and is typically expressed in units such as kiloponds (kp) or Strong-Cobb units (SCU). A hardness of about 10.2 kp or about 14.4 SCU corresponds to a force of 0.1 kN.
  • kp kiloponds
  • SCU Strong-Cobb units
  • F the force required to cause crushing
  • D the diameter of the compact
  • H thickness of the compact (in cm).
  • a compact of diameter 0.7 cm and thickness 0.4 cm having a hardness of 20 SCU (equivalent to a force of 0.139 kN) has a calculated tensile strength of 0.316 kN cm ⁇ 2 .
  • the relationship between tensile strength and solid fraction is next established for the starch sample. This can be done by plotting data for tensile strength and solid fraction on a graph (solid fraction tends to increase with increasing compression force during preparation of the compact) or by performing a regression analysis. From that relationship, tensile strength at a standardized value of solid fraction can be estimated.
  • the standardized value selected is one that is representative of the solid fraction of a desired sustained-release tablet, e.g., 0.8.
  • An especially preferred starch has a tensile strength of at least about 0.175 kN cm ⁇ 2 , even more preferably at least about 0.2 kN cm ⁇ 2 , at a solid fraction representative of a desired sustained-release tablet.
  • pregelatinized starches Even among commercially available pregelatinized starches, the preferred type of starch for use in a composition of the invention, considerable variation exists in tensile strength. Pregelatinized starches not meeting the tensile strength criterion established herein are not readily identified without testing, for example by a method as disclosed above. Such pregelatinized starches are generally unsuitable for commercial-scale manufacture of a sustained-release matrix tablet formulation of a water-soluble drug or prodrug, because of a problem as set forth immediately below.
  • An uncoated tablet, or a tablet core prior to coating, comprising starch and a hydrophilic polymer acting as a matrix for a water-soluble drug or prodrug requires to have a certain minimum hardness in order to be able to resist breakage and/or attrition due to mechanical stresses imposed during a high-speed tableting operation (including all steps up to and including filling of the tablets into containers).
  • the minimum acceptable hardness will depend on a number of factors, including the severity of the mechanical stresses, but is typically at least about 20 SCU, preferably at least about 22 SCU, more preferably at least about 24 SCU (about 17 kp).
  • Hardness can be increased by increasing the compression force applied by the tablet press, but only up to a certain level. At least in the case of tablets as described herein, above a certain compression force, further increases in compression force give little or no further increase in tablet hardness. There is, in other words, a maximum hardness achievable by compression of a particular starch/hydrophilic polymer/active agent composition. A starch providing a maximum hardness inadequate to withstand the mechanical stresses of a high-speed tableting operation is unsuitable for the present purpose. As shown in FIG.
  • starches having low tensile strength (0.1 kN cm ⁇ 2 or less according to the test method of the invention utilizing a dwell time of 90 seconds).
  • the sustained-release tablet of the invention further comprises a coating.
  • a hydrophilic polymer matrix can be inadequate to provide sustained release of sufficiently long duration to permit once daily administration. It is believed that such salts are readily leached out of the hydrophilic matrix when contacted by an aqueous medium such as gastrointestinal fluid. It is therefore desirable to further slow the process of drug release by providing a release-controlling coating around the tablet.
  • a coating typically comprises a hydrophobic or water-insoluble polymer component such as ethylcellulose together with a hydrophilic or water-soluble pore-forming component such as HPMC.
  • the composition is found to be especially suited to a high-speed tableting operation that includes a step of coating the tablet with a release-controlling layer.
  • ethylcellulose and HPMC as components of a release coating layer
  • cellulosic polymers e.g., methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose sodium, cellulose esters such as cellulose acetate, etc.
  • polyvinyl acetate polyvinyl pyrrolidone
  • polymers and copolymers of acrylic acid and methacrylic acid and esters thereof polyethylene glycol, carrageenan and other gums, and the like.
  • a release-controlling layer typically constitutes about 1% to about 15%, preferably about 2.5% to about 10%, by weight of the tablet as a whole.
  • the hydrophobic or water-insoluble component preferably comprising ethylcellulose, typically constitutes about 1% to about 10%, preferably about 2% to about 7%, by weight of the tablet as a whole.
  • the pore-forming component preferably comprising HPMC, is typically present in an amount of about 5% to about 50%, preferably about 10% to about 40%, by weight of the water-insoluble or hydrophobic component.
  • the coating if present, can optionally contain additional pharmaceutically acceptable excipients such as plasticizers, dyes, etc.
  • a release-controlling layer in an amount of about 2.5% to about 5% by weight of the tablet core comprises an ethylcellulose-based material (e.g., Surelease® of Colorcon) and an HPMC-based pore-forming material (e.g., Opadry® of Colorcon) in a weight ratio of about 3:1 to about 4:1.
  • an ethylcellulose-based material e.g., Surelease® of Colorcon
  • an HPMC-based pore-forming material e.g., Opadry® of Colorcon
  • a release-controlling layer or coating should be applied at as uniform a thickness as possible to provide optimum control of release rate of the pramipexole.
  • the sustained-release tablet of the invention comprises a nonfunctional coating.
  • a nonfunctional coating can comprise a polymer component, for example HPMC, optionally with other ingredients, for example one or more plasticizers, colorants, etc.
  • the term “nonfunctional” in the present context means having no substantial effect on release properties of the tablet, and does not imply that the coating serves no useful purpose. For example, such a coating can impart a distinctive appearance to the tablet, provide protection against attrition during packaging and transportation, improve ease of swallowing, and/or have other benefits.
  • a nonfunctional coating should be applied in an amount sufficient to provide complete coverage of the tablet. Typically an amount of about 1% to about 10%, more typically an amount of about 2.5% to about 5%, by weight of the tablet as a whole, will be found suitable.
  • Uncoated tablets and cores of coated tablets of the invention can optionally contain one or more pharmaceutically acceptable excipients in addition to the starch and hydrophilic polymer components described above.
  • excipients include without limitation glidants and lubricants.
  • Other conventional excipients known in the art can also be included.
  • a glidant can be used to improve powder flow properties prior to and during tableting and to reduce caking.
  • Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate and the like.
  • colloidal silicon dioxide is included as a glidant in an amount up to about 2%, preferably about 0.2% to about 0.6%, by weight of the tablet.
  • a lubricant can be used to enhance release of a tablet from apparatus on which it is formed, for example by preventing adherence to the face of an upper punch (“picking”) or lower punch (“sticking”).
  • Suitable lubricants include magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and the like.
  • magnesium stearate is included as a lubricant in an amount of about 0.1% to about 1.5%, preferably about 0.3% to about 1%, by weight of the tablet.
  • Tablets can be of any suitable size and shape, for example round, oval polygonal or pillow-shaped, and optionally bear nonfunctional surface markings. Especially in the case of coated tablets they are preferably designed to be swallowed whole and are therefore typically not provided with a breaking score. Tablets of the invention can be packaged in a container, accompanied by a package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug interactions and adverse reactions.
  • a method of treatment of a subject having a condition or disorder for which a dopamine D 2 receptor agonist is indicated comprising orally administering to the subject a sustained-release pharmaceutical composition in a form of a tablet comprising a water-soluble salt of pramipexole dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN cm ⁇ 2 at a solid fraction representative of the tablet.
  • the composition is administered no more than once daily.
  • condition or disorder is Parkinson's disease or a complication associated therewith.
  • Suitable daily dosage amounts include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0 and 4.5 mg pramipexole dihydrochloride monohydrate.
  • a composition of the invention is administered in combination therapy with one or more additional drugs or prodrugs.
  • the term “combination therapy” herein means a treatment regimen wherein the agent provided by the composition of the invention and a second agent are administered individually or together, sequentially or simultaneously, in such a way as to provide a beneficial effect from co-action of these therapeutic agents.
  • beneficial effect can include, but is not limited to, pharmacokinetic or pharmacodynamic co-action of the therapeutic agents.
  • Combination therapy can, for example, enable administration of a lower dose of one or both agents than would normally be administered during monotherapy, thus decreasing risk or incidence of adverse effects associated with higher doses.
  • combination therapy can result in increased therapeutic effect at the normal dose of each agent in monotherapy.
  • “Combination therapy” herein is not intended to encompass administration of two or more therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in sequential or simultaneous treatment.
  • compositions of the invention can be especially suited to combination therapies, particularly where the second agent is one that is, or can be, administered once daily.
  • the second agent is one that is, or can be, administered once daily.
  • the two components of the combination therapy can be administered in separate dosage forms or in coformulation, i.e., in a single dosage form
  • the second agent can be administered by any suitable route and in any pharmaceutically acceptable dosage form, for example by a route and/or in a dosage form other than the present composition.
  • both components of the combination therapy are formulated together in a single dosage form.
  • Tensile strength of six commercially obtained lots of pregelatinized starch was determined using the triaxial tensile strength test procedure described hereinabove. Data for tensile strength at a solid fraction of 0.8 are presented in Table 1. TABLE 1 Tensile strength of pregelatinized starch lots at a solid fraction of 0.8 (triaxial test procedure) Lot Tensile strength (kN cm ⁇ 2 ) 1 0.323 2 0.220 3 0.074 4 0.119 5 0.287 6 0.236
  • Sumanirole maleate sustained-release tablets were prepared having the compositions shown in Table 3. Tablet strength in mg is expressed as sumanirole base. TABLE 3 Composition of sumanirole maleate tablets of Example 3 Tablet strength (mg) 0.5 1 2 4 8 8 12 24 Ingredient Amount (% by weight) sumanirole maleate 0.23 0.45 0.9 1.8 3.6 3.6 5.4 10.9 HPMC type 2208, 4000 mPa s 35.00 35.00 35.0 35.0 35.0 35.0 35.0 35.0 35.0 35.0 pregelatinized starch 63.87 63.65 63.2 62.3 60.5 60.0 58.2 52.5 colloidal silicon dioxide 0.40 0.40 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4
  • lubricant magnesium stearate
  • All ingredients except the lubricant were screened to remove lumps and were blended thoroughly in a low-shear mixer operating at 24 rpm for 10-30 minutes. The lubricant was then screened into the mixer and the materials were blended for a further 2-5 minutes. The resulting lubricated mixture was compressed into 350 mg pillow-shaped tablets using a Kilian S100 tableting machine.
  • Tablets similar to those of Example 3 were prepared using pregelatinized starches of lots 1-6 as tested in Examples 1 and 2. Maximum hardness of the tablets obtainable with each pregelatinized starch lot was determined.
  • tablets of different hardness were used as cores for coating and were tested for resistance to erosion during a high-speed coating operation.
  • Tablet cores having a hardness of at least about 24 SCU (about 17 kp) were found to have acceptable resistance to erosion.
  • this degree of hardness is achievable using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • Pregelatinized starches of Lots 3 and 4 were unsuitable, having tensile strength less than about 0.15 kN cm ⁇ 2 and providing tablets having a maximum hardness no greater than about 20 SCU (about 14 kp).
  • Pramipexole dihydrochloride sustained-release tablets were prepared having the compositions shown in Table 4. TABLE 4 Composition of pramipexole dihydrochloride tablets of Example 5 Ingredient Amount (mg) pramipexole dihydrochloride 0.375 0.75 1.5 3.0 4.5 0.375 0.375 4.5 monohydrate HPMC type 2208, 4000 mPa s 140.0 140.0 140.0 140.0 140.0 70.0 157.5 157.5 pregelatinized starch 206.5 206.1 205.4 203.9 202.4 101.5 189.0 184.9 colloidal silicon dioxide 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 magnesium stearate 1.75 1.75 1.75 1.75 1.75 1.75 1.75 total 350 350 350 350 350 350 350 350 175 350 350 350 350 350 175 350 350 350
  • the tablets were prepared by the procedure described in Example 3, using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • Coated sustained-release tablets of pramipexole dihydrochloride were prepared having the composition shown in Table 5. TABLE 5 Composition of coated tablets of Example 6 Ingredient Amount (mg) pramipexole dihydrochloride monohydrate 0.375 HPMC type 2208, 4000 mPa s 140.0 pregelatinized starch 206.5 colloidal silicon dioxide 1.4 magnesium stearate 1.75 total core 350 ethylcellulose-based coating material (Surelease ®) 7.88 HPMC-based coating material (Opadry ®) 2.63 total coating 10.5
  • Tablet cores were prepared exactly as in Example 5, using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • a coating solution was prepared as follows. Opadry® HPMC-based material in an amount of 6.004 g was added to 106.682 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 72.045 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
  • the coating solution was applied to the tablet cores in an amount providing a 3% weight gain.
  • the resulting coated tablets were cured using a 12 inch (about 30 cm) Vector LCDS or 24 inch (about 60 cm) Thomas Accela-Coata coating pan for about 15 minutes at a bed temperature of at least about 70° C. After curing, temperature was ramped down over a period of about 8 minutes to an exhaust temperature of about 45° C.
  • Coated sustained-release tablets of pramipexole dihydrochloride were prepared having the composition shown in Table 6. TABLE 6 Composition of coated tablets of Example 7 Ingredient Amount (mg) pramipexole dihydrochloride monohydrate 0.375 HPMC type 2208, 4000 mPa s 140.0 pregelatinized starch 206.5 colloidal silicon dioxide 1.4 magnesium stearate 1.75 total core 350 ethylcellulose-based coating material (Surelease ®) 8.4 HPMC-based coating material (Opadry ®) 2.1 total coating 10.5
  • Tablet cores were prepared exactly as in Example 5, using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • a coating solution was prepared as follows. Opadry® HPMC-based material in an amount of 4.801 g was added to 103.041 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 76.819 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
  • Coated sustained-release tablets of pramipexole dihydrochloride were prepared having the composition shown in Table 7. TABLE 7 Composition of coated tablets of Example 8 Ingredient Amount (mg) pramipexole dihydrochloride monohydrate 0.375 HPMC type 2208, 4000 mPa s 140.0 pregelatinized starch 206.5 colloidal silicon dioxide 1.4 magnesium stearate 1.75 total core 350 ethylcellulose-based coating material (Surelease ®) 13.13 HPMC-based coating material (Opadry ®) 4.38 total coating 17.5
  • Tablet cores were prepared exactly as in Example 5, using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • a coating solution was prepared as follows. Opadry® HPMC-based material in an amount of 10.003 g was added to 177.737 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 120.03 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
  • Coating to a 3% weight gain and curing of the coated tablets were performed exactly as in Example 6. After this first curing step, coating was repeated to provide a total tablet weight gain of about 5%, followed by curing for about 15 minutes at a bed temperature of at least about 70° C. After curing, temperature was ramped down over a period of about 8 minutes to an exhaust temperature of about 45° C.
  • Coated sustained-release tablets of pramipexole dihydrochloride were prepared having the composition shown in Table 8. TABLE 8 Composition of coated tablets of Example 9 Ingredient Amount (mg) pramipexole dihydrochloride monohydrate 0.375 HPMC type 2208, 4000 mPa s 140.0 pregelatinized starch 206.5 colloidal silicon dioxide 1.4 magnesium stearate 1.75 total core 350 ethylcellulose-based coating material (Surelease ®) 14.0 HPMC-based coating material (Opadry ®) 3.5 total coating 17.5
  • Tablet cores were prepared exactly as in Example 5, using pregelatinized starch having a tensile strength of at least about 0.175 kN cm ⁇ 2 .
  • a coating solution was prepared as follows. Opadry® HPMC-based material in an amount of 8.002 g was added to 171.735 g water and mixed for 45 minutes to provide an HPMC mixture. Next, 128.032 g Surelease® ethylcellulose-based material was added to the HPMC mixture and mixed for an additional 30 minutes to provide a coating solution.
  • Dissolution profiles of the 0.375 mg pramipexole dihydrochloride tablets of each of Examples 5, 6 and 9 were evaluated in a standard in vitro USP dissolution assay under the following conditions.
  • USP apparatus 1 was used to stir a dissolution medium (900 ml of 0.05M phosphate buffer at a pH of 6.8) at a spindle rotation speed of 100 rpm and a temperature of 37° C.
  • the uncoated tablet of Example 5 and the tablet of Example 6 having a 3% coating comprising 25% pore-former exhibited very similar overall dissolution profiles.
  • the uncoated tablet of Example 5 showed faster initial dissolution, such that at 1 hour and 2 hour sampling times the percent dissolved was greater, than in the case of the coated tablet of Example 6.
  • the coated tablet of Example 6 showed only 11% dissolution, while the uncoated tablet of Example 5 showed 15% dissolution.
  • the coated tablet of Example 6 showed no more than 20% dissolution, while the uncoated tablet of Example 5 showed 24% dissolution.
  • Dissolution of the tablet of Example 9 having a 5% coating comprising 20% pore-former exhibited a dissolution profile much slower than either the tablet of Example 5 or the tablet of Example 6.
  • the study followed an open-label, 4-way, randomized crossover design and was conducted in healthy male and female subjects ranging from 18 to 55 years of age.
  • the subjects received each of the four treatments during the course of the study, which was conducted at a single center.
  • a total of 12 subjects were enrolled.
  • the subjects were fasted overnight and then given a 0.375 mg oral dose of pramipexole dihydrochloride monohydrate.
  • the IR formulation which was provided as Mirapex® tablets
  • three equally divided doses of 0.125 mg each were given at 8-hour intervals, beginning in the morning.
  • XR formulations of Examples 5, 6 and 9 a single 0.375 mg tablet was given in the morning.
  • Serial blood samples were taken over a 48-hour period for PK assessment. Adverse events were recorded during the same 48-hour period.
  • Plasma pramipexole concentrations were quantitated by an HPLC-MS/MS method, validated over the assay range 0.05-15 ng/ml. All runs met bioanalytical acceptance criteria for calibration standards and quality control. Samples were not diluted prior to analysis as all sample concentrations were within the limits of quantitation.
  • PK parameters for pramipexole were estimated by non-compartmental methods, using the nonlinear regression program Kinetica of Innaphase. Individual plasma concentration data and the actual time-points of blood sampling from each subject were used in the analysis. Plasma concentrations below the lower limit of quantitation at early time-points were set to zero, whereas those in the terminal phase were excluded from the analysis.
  • PK estimates derived from the individual subject data are provided in Table 9. TABLE 9 PK parameters (mean ⁇ standard deviation) IR tablet XR tablets Parameter (Mirapex ®) Example 5
  • Example 6 Example 9 AUC 0- ⁇ (ng ⁇ h/ml) 9.93 ⁇ 3.05 9.05 ⁇ 3.24 9.66 ⁇ 2.91 8.91 ⁇ 4.15 AUC 0-48 (ng ⁇ h/ml) 8.60 ⁇ 2.63 7.76 ⁇ 2.83 7.60 ⁇ 2.00 7.07 ⁇ 2.77
  • Example 10 Mean cumulative absorption data (up to 24 hours) for the XR tablets are shown in Table 10, together with corresponding in vitro dissolution data from Example 10. TABLE 10 In vitro dissolution and in vivo absorption data for XR tablets Example 9 Example 5 Example 6 % diss. % abs. Time % diss. % abs. % diss. % abs.
  • FIGS. 3-5 In vitro/in vivo correlation plots derived from the data of Table 7 are shown in FIGS. 3-5 for the XR tablets of Examples 1, 2 and 5 respectively.
  • the mean plasma pramipexole concentration profile shown in FIG. 5 clearly shows the tablets of Examples 5, 6 and 9 effectively extended the release of pramipexole relative to the IR tablet.
  • the XR tablets of Examples 5 and 6 exhibit a delay of approximately 1 hour in onset of absorption, whereas quantifiable levels of pramipexole were not observed until about 3 hours after administration of the XR tablet of Example 9.
  • the derived PK parameters given in Table 9, in particular the C max and T max data, indicate that of the XR tablets, the tablet of Example 5 exhibited the fastest and the tablet of Example 9 the slowest absorption, the tablet of Example 6 being intermediate in this regard.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US10/626,166 2002-07-25 2003-07-23 Sustained-release tablet composition of pramipexole Abandoned US20050226926A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/626,166 US20050226926A1 (en) 2002-07-25 2003-07-23 Sustained-release tablet composition of pramipexole
US12/716,755 US8399016B2 (en) 2002-07-25 2010-03-03 Sustained-release tablet composition of pramipexole

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US39844702P 2002-07-25 2002-07-25
US39842702P 2002-07-25 2002-07-25
US47951303P 2003-06-18 2003-06-18
US10/626,166 US20050226926A1 (en) 2002-07-25 2003-07-23 Sustained-release tablet composition of pramipexole

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/716,755 Continuation US8399016B2 (en) 2002-07-25 2010-03-03 Sustained-release tablet composition of pramipexole

Publications (1)

Publication Number Publication Date
US20050226926A1 true US20050226926A1 (en) 2005-10-13

Family

ID=31192087

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/626,166 Abandoned US20050226926A1 (en) 2002-07-25 2003-07-23 Sustained-release tablet composition of pramipexole
US12/716,755 Expired - Fee Related US8399016B2 (en) 2002-07-25 2010-03-03 Sustained-release tablet composition of pramipexole

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/716,755 Expired - Fee Related US8399016B2 (en) 2002-07-25 2010-03-03 Sustained-release tablet composition of pramipexole

Country Status (41)

Country Link
US (2) US20050226926A1 (ru)
EP (2) EP1531814B1 (ru)
JP (1) JP4700963B2 (ru)
KR (1) KR100712832B1 (ru)
CN (1) CN1313092C (ru)
AP (1) AP2201A (ru)
AR (1) AR040681A1 (ru)
AT (1) ATE406162T1 (ru)
AU (1) AU2003261241B2 (ru)
BR (1) BR0312960A (ru)
CA (1) CA2492854C (ru)
CR (1) CR7661A (ru)
CU (1) CU23440B7 (ru)
CY (1) CY1110408T1 (ru)
DE (1) DE60323235D1 (ru)
DK (1) DK1531814T3 (ru)
EA (2) EA009663B1 (ru)
EC (1) ECSP055568A (ru)
ES (1) ES2310673T3 (ru)
GE (1) GEP20074048B (ru)
HK (1) HK10777456A1 (ru)
HR (1) HRP20041235B1 (ru)
IL (1) IL166078A0 (ru)
IS (1) IS7623A (ru)
MA (1) MA27328A1 (ru)
ME (1) MEP52308A (ru)
MX (1) MXPA05001054A (ru)
MY (1) MY138846A (ru)
NO (1) NO334298B1 (ru)
NZ (1) NZ537790A (ru)
OA (1) OA13303A (ru)
PA (1) PA8578301A1 (ru)
PE (1) PE20040130A1 (ru)
PL (1) PL215587B1 (ru)
PT (1) PT1531814E (ru)
RS (1) RS51719B (ru)
SI (1) SI1531814T1 (ru)
TW (1) TWI347849B (ru)
UY (1) UY27912A1 (ru)
WO (1) WO2004010997A1 (ru)
ZA (1) ZA200500439B (ru)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050175691A1 (en) * 2002-07-25 2005-08-11 Lee Ernest J. Pramipexole once-daily dosage form
US20060051417A1 (en) * 2004-08-13 2006-03-09 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20060051419A1 (en) * 2004-08-13 2006-03-09 Boehringer Ingelheim International Gmbh Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20060281797A1 (en) * 2001-12-11 2006-12-14 University Of Virginia Patent Foundation Neurorestoration with R(+) Pramipexole
US20070105918A1 (en) * 2001-12-11 2007-05-10 University Of Virginia Patent Foundation Use of Pramipexole to Treat Amyotrophic Lateral Sclerosis
US20070259930A1 (en) * 2006-04-10 2007-11-08 Knopp Neurosciences, Inc. Compositions and methods of using r(+) pramipexole
US20080014259A1 (en) * 2006-05-16 2008-01-17 Knopp Neurosciences, Inc. Compositions of R(+) and S(-) Pramipexole and Methods of Using the Same
US20080176913A1 (en) * 2006-06-29 2008-07-24 Arnaud Grenier Transdermal compositions of pramipexole having enhanced permeation properties
US20080227985A1 (en) * 2007-03-14 2008-09-18 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazoles
US20080234338A1 (en) * 2005-08-15 2008-09-25 University Of Virginia Patent Foundation Neurorestoration With R(+) Pramipexole
WO2008129043A1 (en) * 2007-04-24 2008-10-30 Boehringer Ingelheim International Gmbh Combination with an extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20080299189A1 (en) * 2007-06-04 2008-12-04 Drugtech Corporation Controlled release dopamine agonist compositions
US20090304794A1 (en) * 2008-06-09 2009-12-10 Supernus Pharmaceuticals, Inc. Controlled release formulations of pramipexole
US20110003870A1 (en) * 2009-07-02 2011-01-06 Supernus Pharmaceuticals, Inc. Method of treatment of a neurological disorder
US20110009460A1 (en) * 2009-06-19 2011-01-13 Valentin Gribkoff Compositions and methods for treating amyotrophic lateral sclerosis
US20110150994A1 (en) * 2006-02-10 2011-06-23 Boehringer Ingelheim International Gmbh Modified Release Formulation
US20110195122A1 (en) * 2006-02-10 2011-08-11 Boehringer Ingelheim International Gmbh Extended Release Formulation
WO2011037976A3 (en) * 2009-09-22 2011-08-25 Dr. Reddy's Laboratories Limited Pramipexole pharmaceutical formulations
WO2011148243A1 (en) 2010-05-24 2011-12-01 Lupin Limited Extended release formulation of pramipexole
WO2012002644A3 (en) * 2010-07-02 2012-04-12 Hyundai Pharm Co., Ltd. Sustained-release pharmaceutical composition containing pramipexole or pharmaceutically acceptable salt thereof with improved stability
US8399016B2 (en) 2002-07-25 2013-03-19 Boehringer Ingelheim International Gmbh Sustained-release tablet composition of pramipexole
US8518926B2 (en) 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole
US8524695B2 (en) * 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9763918B2 (en) 2013-08-13 2017-09-19 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY136318A (en) * 2002-07-25 2008-09-30 Pharmacia Corp Sustained-release tablet composition
EP1645568A4 (en) 2003-07-11 2007-06-27 Asahi Kasei Chemicals Corp FUNCTIONAL STARCH POWDER
EP1803447B1 (en) * 2004-09-09 2009-07-22 Psicofarma, S.A. De C.V. Pharmaceutical composition for the sustained release of hydralazine and use thereof as a support for cancer treatment
EP1731514A1 (en) * 2005-06-02 2006-12-13 Sandoz AG Process for the preparation of Pramipexole
WO2007090882A2 (en) * 2006-02-10 2007-08-16 Boehringer Ingelheim International Gmbh Pharmaceutical extended release compositions comprising pramipexole
WO2011086182A2 (en) 2010-01-18 2011-07-21 Synthon Bv Pramipexole extended release tablets
TR201001862A1 (tr) 2010-03-11 2011-10-21 Sanovel �La� San.Ve T�C.A.�. Kontrollü salım gerçekleştiren pramipeksol formülasyonları.
WO2013034173A1 (en) 2011-09-06 2013-03-14 Synthon Bv Pramipexole extended release tablets
EP2732812A1 (de) 2012-11-15 2014-05-21 Aristo Pharma GmbH Pramipexol-Retardtablettenformulierung
CN103520128B (zh) 2013-10-12 2018-08-21 石家庄杏林锐步医药科技股份有限公司 一种普拉克索的缓释片剂、制备方法及其用途
IL312486B2 (en) 2017-04-10 2025-05-01 Chase Therapeutics Corp NK1 antagonist combination and method for treating synucleinopathies
CA3104811C (en) 2017-06-30 2024-05-28 Chase Therapeutics Corporation Composition comprising pramipexole and nk1-antagonists for treating depression
CN109316466B (zh) * 2017-07-31 2022-04-05 深圳翰宇药业股份有限公司 一种盐酸普拉克索缓释制剂及其制备方法
EP3668501A4 (en) 2017-08-17 2021-03-17 Zi-Qiang Gu MONOAMINE PAMOATE SALTS ANTI-PARKINSON AGENTS, THEIR PREPARATION AND USE
CN113876729B (zh) * 2021-11-11 2023-05-30 南通联亚药业股份有限公司 一种盐酸普拉克索缓释片剂及其制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US15735A (en) * 1856-09-16 Improvement in harvesters
US2887440A (en) * 1957-08-12 1959-05-19 Dow Chemical Co Enteric coating
US4731374A (en) * 1984-12-22 1988-03-15 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US5472712A (en) * 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5656296A (en) * 1992-04-29 1997-08-12 Warner-Lambert Company Dual control sustained release drug delivery systems and methods for preparing same
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US6197339B1 (en) * 1997-09-30 2001-03-06 Pharmacia & Upjohn Company Sustained release tablet formulation to treat Parkinson's disease
US6277875B1 (en) * 2000-07-17 2001-08-21 Andrew J. Holman Use of dopamine D2/D3 receptor agonists to treat fibromyalgia
US20030180352A1 (en) * 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions

Family Cites Families (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
JPS58403B2 (ja) 1975-07-24 1983-01-06 武田薬品工業株式会社 Ｌ− アスコルビンサンセイザイノ セイゾウホウ
US4140755A (en) 1976-02-13 1979-02-20 Hoffmann-La Roche Inc. Sustained release tablet formulations
CH649215A5 (de) 1981-04-29 1985-05-15 Hoffmann La Roche Pharmazeutische praeparate.
SE8103843L (sv) 1981-06-18 1982-12-19 Astra Laekemedel Ab Farmaceutisk mixtur
US4424235A (en) 1981-09-14 1984-01-03 Hoffmann-La Roche Inc. Hydrodynamically balanced controlled release compositions containing L-dopa and a decarboxylase inhibitor
DE3447075A1 (de) * 1984-12-22 1986-07-03 Dr. Karl Thomae Gmbh, 7950 Biberach Tetrahydro-benzthiazole, deren herstellung und deren verwendung als zwischenprodukte oder als arzneimittel
US4738851A (en) 1985-09-27 1988-04-19 University Of Iowa Research Foundation, Inc. Controlled release ophthalmic gel formulation
US4709712A (en) 1986-10-22 1987-12-01 Dermatalogical Products Of Texas Polycarboxylic acid polymer gels as protective agents
GB8828020D0 (en) 1988-12-01 1989-01-05 Unilever Plc Topical composition
US5026559A (en) 1989-04-03 1991-06-25 Kinaform Technology, Inc. Sustained-release pharmaceutical preparation
US5133974A (en) 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
JP2955358B2 (ja) 1989-06-09 1999-10-04 ファルマシア・アンド・アップジョン・カンパニー 中枢神経系活性を有する複素環系アミン
US5273975A (en) 1989-06-09 1993-12-28 The Upjohn Company Heterocyclic amines having central nervous system activity
GB9015822D0 (en) 1990-07-18 1990-09-05 Beecham Group Plc Compositions
US5431920A (en) 1993-09-21 1995-07-11 Merck Frosst, Canada, Inc. Enteric coated oral compositions containing bisphosphonic acid antihypercalcemic agents
WO1997004752A1 (en) * 1995-07-26 1997-02-13 Duramed Pharmaceuticals, Inc. Pharmaceutical compositions of conjugated estrogens and methods for their use
AU729529B2 (en) 1997-06-06 2001-02-01 Depomed, Inc. Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs
PL337806A1 (en) 1997-07-01 2000-09-11 Pfizer Sertralin salts and sertalin dosage forms of prolonged release
US5895663A (en) 1997-07-31 1999-04-20 L. Perrigo Company Pseudoephedrine hydrochloride extended-release tablets
CA2211778A1 (en) * 1997-08-14 1999-02-14 Francois Carriere Preparation of pregelatinized high amylose starch and debranched starch useful as an excipient for controlled release of active agents
US6248358B1 (en) 1998-08-25 2001-06-19 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets and methods of making and using the same
US7153845B2 (en) 1998-08-25 2006-12-26 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets
US6624200B2 (en) 1998-08-25 2003-09-23 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets
DE69819748T2 (de) 1997-09-12 2004-09-30 Columbia Laboratories (Bermuda) Ltd. Arzneimittel zur behandlung von dysmenorrhöe und verfrühten wehen
GB9802201D0 (en) * 1998-02-03 1998-04-01 Cerestar Holding Bv Free-flowable directly compressible starch as binder,disintegrant and filler for compresion tablets and hard gelatine capsules
CN1292696A (zh) 1998-03-11 2001-04-25 史密丝克莱恩比彻姆有限公司 组合物
GB9812426D0 (en) 1998-06-10 1998-08-05 Reckitt & Colmann Prod Ltd Improvements in or relating to organic compositions
TW407058B (en) 1998-07-17 2000-10-01 Dev Center Biotechnology Oral cisapride dosage forms with an extended duration
DE19906290A1 (de) 1999-02-15 2000-08-17 Falk Pharma Gmbh Arzneimittel zur Behandlung bzw. Prävention von Darmkrebs
US7374779B2 (en) 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
EA200401009A1 (ru) * 1999-03-31 2004-12-30 Янссен Фармацевтика Н.В. Предварительно желатинированный крахмал в композиции с контролируемым высвобождением
DE19927688A1 (de) 1999-06-17 2000-12-21 Gruenenthal Gmbh Mehrschichttablette zur Verabreichung einer fixen Kombination von Tramadol und Diclofenac
HUP0201623A3 (en) 1999-07-01 2004-12-28 Upjohn Co Use of (s,s)reboxetine a selective norepinephrine reuptake inhibitor for the preparation of pharmaceutical compositions treating disorders of the nervous system
AP2002002410A0 (en) 1999-08-04 2002-03-31 Ranbaxy Laboratories Ltd Hydrodynamically Balancing Oral Drug Delivery System
US6387403B1 (en) 1999-09-15 2002-05-14 Alza Corporation Dosage forms and methods for providing effective reboxetine therapy with once-a-day dosing
CA2384840A1 (en) 1999-09-30 2001-04-05 The General Hospital Corporation Use of pramipexole as a treatment for cocaine craving
NZ519466A (en) * 1999-12-22 2004-02-27 Pharmacia Corp Sustained-release formulation of a cyclooxygenase-2 inhibitor
US6467637B2 (en) 2000-01-27 2002-10-22 The York Group, Inc. Death care merchandising system
CN1660435A (zh) 2000-02-24 2005-08-31 法玛西雅厄普约翰美国公司 新的药物联合形式
ES2187249B1 (es) 2000-09-18 2004-09-16 Synthon Bv Procedimiento para la preparacion de 2-amino-6-(alquil)amino-4,5,6,7-tetrahidrobenzotiazoles.
SE0004671D0 (sv) 2000-12-15 2000-12-15 Amarin Dev Ab Pharmaceutical formulation
DE10138275A1 (de) 2001-08-10 2003-02-27 Boehringer Ingelheim Pharma Verbindungen zur Beseitigung der Anhedonie
BR0215262A (pt) 2001-12-20 2004-12-28 Pharmacia Corp Formas de dosagem com liberação sustentada de ordem zero e processo para a fabricação das mesmas
AU2003261223A1 (en) 2002-07-25 2004-02-16 Pharmacia Corporation Method of preparing solid dosage forms coated in two layers comprising a water-insoluble polymer and a water-soluble pore former
MY136318A (en) 2002-07-25 2008-09-30 Pharmacia Corp Sustained-release tablet composition
MY142204A (en) 2002-07-25 2010-10-29 Pharmacia Corp Pramipexole once-daily dosage form
US20050226926A1 (en) 2002-07-25 2005-10-13 Pfizer Inc Sustained-release tablet composition of pramipexole
US20040121010A1 (en) 2002-10-25 2004-06-24 Collegium Pharmaceutical, Inc. Pulsatile release compositions of milnacipran
WO2004080440A1 (en) 2003-03-11 2004-09-23 Korea United Pharm, Inc. Process for the preparing of hardcapsule formulation containing lansoprazole
CA2520321A1 (en) 2003-04-04 2004-10-14 Pharmacia Corporation Oral extended release compressed tablets of multiparticulates
US20050020589A1 (en) 2003-06-18 2005-01-27 Pfizer Inc. Sustained-release tablet composition comprising a dopamine receptor agonist
EA200700388A1 (ru) 2004-08-13 2007-08-31 Бёрингер Ингельхайм Интернациональ Гмбх Композиция пеллеты пролонгированного высвобождения, содержащая прамипексол или его фармацевтически приемлемую соль, способ её изготовления и её применение
JP4757872B2 (ja) 2004-08-13 2011-08-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング プラミペキソール又はその医薬品として許容される塩を含む放出が延長された錠剤調合物、その製造方法及びその使用
WO2006046256A1 (en) 2004-10-27 2006-05-04 Alembic Limited Extended release formulation of pramipexole dihydrochloride
WO2007002518A1 (en) 2005-06-23 2007-01-04 Spherics, Inc. Delayed release or extended-delayed release dosage forms of pramipexole
US20070148238A1 (en) 2005-06-23 2007-06-28 Spherics, Inc. Dosage forms for movement disorder treatment
AU2006279643B2 (en) 2005-08-15 2010-06-17 University Of Virginia Patent Foundation Neurorestoration with R(+) pramipexole
WO2007054976A2 (en) 2005-11-08 2007-05-18 Panacea Biotec Ltd. Lipid based controlled release pharmaceutical composition
WO2007090881A2 (en) 2006-02-10 2007-08-16 Boehringer Ingelheim International Gmbh Modified release formulation
WO2007090882A2 (en) 2006-02-10 2007-08-16 Boehringer Ingelheim International Gmbh Pharmaceutical extended release compositions comprising pramipexole
US20090098202A1 (en) 2006-02-10 2009-04-16 Boehringer Ingelheim International Gmbh Extended Release Formulation
EP1886665A1 (en) 2006-08-01 2008-02-13 Boehringer Ingelheim Pharma GmbH & Co. KG Gastro retentive delivery system

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US15735A (en) * 1856-09-16 Improvement in harvesters
US2887440A (en) * 1957-08-12 1959-05-19 Dow Chemical Co Enteric coating
US4731374A (en) * 1984-12-22 1988-03-15 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
US5472712A (en) * 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5656296A (en) * 1992-04-29 1997-08-12 Warner-Lambert Company Dual control sustained release drug delivery systems and methods for preparing same
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US6197339B1 (en) * 1997-09-30 2001-03-06 Pharmacia & Upjohn Company Sustained release tablet formulation to treat Parkinson's disease
US6056977A (en) * 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
US20030180352A1 (en) * 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6277875B1 (en) * 2000-07-17 2001-08-21 Andrew J. Holman Use of dopamine D2/D3 receptor agonists to treat fibromyalgia

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060281797A1 (en) * 2001-12-11 2006-12-14 University Of Virginia Patent Foundation Neurorestoration with R(+) Pramipexole
US20070105918A1 (en) * 2001-12-11 2007-05-10 University Of Virginia Patent Foundation Use of Pramipexole to Treat Amyotrophic Lateral Sclerosis
US8399016B2 (en) 2002-07-25 2013-03-19 Boehringer Ingelheim International Gmbh Sustained-release tablet composition of pramipexole
US20050175691A1 (en) * 2002-07-25 2005-08-11 Lee Ernest J. Pramipexole once-daily dosage form
US8377977B2 (en) 2004-08-13 2013-02-19 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20060198887A1 (en) * 2004-08-13 2006-09-07 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US8715728B2 (en) 2004-08-13 2014-05-06 Boehringer Ingelheim International Gmbh Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20060051419A1 (en) * 2004-08-13 2006-03-09 Boehringer Ingelheim International Gmbh Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US7695734B2 (en) 2004-08-13 2010-04-13 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20090182024A1 (en) * 2004-08-13 2009-07-16 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20090281153A1 (en) * 2004-08-13 2009-11-12 Boehringer Ingelheim International Gmbh Extended Release Tablet Formulation Containing Pramipexole or a Pharmaceutically Acceptable Salt Thereof
US20060051417A1 (en) * 2004-08-13 2006-03-09 Boehringer Ingelheim International Gmbh Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20100086589A1 (en) * 2004-08-13 2010-04-08 Thomas Friedl Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20110218222A1 (en) * 2005-08-15 2011-09-08 University Of Virginia Patent Foundation Neurorestoration with r(+) pramipexole
US20080234338A1 (en) * 2005-08-15 2008-09-25 University Of Virginia Patent Foundation Neurorestoration With R(+) Pramipexole
US20110195122A1 (en) * 2006-02-10 2011-08-11 Boehringer Ingelheim International Gmbh Extended Release Formulation
US20110150994A1 (en) * 2006-02-10 2011-06-23 Boehringer Ingelheim International Gmbh Modified Release Formulation
US20070259930A1 (en) * 2006-04-10 2007-11-08 Knopp Neurosciences, Inc. Compositions and methods of using r(+) pramipexole
US8518926B2 (en) 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole
US8445474B2 (en) 2006-05-16 2013-05-21 Knopp Neurosciences, Inc. Compositions of R(+) and S(−) pramipexole and methods of using the same
US8017598B2 (en) 2006-05-16 2011-09-13 Knopp Neurosciences, Inc. Compositions of R(+) and S(−) pramipexole and methods of using the same
US20080014259A1 (en) * 2006-05-16 2008-01-17 Knopp Neurosciences, Inc. Compositions of R(+) and S(-) Pramipexole and Methods of Using the Same
US20080176913A1 (en) * 2006-06-29 2008-07-24 Arnaud Grenier Transdermal compositions of pramipexole having enhanced permeation properties
US8524695B2 (en) * 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same
US20080227985A1 (en) * 2007-03-14 2008-09-18 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazoles
US10179774B2 (en) 2007-03-14 2019-01-15 Knopp Biosciences Llc Synthesis of chirally purified substituted benzothiazole diamines
US8519148B2 (en) 2007-03-14 2013-08-27 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazole diamines
US20100092554A1 (en) * 2007-04-24 2010-04-15 Boehringer Ingelheim International Gmbh Combination with an extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
WO2008129043A1 (en) * 2007-04-24 2008-10-30 Boehringer Ingelheim International Gmbh Combination with an extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
US20080299189A1 (en) * 2007-06-04 2008-12-04 Drugtech Corporation Controlled release dopamine agonist compositions
US20090304794A1 (en) * 2008-06-09 2009-12-10 Supernus Pharmaceuticals, Inc. Controlled release formulations of pramipexole
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
US20110009460A1 (en) * 2009-06-19 2011-01-13 Valentin Gribkoff Compositions and methods for treating amyotrophic lateral sclerosis
WO2011002891A1 (en) * 2009-07-02 2011-01-06 Supernus Pharmaceuticals, Inc. A method of treatment of a neurological disorder
US20110003870A1 (en) * 2009-07-02 2011-01-06 Supernus Pharmaceuticals, Inc. Method of treatment of a neurological disorder
WO2011037976A3 (en) * 2009-09-22 2011-08-25 Dr. Reddy's Laboratories Limited Pramipexole pharmaceutical formulations
WO2011148243A1 (en) 2010-05-24 2011-12-01 Lupin Limited Extended release formulation of pramipexole
KR101307334B1 (ko) 2010-07-02 2013-09-12 주식회사 바이오파마티스 프라미펙솔 또는 이의 약학적으로 허용되는 염을 포함하는 안정성이 개선된 서방형 약학 조성물
WO2012002644A3 (en) * 2010-07-02 2012-04-12 Hyundai Pharm Co., Ltd. Sustained-release pharmaceutical composition containing pramipexole or pharmaceutically acceptable salt thereof with improved stability
US10208003B2 (en) 2011-12-22 2019-02-19 Knopp Biosciences Llc Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10285981B2 (en) 2013-02-28 2019-05-14 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9956206B2 (en) 2013-02-28 2018-05-01 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10828284B2 (en) 2013-07-12 2020-11-10 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10383856B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US10980783B2 (en) 2013-07-12 2021-04-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US11026928B2 (en) 2013-07-12 2021-06-08 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US11612589B2 (en) 2013-07-12 2023-03-28 Areteia Therapeutics, Inc. Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US12138249B2 (en) 2013-07-12 2024-11-12 Areteia Therapeutics, Inc. Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US10028940B2 (en) 2013-08-13 2018-07-24 Knopp Biosciences Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US10195183B2 (en) 2013-08-13 2019-02-05 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US10456381B2 (en) 2013-08-13 2019-10-29 Knopp Biosciences Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US9763918B2 (en) 2013-08-13 2017-09-19 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria

Also Published As

Publication number Publication date
KR100712832B1 (ko) 2007-04-30
CR7661A (es) 2005-06-08
AR040681A1 (es) 2005-04-13
SI1531814T1 (sl) 2008-12-31
AP2201A (en) 2011-01-24
EP1531814A1 (en) 2005-05-25
DK1531814T3 (da) 2008-10-13
GEP20074048B (en) 2007-02-26
HRP20041235A2 (en) 2005-06-30
DE60323235D1 (de) 2008-10-09
CN1671382A (zh) 2005-09-21
AP2005003205A0 (en) 2005-03-31
ZA200500439B (en) 2006-08-30
CY1110408T1 (el) 2015-04-29
ES2310673T3 (es) 2009-01-16
IL166078A0 (en) 2006-01-15
UY27912A1 (es) 2004-02-27
MEP52308A (en) 2011-02-10
PL375696A1 (en) 2005-12-12
KR20050062516A (ko) 2005-06-23
RS20050059A (en) 2007-08-03
EA200500079A1 (ru) 2005-06-30
ECSP055568A (es) 2005-04-18
AU2003261241A1 (en) 2004-02-16
PE20040130A1 (es) 2004-03-06
CN1313092C (zh) 2007-05-02
TW200418523A (en) 2004-10-01
NO334298B1 (no) 2014-01-27
HK10777456A1 (en) 2007-11-30
WO2004010997A8 (en) 2005-02-24
CU23440B7 (es) 2009-10-16
CA2492854C (en) 2009-10-20
OA13303A (en) 2007-04-13
US8399016B2 (en) 2013-03-19
WO2004010997A1 (en) 2004-02-05
JP4700963B2 (ja) 2011-06-15
HRP20041235B1 (hr) 2013-07-31
PT1531814E (pt) 2008-10-29
MY138846A (en) 2009-07-31
ATE406162T1 (de) 2008-09-15
EP1531814B1 (en) 2008-08-27
EP1987832A1 (en) 2008-11-05
NZ537790A (en) 2005-10-28
AU2003261241B2 (en) 2009-06-18
RS51719B (sr) 2011-10-31
PA8578301A1 (es) 2004-07-20
IS7623A (is) 2004-12-29
BR0312960A (pt) 2005-06-14
EA200702187A1 (ru) 2008-06-30
MXPA05001054A (es) 2005-04-08
JP2005538106A (ja) 2005-12-15
CA2492854A1 (en) 2004-02-05
TWI347849B (en) 2011-09-01
EA009663B1 (ru) 2008-02-28
MA27328A1 (fr) 2005-05-02
NO20050093L (no) 2005-02-24
US20100316710A1 (en) 2010-12-16
PL215587B1 (pl) 2013-12-31

Similar Documents

Publication Publication Date Title
US8399016B2 (en) Sustained-release tablet composition of pramipexole
US8679533B2 (en) Pramipexole once-daily dosage form
US20050020589A1 (en) Sustained-release tablet composition comprising a dopamine receptor agonist
HK1078007B (en) Pramipexole once-daily dosage form

Legal Events

Date Code Title Description
AS Assignment

Owner name: PHARMACIA CORPORATION, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:AMIDON, GREGORY;GANORKAR, LOKSIDH D.;HEIMLICH, JOHN M.;AND OTHERS;REEL/FRAME:014584/0655;SIGNING DATES FROM 20030930 TO 20031006

AS Assignment

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH,GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PHARMACIA CORPORATION;REEL/FRAME:024073/0169

Effective date: 20100205

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PHARMACIA CORPORATION;REEL/FRAME:024073/0169

Effective date: 20100205

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION