EP2136638A1 - Modifizierte freisetzungsformulierungen von (6r)-4,5,6,7-tetrahydro-n6-propyl-2,6-benzothiazoldiamin und verwendungsverfahren - Google Patents

Modifizierte freisetzungsformulierungen von (6r)-4,5,6,7-tetrahydro-n6-propyl-2,6-benzothiazoldiamin und verwendungsverfahren

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Publication number
EP2136638A1
EP2136638A1 EP08743922A EP08743922A EP2136638A1 EP 2136638 A1 EP2136638 A1 EP 2136638A1 EP 08743922 A EP08743922 A EP 08743922A EP 08743922 A EP08743922 A EP 08743922A EP 2136638 A1 EP2136638 A1 EP 2136638A1
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EP
European Patent Office
Prior art keywords
composition
rppx
tetrahydro
milligrams
benzothiazole
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Withdrawn
Application number
EP08743922A
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English (en)
French (fr)
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EP2136638A4 (de
Inventor
Michael E. Bozik
Valentin Gribkoff
Thomas Petzinger, Jr.
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Knopp Neurosciences Inc
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Knopp Neurosciences Inc
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Priority claimed from US11/957,157 external-priority patent/US8518926B2/en
Application filed by Knopp Neurosciences Inc filed Critical Knopp Neurosciences Inc
Publication of EP2136638A1 publication Critical patent/EP2136638A1/de
Publication of EP2136638A4 publication Critical patent/EP2136638A4/de
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/41—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • 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 compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole with a chiral carbon at the 6 position and that exists as a pair of optical enantiomers depending on whether the 6-propylamino group is in the S(-) or R(+) orientation.
  • Each is able to confer clinical neuroprotection in patients by accumulating in the cells of the brain and the spinal cord and, more specifically, in the mitochondria of these cells where they exert a dopamine independent effect on neurological function, presumably through inhibition of lipid peroxidation, normalization of mitochondrial metabolism and/or detoxification of oxygen radicals.
  • these compounds may have utility as inhibitors of the cell death cascades and loss of cell viability observed in neurodegenerative diseases.
  • the maximum allowable single starting dose for Mirapex ⁇ (an immediate release composition) is 0.125 mg, given three times a day (t.i.d.); and the maximum allowable dose for Mirapex is 1.5 mg ti.d., providing a maximum daily dose of 4.5 mg of Mirapex ® after 7-8 weeks of titration.
  • Embodiments of the present invention are generally in the field of modified release formulations of pramipexole, particularly RPPX and pharmaceutically acceptable salts thereof. Such modified release formulations may be useful in treating neurodegenerative disorders.
  • the present invention unlocks the therapeutic potential of RPPX by achieving clinically purified RPPX and determining the actual in vitro and in vivo binding affinity and tolerance of a patient to purified RPPX.
  • larger doses of RPPX can be administered to a patient in need thereof.
  • the present invention further provides a method of treating neurodegenerative disease in a patient in need thereof, comprising administering to the patient a daily dose amount of about 25 mgs to about 5,000 mgs of RPPX, more preferably about 500 mgs to about 2,100, most preferably above 500 mgs and less than 2,100 mgs of RPPX on a daily basis, preferably in a modified release formulation of RPPX.
  • the disease to be treated is acute and in others it is chronic.
  • the chronic neurodegenerative disease is selected from primary neurodegenerative disease, Huntington's Chorea, metabolically induced neurological damage, senile dementia of Alzheimer's type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy, and chronic encephalitis.
  • the chronic neurodegenerative disease is amyotrophic lateral sclerosis.
  • the patient is a na ⁇ ve patient.
  • Modified release compositions containing RPPX are described herein.
  • the compositions can be formulated to comprise the R(+) enantiomer of pramipexole substantially free of the S(-) enantiomer.
  • the modified release formulations may provide sustained plasma levels of pramipexole over an extended time period.
  • Substantially free of PPX refers to a pramipexole formulation wherein greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, greater than 99.9%, preferably greater than 99.95%, and more preferably greater than 99.99% of the pramipexole molecules are RPPX, or the R(+) enantiomer.
  • Figure 1 depicts the mean plasma RPPX concentrations after oral administration of single immediate release 50 mg, 150 mg, and 300 mg doses to healthy volunteers under fasted conditions.
  • Figure 2 depicts mean plasma RPPX concentrations after oral administration of single immediate release 150 mg doses to healthy volunteers under fasted and fed conditions.
  • Figure 3 depicts mean plasma RPPX concentrations on Days 1 and 7 during oral administration of immediate release 50 mg and 100 mg doses on Day 1 , Q12H on Days 3 through 6, and a single dose on Day 7 to healthy volunteers under fasted conditions.
  • Figure 4 depicts an exposure (AUC) vs. dose (mg/m 2 ) for male and female rats and humans (both genders),
  • Figure 5 depicts mean exposure (AUC) vs. dose (mg/m 2 ) for male and female minipigs and humans (both genders).
  • Figure 6 depicts the predicted steady-state plasma concentrations of the oral administration of an exemplary 300 mg modified-release formulation once daily.
  • Figure 7 depicts the predicted in vivo release profile of the oral administration of an exemplary 300 mg modified-release formulation once daily.
  • the present invention provides evidence that the dopamine receptor affinity of RPPX is actually much lower than that previously assumed, which greatly increases the clinical usefulness of the composition. It is also demonstrated herein that the functional affinity difference between the PPX and RPPX enantiomers ⁇ e.g. 10,000-20,000 fold) is much greater than previously reported. These data demonstrate that RPPX can be dosed at levels that can more fully and unexpectedly exploit the lower-potency neuroprotective potential of the compound without the theoretical limitation imposed by the assumptions about separation in dopamine receptor affinity between the enantiomers. This dosing may occur without the need for dose titration.
  • the present invention provides a modified release pharmaceutical composition
  • a modified release pharmaceutical composition comprising RPPX of a sufficient dose to achieve neuroprotective, anti-oxidative, anti-apoptotic, or other beneficial cellular effects without simultaneously causing significant side effects, especially those related to dopaminergic activity.
  • the ability to deliver clinically effective doses without dose limiting side effects is made possible by two basic discoveries: (i) the synthesis of RPPX that is pure within limits of the detection discussed herein; and (ii) the discovery that RPPX possesses substantially less affinity for dopamine receptors than previously reported.
  • the modified release pharmaceutical composition of the present invention may be dependent, in some embodiments, on either or both the optical purity of the RPPX used in the composition and upon the limited dopaminergic activity of the chirally pure RPPX used in the composition.
  • the compound 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is a synthetic aminobenzothiazole derivative, having two enantiomers with the structures shown below.
  • the (S) enantiomer is a potent agonist of the D ? family of dopamine receptors, with particular affinity for the Dj receptor subtype.
  • PPX activates dopamine receptors, thus mimicking the effects of the neurotransmitter dopamine.
  • the PPX stereoisomer is a potent agonist of dopamine, with only small daily doses required and indeed tolerated by patients.
  • Both enantiomers are thought to confer neuroprotective effects by their ability to accumulate in the brain, the spinal cord and mitochondria, and by normalization of mitochondrial function and/or detoxification of oxygen radicals independent of the dopamine agonist activity, presumably through inhibition of lipid peroxidation .
  • these compounds may have utility as inhibitors of the cell death cascades and loss of cell viability observed in neurodegenerative diseases.
  • the degree to which dosing of a molecule has demonstrable phenotypic activity resulting from affinity to particular receptors or other pharmaco -effective proteins, even when the activity results from affinities to unknown targets, can be operationally defined in terms of whether this activity contributes in a positive way ('on-target' activity) or a negative way ('off-target' activity) to a specific and desired therapeutic effect.
  • a number of 'off-target' activities can theoretically be identified, but On- target' activity is restricted to the desired therapeutic effect.
  • an index of activity can be generated for each of these categories (the 'activity equivalent 1 , or AE), and one or more ratios generated to compare 'off-target' to 'on-target' activities, useful to compare potential risk-benefit ratios between molecules.
  • DAE dopaminergic activity equivalent
  • a dosage of RPPX having a DAE of 0.01 would have activity at the dopamine receptors which is equivalent to the activity of 0.01 mg of PPX.
  • the DAE can also be related to a variety of pharmaceutical terms, including maximum tolerated dose (MTD), no observable adverse effect level (NOAEL), and non-effective dose amount for the sake of clarity.
  • MTD maximum tolerated dose
  • NOAEL no observable adverse effect level
  • non-effective dose amount for PPX in an IMMEDIATE RELEASE is most preferably below 0.05 mg. This, in turn, corresponds to a DAE of below 0.05.
  • a dose amount of RPPX having a DAE of 0.01 would, therefore, be below the DAE for the most preferable PPX NOAEL dose amount of 0.05 mg.
  • DAE is determined by measuring the binding affinity (IC50) or activity (EC 50 ) at the D 2 and/or Dj receptors relative to the same parameter for 1 mg of PPX. In some embodiments, DAE is determined by the binding affinity or activity at the Dj receptor. In some embodiments, DAE is determined by the binding affinity or activity at the D 3 receptor. In some embodiments, DAE is determined by the binding affinity at the D 2 receptor, In some embodiments, DAE is determined by the binding affinity at the D 3 receptor. In some embodiments, DAE is determined by a suitable in vitro assay such as an IC 50 binding affinity assay for the D 2 or D 3 receptor, including those described by Schneider, C.
  • IC50 binding affinity
  • EC 50 activity
  • the other activity of RPPX and PPX is neuroprotection.
  • Neuroprotection is a phenomenon independent of mechanism, and hence qualifies as a category of activity.
  • This 'on-target' activity of RPPX for the treatment of neurodegenerative disorders is measurable and approximately equivalent in both enantiomers, and can be defined in relative terms as the neuroprotective activity equivalent or NAE.
  • the neuroprotective activity equivalent (NAE) refers to the neuroprotective activity inherent in 1 mg of PPX. Unlike the DAE, NAE has been shown to be equal in both enantiomers in a number of in vitro tests.
  • the DAE is seen as a unit measure of the potential for adverse effects, while the NAE is seen as a unit measure of the potential for therapeutic benefit.
  • the NAEs of both RPPX and Mirapex® may be determined from the concentrations needed to produce neuroprotection in in vitro assays.
  • NAE can be determined by measuring the neuroprotective activity in a standard in vitro neuroprotective assay relative to the activity of 1 mg of PPX.
  • the neuroprotective activity is determined by measuring cell death in the presence of MPP+ and/or rotenone in dopaminergic and/or non- dopaminergic cells (as a non-limiting example, see the assay in M. Gu, Journal of Neurochemistry, 91 : 1075- 1081 (2004)),
  • a preferred intent of the present invention is to maximize the NAE's delivered to a patient, while minimizing the number of activity equivalents suggestive of adverse events, in this case the DAE.
  • PPX has a high DAE/NAE ratio, due to the high dopamine affinity, while the corresponding ratio for RPPX is significantly lower.
  • the embodiments of the present invention provide significantly greater NAE levels and greater NAE/DAE levels than previously could have been predicted, maximizing the probability that a therapeutically effective dose amount of the neuroprotectant can be administered to a patient in need.
  • the NAE and the DAE may be useful in terms of a ratio, particularly as a ratio of beneficial to adverse effects, and useful to define a range over which a particular composition may be administered.
  • NOAEL dose amount refers to an amount of active compound or pharmaceutical agent that produces no statistically or biologically significant increases in the frequency or severity of adverse effects between an exposed population and its appropriate control; some effects may be produced at this level, but they are not considered as adverse, or as precursors to adverse effects.
  • the exposed population may be a system, tissue, animal, individual or human that is being treated by a researcher, veterinarian, medical doctor or other clinician.
  • exemplary adverse events are dizziness, hallucination, nausea, hypotension, somnolence, constipation, headache, tremor, back pain, postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilatation, flu syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritis, hypokinesia, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, tinnitus, lacrimation, mydriasis and diplopia.
  • a immediate release dose of 1.5 mg of PPX has been shown to cause somnolence in human subjects (Public Statement on Mirapex®, Sudden Onset of Sleep from the European Agency for the Evaluation of Medicinal Products; Boehringer Ingelheim product insert for Mirapex® which indicates that the drug is administered as three doses per day).
  • studies performed in dogs, as presented herein, indicate that the NOAEL immediate release dose may be as low as 0.00125 mg/kg, which is equivalent to a human dose of 0.0007 mg/kg or 0.05 mg for a 70 kg individual.
  • a NOAEL immediate release dose amount may be an amount below 1.5 mg, below 0.50 mg, or more preferably below 0,05 mg.
  • a NOAEL dose may have a DAE of below 1.5, below 0.5, or more preferably below 0.05.
  • a NOAEL dose amount may be an amount below 3.0mg, below 1.5 mg or more preferably below 0.15mg. (0032]
  • an amount larger than the non-effective dose amount of PPX is necessary to have a therapeutic effect in treating diseases alleviated by dopamine agonist activity. This amount, however, may not be desired when a neuroprotective effect is sought, as it may lead to the described adverse side effects.
  • non-effective dose amount refers to an amount of active compound or pharmaceutical agent that elicits a biological or medicinal response similar to the biological or medicinal response of a placebo as observed in a tissue, system, animal, individual or human that is being treated by a researcher, veterinarian, medical doctor or other clinician.
  • a “non-effective dose amount” may therefore elicit no discernable difference from placebo in positive effects as observed in a tissue, system, animal, individual or human that is being treated by a researcher, veterinarian, medical doctor or other clinician.
  • the "non-effective dose amount" is not expected to (1) prevent a disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibit the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology), or (3) ameliorate the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or reducing the pathology and/or symptomatology).
  • the lowest effective oral immediate release dose of PPX with a significant effect versus placebo in the treatment of Parkinson's disease was found to be 1.1 mg/day. Individual patients may need doses higher than 1.1 mg/day to gain a sufficient effect above the placebo effect (Initial Scientific Discussion for the Approval of Mir apex from the European Agency for the Evaluation of Medicinal Products).
  • the lowest effective dose with a significant effect versus placebo in the treatment of restless legs syndrome was found to be 0.25 mg/day (Boehringer Ingelheim product insert for Mirapex®).
  • a non-effective dose amount may be an amount below 1.0 mg/day, below 0.75 mg/day, below 0.5 mg/day, below 0,25 mg/day, or preferably below 0.125 mg/day.
  • a non-effective dose amount per day may have a DAE per day below 1.0, below 0.75, below 0.5, below 0.25, or preferably below 0.125.
  • MRTD maximum recommended therapeutic dose
  • MRTD refers to the dosages compiled by the FDA's Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Informatics and Computational Safety Analysis Staffs Maximum Recommended Therapeutic Dose and as described in Matthews, et al., "Assessment of the Health Effects of Chemicals in Humans: I. QSAR Estimation of the Maximum Recommended Therapeutic Dose (MRTD) and No Effect Level (NOEL) of Organic Chemicals Based on Clinical Trial Data," Current Drug Discovery Technologies, 2004, 1:61-76).
  • the FDA's MRTD database cites a MRTD for PPX of 0.1 mg/kg/day or 7.0 mg/day for a 70 3b. person.
  • Matthews estimates that a NOEL (no adverse effect level) usually is about one-tenth of the MRTD, which corresponds to 0.01 mg/kg or about 0.7 mg/day for a 70 Ib. person.
  • PPX must be titrated over the course of weeks to reach these dosages without dose limiting adverse effects (such as that documented in Boehringer lngelheim product insert for Mirapex®).
  • the recommended starting daily dose amount of Mirapex® which is an immediate release composition, is 0.125 mg taken once daily 2-3 hours before bedtime.
  • the daily dose may be increased to 0.25 mg over 4 to 7 day period and then to 0.5 mg over a second 4 to 7 day period.
  • the package insert recommends the following titration schedule for Mirapex®:
  • a “maximum tolerated dose” refers to an amount of active compound or pharmaceutical agent which elicits significant toxicity in a tissue, system, animal, individual or human that is being treated by a researcher, veterinarian, medical doctor or other clinician.
  • Single dose toxicity of PPX after oral administration has been studied in rodents, dogs, monkeys and human. Ln rodents, deaths occurred at immediate release doses of 70-105 mg/kg and above (Initial Scientific Discussion for the Approval of Mirapex from the European Agency for the Evaluation of Medicinal Products).
  • a human dose of 7-12 mg/kg, or approximately 500-850 mg for a 70 kg individual In human subjects, a starting daily dose of PPX of greater than 0.20 mg was not tolerated when administered to a naive patient. In dogs, vomiting occurred at 0,0007 mg/kg and above while monkeys displayed major excitation at 3.5 mg/kg. Further, the product insert for Mirapex® sets the maximally tolerated dose for humans at 4.5 mg/day, administered as three 1.5 mg single dosages. However, the 4.5 mg/day dosage is not administered to a naive patient, but, instead, reached after a titration regimen (such as that documented in the product insert for Mirapex®).
  • the starting daily dosage for administration to a naive patient is a 0.125 mg immediate release dose administered three times per day and a seven-week titration schedule is recommended to reach a 1.5 mg dose administered three times daily.
  • All species showed signs of toxicity related to exaggerated pharmacodynamic responses to PPX. For example, behavioral changes including hyperactivity were common and led to a number of secondary effects, such as reduced body weight and other stress-induced symptoms.
  • PPX moderately affected cardiovascular parameters.
  • the potent prolactin-inhibitory effect of pramipexole affected reproductive organs e.g.
  • MTD amount of PPX for a human subject may be an amount below 4.5 mg/day, preferably below 1.5 mg/day. Further, the MTD amount for a human subject may be an amount below 0.3 mg/immedtate release dose based on results of studies disclosed herein, and preferably below 0.2 mg/immedtate release dose (see Table 11). With reference to DAE, the MTD amount may have a DAE of below 1.5, 0,9 and 0.6.
  • the NOAEL dose amount for PPX is below 4.5 mg, preferably below 1.50 mg, or more preferably below 0.15 mg, which are each equivalent to DAE, DAE, and DAE, respectively.
  • a ER dosage of 50 mg with a DAE of 5.55 when referring solely to the literature derived comparative binding affinity ratios.
  • use of a high chiral purity of 99,95% as used in these theoretical dosages would result in unacceptably high DAE of 5.55 the daily dosage MTD DAE of 4,5 mg, and far beyond the preferable NOAELs of 1.5 DAE and 0.15 DAE.
  • an aspect of the present invention involves unexpectedly high chiral purities that have been attained. These purities have led to MTDs or NOAELs for RPPX which are higher than previously appreciated based on the literature derived comparative binding affinities.
  • the present invention provides modified release pharmaceutical compositions, starting doses, method of treatment, and kits comprising RPPX of high chiral purity. Pursuant the discussion above, a 50 mg modified release dosage with a similar chiral purity of 99.95% would be predicted to be well above the MTD or NOAEL for PPX and, therefore, result in observable adverse side effects.
  • the present invention further provides modified release pharmaceutical compositions, starting doses, methods, and kits comprising RPPX with higher dosages and higher chiral purities.
  • RPPX comparative binding affinity ratios at the D 2 and D 3 receptors were approximately 9 to 21, and 50, respectively (See Example 1 and Table 10 below). It has been unexpectedly found that the comparative binding affinity ratios of PPX:RPPX at the D 2 and D3 receptors are approximately 290 and 649, when using high chiral purity RPPX.
  • Table 1 attempts to illustrate the importance of both purity and affinity on even a 25 mg single oral dosage. Assumptions regarding dopaminergic activity of the RPPX at the dopamine receptors would seemingly preclude even a high purity (even 100% pure) 25 mg RPPX tablet. Based upon the disclosure of the present invention one can immediately envisage numerous tables to illustrate the point. Tables IA and IB below are intended to illustrate the importance of purity for a single oral dosage form of RPPX by illustrating the impact of even the smallest contamination of the composition by PPX
  • Table 2 shows DAE as a function of a dosage of RPPX (left hand column) and the comparative ratio (top row).
  • a unit dose can be chosen which allows for an amount of RPPX having DAE which is equal to the non-effective amount of PPX. Indeed, unless a dual DAE/NAE effect is desired, a DAE would be avoided or minimized in a pharmaceutical composition. Thus, any ER dose greater than 50 milligrams would not be expected to avoid off-target activity and would be expressly avoided by one skilled in the art. This is not true if, as in present invention, the comparative ratios exceed 200. This is best illustrated by Table 2.
  • Table 4 shows DAE as a function of a dosage of RPPX (left hand column) and the comparative ratio (top row).
  • a unit dose can be chosen which allows a dose amount of RPPX having a particular DAE.
  • the term “comparative binding affinity ratio” refers to the binding affinity at the D 2 or D 3 dopamine receptors (IC50 value) of RPPX divided by the binding affinity at the D 2 or D 3 dopamine receptors (IC50 value) of PPX.
  • the comparative binding affinity ratio refers to the ratio of the IC5 0 values at the D 2 receptor.
  • the comparative binding affinity ratio refers to the ratio of the IC 50 values at the D 3 receptor.
  • the term "comparative ratio” refers one of the following: 1) the ratio of the IC 50 values at the D 2 or D 3 receptors for RPPX to PPX; 2); the ratio of MTD amounts for RPPX to PPX; or 3) the ratio of NOAEL dose amounts for RPPX to PPX.
  • controlled release refers to a dosage form that release drug at a controlled rate over an extended period of time, preferably more than about 12 hours, more preferably about 24 hours.
  • the term "daily dose amount” refers to the amount of drug per day that is administered or prescribed to a patient. This amount can be administered in multiple unit doses or in a single unit dose, in a single time during the day or at multiple times during the day. Preferably, the daily dose amount is administered in a modified release pharmaceutical composition.
  • DAE dopaminergic activity equivalent
  • a "dose amount” as used herein is generally equal to the dosage of the active ingredient which may be administered once per day, or may be administered several times a day (e.g. the unit dose is a fraction of the desired daily dose).
  • a non-effective dose amount of 0.5 mg/day of PPX may be administered as 1 dose of 0.5 mg, 2 doses of 0.25 mg each or 4 doses of 0.125 mg.
  • the term "unit dose” as used herein may be taken to indicate a discrete amount of the therapeutic composition which comprises a predetermined amount of the active compound.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which may be administered once per day, or may be administered several times a day (e.g.
  • the unit dose is a fraction of the desired daily dose).
  • the unit dose may also be taken to indicate the total daily dose, which may be administered once per day or may be administered as a convenient fraction of such a dose (e.g. the unit dose is the total daily dose which may be given in fractional increments, such as, for example, one-half or one-third the dosage).
  • the terms “enantiomers”, “stereoisomers” and “optical isomers” may be used interchangeably, and refer to molecules which contain an asymmetric or chiral center and are non-superimposable mirror images of one another.
  • the term “chirally pure” or “enantiomerically pure” may be taken to indicate that the compound contains at least 99.95% of a single optical isomer.
  • the term “enantiomerically enriched”, unless a number is mentioned, may be taken to indicate that at least 51% of the material is a single enantiomer.
  • enantiomeric enrichment refers to an increase in the amount of one enantiomer as compared to the other.
  • a “racemic” mixture is a mixture of equal amounts of (R)- and (S)-enantiomers of a chiral molecule.
  • Extended release and/or sustained release refers to a dosage form that releases a drug (or drugs) over an extended period of time such that the frequency of administration may be reduced as compared to immediate release dosage forms, particularly a dosage form that allows at least a twofold reduction in dosing frequency of a drug as compared to that drug presented as a conventional dosage form (e.g. as a solution or prompt drug-releasing, conventional solid dosage form).
  • an extended release dosage form may release the drug over a period of time of about more than 12 hours, preferably about 24 hours. Extended release is used interchangeably herein with sustained release and slow release.
  • a “kit” refers to one or more pharmaceutical compositions and instructions for administration or prescription of the one or more compositions.
  • the instructions may consist of product insert, instructions on a package of one or more pharmaceutical compositions, or any other instruction.
  • Mirapex ® refers to tablets containing pramipexole dihydrochloride, which has the chemical name, (S)-2 ⁇ amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole dihydrochloride monohydrate.
  • Modified release refers to a dosage form for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms.
  • Modified release of active ingredient(s) allows simplification of the patient's administration scheme by reducing the amount of recommended daily intakes, improves patient's compliance, and attenuates adverse events, e.g., related to high plasma peaks.
  • Modified release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise formulations with a controlled, a prolonged, a sustained, a slow or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms.
  • the modified release formulations are capable of release a therapeutically effective amount of the drug, RPPX, over an extended period of time, preferably about more than twelve hours, more preferably about twenty-four hours.
  • Controlled release, extended release, and sustained release dosage forms and their combinations are types of modified release dosage forms. Unless otherwise indicated all such terms are used interchangeably.
  • the term "na ⁇ ve patient” refers to a patient that has not previously received treatment (either RPPX or PPX) or who has not received a titration regimen previous to receiving a starting dose.
  • the term “neuroprotectant” refers to any agent that may prevent or slow the progression of neuronal degeneration and/or may prevent neuronal cell death.
  • the term “patient” and “subject” are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention.
  • the terms “patient” and “subject” may include, but is not limited to, any non-human mammal, primate or human.
  • the "patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
  • the patient or subject is an adult, child or infant.
  • the patient or subject is a human.
  • the term "pharmaceutically acceptable salt” is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by-reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • non-aqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., p. 704 (2000) and Berge el ai (1977) J. Pharm. Sciences, VoI 6. 1-19.
  • composition shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • RPPX refers the (R)-enantiomer of pramipexole, or its pharmaceutically acceptable salt thereof, preferably the R(+) enantiomer of pramipexole, or pharmaceutically acceptable salt thereof.
  • RPPX can also include the hydrate of the (R)- enantiomer of pramipexole, or pharmaceutically acceptable salt thereof.
  • RPPX is RPPX dihydrochloride monohydrate.
  • PPX refers to pramipexole, which is an (S)- enantiomer, or pharmaceutically acceptable salt thereof
  • 11 PPX can also include the hydrate of pramipexole, or pharmaceutically acceptable salt thereof.
  • the term "salt" of the RPPX as used herein is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesuifonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or p- toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt.
  • halogenic acid salts
  • starting daily dose amount refers to the amount of pramipexole per day that is administered or prescribed to a patient beginning pramipexole treatment, who has not previously been subjected to a titration regimen of pramipexole. This amount can be administered in multiple unit doses or in a single unit dose, in a single time during the day or at multiple times during the day.
  • Therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or reducing the pathology and/
  • treating may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and/or prevention of the symptoms associated with a specific disorder, disease or condition.
  • the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition.
  • the term refers to slowing the progression of the disorder, disease or condition.
  • the term refers to alleviating the symptoms associated with the specific disorder, disease or condition.
  • the term refers to restoring function which was impaired or lost due to a specific disorder, disease or condition.
  • Trituration may be taken to indicate a method of solidifying a chemical compound. Trituration involves agitating the compound by stirring, beating or a method of the like until the chemical compound forms a crystalline solid or precipitate. This solid may act to seed the remaining chemical compound in solution, causing it to precipitate or crystallize from solution.
  • the present invention provides a modified release pharmaceutical composition comprising RPPX.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • the amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 ,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day. In some embodiments, amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day.
  • the amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the dosage may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1 ,000 mg.
  • the amount of RPPX in the modified release compositions may be about from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1,000 mg.
  • the amount of RPPX is from about 600 mg to about 900 mg.
  • these doses may be administered in a modified release pharmaceutical composition that provides release of a dose of RPPX over preferably more than about twelve hours, and more preferably about twenty-four hours,
  • the amount of RPPX is from about 50 mg to about 5000 mg.
  • the amount of RPPX is from about 100 mg to about 3000 mg.
  • the amount of RPPX is from about 300 mg to about 1500 mg.
  • the amount of RPPX is from about 500 mg to about 1000 mg.
  • the modified release composition is suitable for oral administration.
  • the modified release composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the modified release composition has a chiral purity for RPPX of 99.9% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.95% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.99% or greater.
  • the modified release composition is suitable for oral administration.
  • the modified release composition is a solid oral dosage form.
  • the modified release composition is a capsule.
  • the modified release composition is a tablet.
  • the present invention relates to modified release compositions which are chirally pure for RPPX.
  • the amount of RPPX may be from about 0,01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 1,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day.
  • the amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day.
  • the amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiment, the amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the dosage may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day, In some embodiments, the compositions are administered in doses of from about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, or from about 500 mg to about 1 ,000 mg of RPPX.
  • the modified release compositions are administered in doses of from 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1 ,000 mg, or from 450 mg to about 1,000 mg of RPPX.
  • the amount of RPPX is from about 600 mg to about 900 mg.
  • these doses may be administered in a modified release pharmaceutical composition that provides release of the dose of RPPX over preferably more than twelve hours, and more preferably at least about twenty- four hours.
  • These doses preferably are in preparations which have a chemical purity of 97% or greater and a chiral purity for RPPX of 99.6% or greater, 99.7% or greater, 99.8% or greater, 99.9% or greater, preferably 99.95% or greater and more preferably 99.99% or greater.
  • the modified release compositions may have a chiral purity for RPPX of 100%.
  • the modified release compositions may further comprise a carrier.
  • modified release compositions of the present invention may be administered orally, preferably as a solid oral dose, and more preferably as a solid oral dose that may be a capsule or tablet.
  • the modified release compositions of the present invention may be formulated as tablets for oral administration.
  • the present invention further provides a modified release composition comprising a therapeutically effective amount of RPPX.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 0.1 mg/kg/day to about 1,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day.
  • the therapeutically effective amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day.
  • the therapeutically effective amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiment, the therapeutically effective amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the dosage may be 10 mg/day to 1 ,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the therapeutically effective amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1 ,000 mg.
  • the therapeutically effective amount of RPPX in the modified release compositions may be about from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1 ,000 mg, or from 450 mg to about 1,000 mg.
  • the amount of RPPX is from about 600 mg to about 900 mg.
  • these doses may be administered in a modified release pharmaceutical composition that provides release of a dose of RPPX over preferably more than about twelve hours, and more preferably about twenty-four hours.
  • the therapeutically effective amount of RPPX is from about 50 mg to about 5000 mg.
  • the therapeutically effective amount of RPPX is from about 100 mg to about 3000 mg.
  • the therapeutically effective amount of RPPX is from about 300 mg to about 1500 mg.
  • the therapeutically effective amount of RPPX is from about 500 mg to about 1000 mg.
  • the modified release composition is suitable for oral administration.
  • the modified release composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the modified release composition has a chiral purity for RPPX of 99.9% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.95% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.99% or greater.
  • the modified release composition is suitable for oral administration, In some embodiments, the modified release composition is a solid oral dosage form. In some embodiments, the modified release composition is a capsule. In some embodiments, the modified release composition is a tablet.
  • the present invention provides a modified release composition consisting essentially of a therapeutically effective amount of RPPX, wherein the chiral purity for the RPPX is 99.9%, or greater. In some embodiments, the chiral purity for RPPX is 99.95% or greater. In some embodiments, the chiral purity for RPPX is 99.99% or greater. In some embodiments, the chiral purity for RPPX is 100%.
  • the modified release composition is suitable for oral administration.
  • the modified release composition is a solid oral dosage form.
  • the modified release composition is a capsule, hi some embodiments, the modified release composition is a tablet.
  • the present invention further provides a modified release composition comprising a therapeutically effective amount of RPPX and a non-effective dose amount of PPX.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • the amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 0.1 mg/kg/day to about 1,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 ,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day. In some embodiments, the amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day.
  • the amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the dosage may be 10 mg/day to 1 ,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1,000 mg.
  • the amount of RPPX in the modified release compositions may be about from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1 ,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1,000 mg.
  • these doses may be administered in a modified release pharmaceutical composition that provides release of a dose of RPPX over preferably more than about twelve hours, and more preferably about twenty-four hours.
  • the amount of RPPX is from about 50 mg to about 5000 mg. In some embodiments, the amount of RPPX is from about 100 mg to about 3000 mg. In some embodiments, the amount of RPPX is from about 300 mg to about 1500 mg. hi some embodiments, the amount of RPPX is from about 500 mg to about 1000 mg. In some embodiments, the amount of RPPX is from about 600 mg to about 900 mg.
  • the modified release composition is suitable for oral administration. In some embodiments, the composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the modified release composition has a chiral purity for RPPX of 99.9% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.95% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.99% or greater.
  • the non-effective dose amount of PPX is an amount that does not exceed about 1.0 mg. In more preferred embodiments, the non-effective dose amount of PPX is an amount that does not exceed about 0.75 mg, about 0.5 mg, about 0,25 mg, or about 0.125 mg. In some embodiments, the non-effective dose amount of PPX is less than about 0.125 mg.
  • the modified release composition is suitable for oral administration.
  • the modified release composition is a solid oral dosage form.
  • the modified release composition is a capsule.
  • the modified release composition is a tablet.
  • the present invention provides a modified release pharmaceutical composition
  • a modified release pharmaceutical composition comprising a therapeutically effective amount of RPPX and a non-effective dose amount of PPX administered in a unit dose form.
  • Preferable unit dose forms include those suitable for oral administration, including but not limited to, capsules, tablets and the like.
  • Table 5 shows various exemplary embodiments. Shown in each column of Table 5 is the amount of PPX that may be co-administered in a non-effective dose amount as a function of the chiral purity of the composition for the (R)-enantiomer of pramipexole.
  • the therapeutically effective amount of RPPX may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1 ,500 mg, from about 500 mg to about 1 ,000 mg. In some embodiments, therapeutically effective amount of RPPX may be about from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 nig, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1 ,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1 ,
  • the non-effective dose amount of PPX may be preferably below 1.0 mg/day, below 0.5 mg/day, and below 0.125 mg/day.
  • a dose of 500 mg/day administered to a patient as a single unit dose may have a chiral purity for the R(+) enantiomer of pramipexole of at least about 99.80% so that the non-effective dose amount of PPX may remain below 1.0 mg/day, more preferably about 99.90% so that the non-effective dose amount of PPX may remain below 0.5 mg/day, and more preferably about 99.975% so that the non-effective dose amount of PPX may remain below 0.125 mg/day.
  • any combination of chiral purity and unit dose may be used which allows for the desired combination of a therapeutically effective amount of RPPX and a non-effective dose amount of PPX as stated herein.
  • the modified release pharmaceutical composition is suitable for oral administration and comprises an amount of RPPX greater than 100 mg and a non-effective dose amount of PPX that is less than about 0.125 mg.
  • Another preferred embodiment is a modified release pharmaceutical composition suitable for oral administration comprising an amount of RPPX greater than 250 mg and a non-effective dose amount of PPX that is less than about 0.125 mg.
  • Yet another preferred embodiment of the invention is a modified release pharmaceutical composition suitable for oral administration comp ⁇ sing an amount of RPPX greater than 500 mg and a non-effective dose amount of PPX that is less than about 0 125 mg
  • Preferred modified release pharmaceutical compositions for oral administration include tablets, capsules and the like
  • the modified release pharmaceutical composition is formulated as a tablet suitable for oral administration and comprises an amount of RPPX greater than 50 mg and a non-effective dose amount of PPX that is less than about 0 50 mg, preferably an amount of RPPX greater than 100 mg and a non-effective dose amount of PPX that is less than about 0 50 mg, and more preferably an amount of RPPX greater than 250 mg and a non-effective dose amount of PPX that is less than about 0.50 mg
  • Another preferred embodiment is a modified release pharmaceutical composition formulated as a tablet suitable for oral administration comprising an amount of RPPX greater than 500 mg and a noneffective dose amount of PPX that is less than about 0 50 mg.
  • Another embodiment of the invention is a modified release pharmaceutical composition formulated as a tablet suitable for oral administration comprising an amount of RPPX greater than 50 mg and a non-effective dose amount of PPX that is less than about 0.25 mg, preferably an amount of RPPX greater than 100 mg and a non-effective dose amount of PPX that is less than about 0.25 mg, and more preferably an amount of RPPX greater than 250 mg and a non-effective dose amount of PPX that is less than about 0.25 mg.
  • Another preferred embodiment is a modified release pharmaceutical composition formulated as a tablet suitable for oral administration comprising an amount of RPPX greater than 500 mg and a non-effective dose amount of PPX that is less than about 0.25 mg.
  • the present invention provides a modified release composition comprising a therapeutically effective amount of RPPX and a no observable adverse effect level (NOAEL) dose amount of PPX.
  • the therapeutic composition may further comprise a pharmaceutically acceptable carrier.
  • the amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 0.1 mg/kg/day to about 1,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 ,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day. In some embodiments, the amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day.
  • the amount of PvPPX may be from about 3 mg/kg/day to about 50 mg/kg/day- In some embodiments, the dosage may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about LOOO mg.
  • the amount of RPPX in the modified release compositions may be about from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1 ,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1,000 mg.
  • the amount of RPPX is from about 600 mg to about 900 mg. In some embodiments, the amount of RPPX is from about 50 mg to about 5000 mg. In some embodiments, the amount of RPPX is from about 100 mg to about 3000 mg. In some embodiments, the amount of RPPX is from about 300 mg to about 1500 mg. In some embodiments, the amount of RPPX is from about 500 mg to about 1000 mg. In some embodiments, the composition is suitable for oral administration. In some embodiments, the modified release composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the modified release composition has a chiral purity for RPPX of 99,9% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.95% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.99% or greater.
  • the no observable adverse effect level dose amount of PPX is less than about 4.50 mg. In some embodiments, the no observable adverse effect level amount of PPX is less than about 0.15 mg. In some embodiments, the no observable adverse effect level amount of PPX is less than about 0.15 mg.
  • the modified release composition is suitable for oral administration, hi some embodiments, the modified release composition is a solid oral dosage form. In some embodiments, the modified release composition is a capsule. In some embodiments, the modified release composition is a tablet.
  • the present invention provides a modified release pharmaceutical composition comprising a therapeutically effective amount of RPPX and a NOAEL dose amount of PPX administered in a unit dose form.
  • Preferable unit dose forms include those suitable for oral administration, including but not limited to, capsules, tablets and the like.
  • Table 6 shows various exemplary embodiments. Shown in each column of Table 6 is the amount of PPX that may be co-administered in a NOAEL dose amount as a function of the chiral purity of the modified release composition for the R(+) enantiomer of pramipexole.
  • the therapeutically effective amount of RPPX may preferably be about 50 mg to about 5,000 mg, preferably from about 100 mg to about 3,000 mg, preferably from about 300 mg to about 1 ,500 mg, more preferably from about 500 mg to about 1 ,000 mg. In some embodiments, therapeutically effective amount of RPPX may be about from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 tng, from about 200 mg to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1
  • the NOAEL dose of PPX may be preferably below 4.5 mg, preferably below 1.5 mg, or more preferably below 0.15 mg.
  • an embodiment of the invention may be a dose of 1,500 mg/day administered to a patient as a single unit dose which may have a chiral purity for the R(+) enantiomer of pramipexole that is at least about 99.967% so that the non-adverse dose of PPX may remain below 0.50 mg/dose.
  • a dose of 1,500 mg/day administered to a patient as three individual doses of 500 mg may have a chiral purity of the RPPX that is at least about 99.90% so that the non- adverse dose of PPX may remain below 0.50 mg/dose or 1.5 mg/day.
  • the embodiments for the therapeutically effective amount of RPPX, the NOAEL dose amount of PPX, and the chiral purity embodiments listed herein may be combined in any suitable combination. With reference to Table 6, any combination of chiral purity and unit dose may be used which allows for the desired combination of a therapeutically effective amount of RPPX and a non- adverse effect dose amount of PPX as stated herein,
  • the modified release pharmaceutical composition is formulated as a tablet suitable for oral administration and comprises an amount of RPPX greater than 50 mg and a NOAEL dose amount of PPX that is less than about 0.15 mg, preferably an amount of RPPX greater than 100 mg and a NOAEL dose amount of PPX that is less than about 0 15 mg, and more preferably an amount of RPPX greater than 250 mg and a NOAEL dose amount of PPX that is less than about 0 15 mg
  • the modified release pharmaceutical composition is formulated as a tablet suitable for oral administration and comprises an amount of RPPX greater than 500 mg and a NOAEL dose amount of PPX that is less than about 0,15 mg.
  • the present invention provides a modified release composition for use as a neuroprotectant comprising a therapeutically effective amount of RPPX and a therapeutically effective amount of PPX.
  • the modified release composition may further comprise a pharmaceutically acceptable carrier.
  • the modified release composition may be useful in the treatment of diseases which may be alleviated by the action of a neuroprotectant.
  • An additional embodiment of the invention is a therapeutic composition for use as a neuroprotectant comprising a therapeutically effective amount of RPPX and a therapeutically effective amount of PPX.
  • the modified release composition may further comprise a pharmaceutically acceptable carrier.
  • the therapeutic composition may be useful in the treatment of diseases related to neuronal degeneration or neuronal cell death.
  • the modified release compositions of RPPX may be used to restore or improve neuronal, retinal and muscle function in adults and children. Further, the compositions of RPPX may be used to treat neurodegenerative diseases, or other diseases associated with mitochondrial dysfunction or increased oxidative stress. In some embodiments, the compositions of RPPX may treat neurodegenerative dementias, neurodegenerative movement disorders and ataxias, seizure disorders, motor neuron disorders or diseases, and inflammatory demyelinating disorders in adults and children. The compositions of the present invention may also be useful in the treatment of other disorders not listed herein, and any listing provided in this invention is for exemplary purposes only and is non-limiting.
  • the modified release compositions which comprise RPPX may be effective as inhibitors of oxidative stress, inhibitors of lipid peroxidation, in the detoxification of oxygen radicals, and the normalization of mitochondrial function.
  • Oxidative stress may be caused by an increase in oxygen and other free radicals, and has been associated with the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS).
  • ALS is a progressive neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. About 10% of all ALS patients are familial cases, of which 20% have mutations in the superoxide dismutase 1 (SOD-I) gene.
  • the SOD-I enzyme may play a pivotal role in the pathogenesis and progression of familial amyotrophic lateral sclerosis (FALS). Recent studies also link the premature neuronal death associated with ALS to mutated mitochondrial genes which lead to abnormalities in functioning of the energy production pathways in mitochondria.
  • FALS familial amyotrophic lateral sclerosis
  • Modified release compositions which comprise RPPX may also be effective in the treatment of age related macular degeneration.
  • an embodiment of the invention may be a modified release composition comprising RPPX suitable for systemic administration, ocular administration or topical administration to the eye.
  • the neuroprotective effect of the modified release compositions of the present invention may derive at least in part from the ability of the (R)-enantiomer of pramipexole to prevent neural cell death by at least one of three mechanisms.
  • the (R)- enantiomer of pramipexole may be capable of reducing the formation of reactive oxygen species in cells with impaired mitochondrial energy production.
  • the (R)-enantiomer of pramipexole may partially restore the reduced mitochondrial membrane potential that has been correlated with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
  • the (R)-enantiomer of pramipexole may block the cell death pathways which are produced by pharmacological models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis diseases and mitochondrial impairment.
  • the modified release compositions of these several embodiments which comprise RPPX as an active agent may be effective as inhibitors of oxidative stress, inhibitors of lipid peroxidation, in the detoxification of oxygen radicals, and the normalization of mitochondrial function. Further, they may be effective as treatment for impaired motor function, and in degenerative diseases that may affect cardiac and striated muscle and retinal tissues, As such, they may be effective in the treatment of neurodegenerative diseases such as ALS, Parkinson's disease and Alzheimer's disease, and macular degeneration.
  • Another embodiment of the invention is a modified release composition consisting essentially of a therapeutically effective amount of RPPX and a non-effective dose amount of PPX.
  • Another embodiment of the invention is a modified release composition consisting essentially of a therapeutically effective amount of RPPX and a NOAEL dose amount of PPX.
  • Another embodiment of the invention is a modified release composition consisting of a therapeutically effective amount of RPPX and a non-effective dose amount of PPX.
  • Such compositions may preferably be therapeutic or pharmaceutical compositions.
  • Another embodiment of the invention is a modified release composition consisting of a therapeutically effective amount of RPPX and a NOAEL dose amount of PPX.
  • Such compositions may preferably be therapeutic or pharmaceutical compositions.
  • the present invention provides a modified release tablet comprising at least about 100 mg of RPPX and no more than about 4.5 mg of PPX.
  • the tablet comprises about 150 mg of RPPX.
  • the tablet comprises about 200 mg of RPPX.
  • the tablet comprises about 250 mg of RPPX.
  • the tablet comprises about 500 mg of RPPX.
  • the tablet comprises about 1000 mg of RPPX.
  • the tablet comprises no more than 3.0 mg of PPX.
  • the tablet comprises no more than 0.1 mg of PPX.
  • the tablet comprises no more than 0.9 mg of PPX.
  • the tablet comprises no more than 0.6 mg of PPX. Ln some embodiments, the tablet comprises no more than 0.375 mg of PPX.
  • the tablet further comprises a pharmaceutically acceptable carrier.
  • the modified release tablet comprises about 150 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the tablet comprises about 150 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the tablet comprises about 150 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the tablet comprises about 150 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the tablet comprises about 150 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release tablet comprises about 200 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the tablet comprises about 200 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the tablet comprises about 200 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the tablet comprises about 200 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the tablet comprises about 200 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release tablet comprises about 250 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the tablet comprises about 250 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the tablet comprises about 250 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the tablet comprises about 250 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the tablet comprises about 250 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release tablet comprises about 500 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the tablet comprises about 500 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the tablet comprises about 500 mg of RPPX and no more than about 0,9 mg of PPX. In some embodiments, the tablet comprises about 500 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the tablet comprises about 500 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release tablet comprises about 1000 mg of RPPX and no more than about 3.0 mg of PPX.
  • the tablet comprises about 1000 mg of RPPX and no more than about 0.1 mg of PPX.
  • the tablet comprises about 1000 mg of RPPX and no more than about 0.9 mg of PPX.
  • the tablet comprises about 1000 mg of RPPX and no more than about 0.6 mg of PPX.
  • the tablet comprises about 1000 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release tablet may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the tablet has a chiral purity for RPPX of 99.9% or greater.
  • the tablet has a chiral purity for RPPX of 99.95% or greater, hi some embodiments, the tablet has a chiral purity for RPPX of 99.99% or greater.
  • the present invention provides a modified release capsule comprising at least about 100 mg of RPPX and no more than about 4.5 mg of PPX.
  • the capsule comprises about 150 mg of RPPX.
  • the capsule comprises about 200 mg of RPPX.
  • the capsule comprises about 250 mg of RPPX.
  • the capsule comprises about 500 mg of RPPX.
  • the capsule comprises about 1000 mg of RPPX.
  • the capsule comprises no more than 3.0 mg of PPX.
  • the capsule comprises no more than 0.1 mg of PPX.
  • the capsule comprises no more than 0.9 mg of PPX.
  • the capsule comprises no more than 0.6 mg of PPX.
  • the capsule comprises no more than 0.375 mg of PPX.
  • the capsule further comprises a pharmaceutically acceptable carrier.
  • the modified release capsule comprises about 150 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the capsule comprises about 150 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the capsule comprises about 150 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the capsule comprises about 150 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the capsule comprises about 150 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release capsule comprises about 200 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the capsule comprises about 200 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the capsule comprises about 200 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the capsule comprises about 200 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the capsule comprises about 200 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release capsule comprises about 250 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the capsule comprises about 250 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the capsule comprises about 250 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the capsule comprises about 250 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the capsule comprises about 250 mg of RPPX and no more than about 0.375 mg of PPX. f 00123] In some embodiments, the modified release capsule comprises about 500 mg of RPPX and no more than about 3.0 mg of PPX.
  • the capsule comprises about 500 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the capsule comprises about 500 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the capsule comprises about 500 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the capsule comprises about 500 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release capsule comprises about 1000 mg of RPPX and no more than about 3.0 mg of PPX. In some embodiments, the capsule comprises about 1000 mg of RPPX and no more than about 0.1 mg of PPX. In some embodiments, the capsule comprises about 1000 mg of RPPX and no more than about 0.9 mg of PPX. In some embodiments, the capsule comprises about 1000 mg of RPPX and no more than about 0.6 mg of PPX. In some embodiments, the capsule comprises about 1000 mg of RPPX and no more than about 0.375 mg of PPX.
  • the modified release capsule may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the capsule has a chiral purity for RPPX of 99.9% or greater.
  • the capsule has a chiral purity for RPPX of 99.95% or greater.
  • the capsule has a chiral purity for RPPX of 99.99% or greater.
  • the present invention provides a modified release pharmaceutical composition comprising at least about 25 mg of RPPX and less than about 4.5 dopaminergic activity equivalents ("DAE").
  • DAE dopaminergic activity equivalents
  • RPPX as a function of a particular chiral purity of the RPPX in the dose and the comparative binding affinity ratio.
  • the modified release pharmaceutical composition comprises less than about 1.5 dopaminergic activity equivalents (DAE). In some embodiments, the modified release pharmaceutical composition comprises less than about 0.15 dopaminergic activity equivalents. These DAE values are derived from the no observable adverse effect levels of RPPX as discussed herein. In some embodiments, the composition has a DAE which is less than the DAE as calculated from the MTD amount or non-effective dose amounts of PPX. With reference to non-effective dose amounts of PPX, in some embodiments, the DAE does not exceed about 1.0, does not exceed about 0.75, does not exceed about 0.5, does not exceed about 0,25, or does not exceed about 0.125. With reference to MTD amount, the modified release composition may have a DAE of below 4,5, below 0.9, or below 0.6.
  • the modified release pharmaceutical composition comprises at least about 50 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 75 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 125 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 150 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 200 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 250 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 300 mg of RPPX. In some embodiments, the pharmaceutical composition comprises at least about 400 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 500 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 50 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 75 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 125 mg of RPPX. In some embodiments, the modified
  • release pharmaceutical composition comprises at least about 600 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 750 mg of RPPX. In some embodiments, the modified release pharmaceutical composition comprises at least about 1000 mg of RPPX.
  • the modified release composition is suitable for oral administration.
  • the composition is a solid oral dosage form.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is a capsule.
  • the amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 ,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day.
  • the amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day, In some embodiment, the amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day, In some embodiments, the dosage maybe 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1,000 mg.
  • the amount of RPPX in the modified release compositions may be from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1,000 mg, In some embodiments, the amount of RPPX is from about 600 mg to about 900 mg.
  • the amount of RPPX is from about 50 mg to about 5000 mg. In some embodiments, the amount of RPPX is from about 100 mg to about 3000 mg. In some embodiments, the amount of RPPX is from about 300 mg to about 1500 mg. In some embodiments, the amount of RPPX is from about 500 mg to about 1000 mg. In some embodiments, the composition is suitable for oral administration. In some embodiments, the composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%,
  • the modified release composition has a chiral purity for RPPX of 99.9% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.95% or greater.
  • the modified release composition has a chiral purity for RPPX of 99.99% or greater.
  • the present invention provides a starting daily dose of RPPX of at least about 25 mg of RPPX.
  • the starting daily dose comprises at least about 50 mg of RPPX.
  • the starting daily dose comprises at least about 75 mg of RPPX.
  • the starting daily dose comprises at least about 125 mg of RPPX.
  • the starting daily dose comprises at least about 350 mg of RPPX.
  • the starting daily dose comprises at least about 200 mg of RPPX.
  • the starting daily dose comprises at least about 300 mg of RPPX.
  • the starting daily dose comprises at least about 400 mg of RPPX.
  • the starting daily dose comprises at least about 500 mg of RPPX. In some embodiments, the starting daily dose comprises at least about 600 mg of RPPX. In some embodiments, the starting daily dose comprises at least about 750 mg of RPPX. In some embodiments, the starting daily dose comprises at least about 1000 mg of RPPX. In some embodiments, the starting daily dose comprises from about 600 mg to about 900 mg of RPPX.
  • the starting daily dose amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 0.1 mg/kg/day to about 1,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the starting daily dose amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day.
  • the starting daily dose amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiment, the starting daily dose amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the starting daily dose amount may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the starting daily dose amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1,000 mg.
  • the starting daily dose amount of RPPX in the modified release compositions may be about from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1 ,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1 ,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1,000 mg.
  • the starting daily dose amount of RPPX is from about 600 mg to about 900 mg. In some embodiments, the starting daily dose amount of RPPX is from about 50 mg to about 5000 mg. In some embodiments, the starting daily dose amount of RPPX is from about 100 mg to about 3000 mg. In some embodiments, the starting daily dose amount of RPPX is from about 300 mg to about 1500 mg. In some embodiments, the starting daily dose amount of RPPX is from about 500 mg to about 1000 mg.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the composition has a chiral purity for RPPX of 99.9% or greater.
  • the composition has a chiral purity for RPPX of 99.95% or greater.
  • the composition has a chiral purity for RPPX of 99.99% or greater.
  • the modified release composition is suitable for oral administration, ⁇ n some embodiments, the composition is a solid oral dosage form. In some embodiments, the pharmaceutical composition is a tablet, In some embodiments, the pharmaceutical composition is a capsule.
  • the present invention provides a modified release pharmaceutical formulation comprising microcrystalline cellulose in an amount from about 20% to about 50% by weight of said formulation; mannito! in about from about 10% to about 30% by weight of said formulation; crospovidone in an amount from about 2% to about 6% of said formulation; magnesium stearate in an amount from about 0.01% to about 2% of said composition; and RPPX.
  • the modified release pharmaceutical composition comprises a diluent in an amount from about 20% to about 50% by weight of said formulation; optionally, a second diluent in an amount from about 10% to about 30% by weight of said formulation; optionally, a disintegrant in an amount from about 2% to about 6% of said formulation; optionally, a lubricant in an amount from about 0.01% to about 2% of said composition; and RPPX.
  • the modified release pharmaceutical composition comprises microcrystalline cellulose, mannito], croscarmellose sodium, magnesium stearate, or combination thereof.
  • the pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol or combination thereof; and further optionally comprises croscarmellose sodium or magnesium stearate, or combination thereof.
  • the modified release formulation may have a chiral purity for RPPX of at least 99.5%, preferably at least 99,6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the formulation has a chiral purity for RPPX of 99.9% or greater.
  • the formulation has a chiral purity for RPPX of 99.95% or greater.
  • the formulation has a chiral purity for RPPX of 99.99% or greater.
  • the amount of RPPX in the modified release formulation may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1,000 mg.
  • the starting daily dose amount of RPPX in the formulation may be from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 nig to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1 ,000 mg, from about 250 mg to about 1 ,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1 ,000 mg, from about 600
  • the present invention provides a modified release pharmaceutical composition
  • a modified release pharmaceutical composition comprising a pharmaceutical composition comprising microcrystalline cellulose in an amount from about 20% to about 50% by weight of said composition; mannitol in an amount from about 10% to about 30% by weight of said composition; crospovidone in an amount from about 2% to about 6% of said composition; magnesium stearate in an amount from about 0.01% to about 2% of said composition; and RPPX.
  • the modified release composition is suitable for oral administration.
  • the composition is a solid oral dosage form.
  • the modified release composition may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95%, or more preferably at least 99.99%.
  • the chiral purity for RPPX is 100%.
  • the composition has a chiral purity for RPPX of 99.9% or greater.
  • the composition has a chiral purity for RPPX of 99.95% or greater.
  • the composition has a chiral purity for RPPX of 99.99% or greater.
  • the amount of RPPX in the modified release compositions may preferably be about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, from about 500 mg to about 1,000 mg.
  • the starting daily dose amount of RPPX in the modified release compositions may be about from about 25 mg to about 5,000 mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg, to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1 ,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 3,000 mg,
  • the amount of RPPX is from about 600 mg to about 900 mg.
  • the present invention further provides modified release pharmaceutical compositions comprising RPPX having about 25 neuroprotective activity equivalents and less than about 4.5 dopaminergic activity equivalents.
  • the modified release pharmaceutical composition has less than about 1.5 dopaminergic activity equivalents, hi some embodiments, the modified release pharmaceutical composition has less than about 0.15 dopaminergic activity equivalents.
  • the modified release pharmaceutical composition has at least about 50, at least about 75, at least about 125, at least about 150, at least about 200, at least about 300, at least about 400, at least about 500, at least about 750, at least about 750, or at least about 100 neuroprotective activity equivalents, hi some embodiments, the modified release pharmaceutical composition has from about 50 to about 5,000, from about 100 to about 3,000, from about 300 to about 1,500, from about 500 to about 1,000, from about 25 to about 5,000, from about 100 to about 5,000, from about 200 to about 5,000, from about 250 to about 5,000, from about 300 to about 5,000, from about 400 to about 5,000, from 450 to about 5,000, from about 200, to about 3,000, from about 250 to about 3,000, from about 300 to about 3,000, from about 400 to about 3,000, from 450 to about 3,000, from about 100 to about 1,000, from about 200 to about 1,000, from about 250 to about 1,000, from about 300 to about 1,000, from about 400 to about 1,000, from
  • the modified release pharmaceutical composition has from about 50 to about 5,000 neuroprotective activity equivalents; and less than from about 1.5 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 100 to about 3,000 neuroprotective activity equivalents; and less than from about 1.5 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 200 to about 3,000 neuroprotective activity equivalents; and less than from about 1.5 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 300 to about 1,500 neuroprotective activity equivalents; and less than from about 1.5 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 500 to about 1,000 neuroprotective activity equivalents; and less than from about 1.5 dopaminergic activity equivalents.
  • the pharmaceutical composition has about 50 to about 5,000 neuroprotective activity equivalents; and less than from about 0.15 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 100 to about 3,000 neuroprotective activity equivalents; and less than from about 0.15 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 200 to about 3,000 neuroprotective activity equivalents; and less than from about 0.15 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 300 to about 1,500 neuroprotective activity equivalents; and less than from about 0.15 dopaminergic activity equivalents. In some embodiments, the pharmaceutical composition has about 500 to about 1,000 neuroprotective activity equivalents; and less than from about 0.15 dopaminergic activity equivalents.
  • the modified release pharmaceutical composition is a solid oral dosage form.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is a capsule.
  • Extended Release Formulations Many active pharmaceutical agents, including drugs and prodrugs, have been formulated as orally deliverable dosage forms providing sustained release (otherwise known as slow release or extended release) of such agents over a period of time effective to permit once daily administration.
  • 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, often described 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.
  • the extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington-The Science and Practice of Pharmacy” (20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000).
  • a diffusion system typically consists of two types of devices, reservoir devices and matrix devices, both of which are well known and described in the art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • Plastic matrices include, but are not limited to, methyl acrylate-co-methyl methacrylate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and CARBOPOL 934, and polyethylene oxides.
  • Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form.
  • the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.
  • sustained-release oral dosage forms that provide drug release at a substantially constant release rate over an extended time period.
  • the plasma drug concentration initially ascends for a short period of time as drug release begins and then remains substantially constant over an extended time period as drug release continues at a constant rate.
  • this substantially constant plasma drug concentration correlates with substantially constant drug effectiveness over a prolonged therapy period, in addition, because an initial relatively high peak plasma drug concentration is avoided, side effects may be less of a problem. Accordingly, advantages of constant-release dosage forms include decreasing the number of doses of a drug that need to be administered over time and providing a better balance of desired and undesired pharmacological effects of the drug.
  • Osmotic dosage forms in particular, have been notably successful at providing constant-release of drugs over extended time periods.
  • Osmotic dosage forms in general, utilize osmotic pressure to generate a driving force for imbibing fluid into a compartment formed, at least in part, by a semipermeable wall that permits free diffusion of fluid but not drug or osmotic agent(s), if present.
  • a substantially constant rate of drug release can be achieved by designing the system to provide a relatively constant osmotic pressure and having suitable exit means for the drug formulation to permit the drug formulation to be released at a rate that corresponds to the rate of fluid imbibed as a result of the relatively constant osmotic pressure.
  • a significant advantage to osmotic systems is that operation is pH- independent and thus continues at the osmotically-determined rate throughout an extended time period even as the dosage form transits the gastrointestinal tract and encounters differing microenvironments having significantly different pH values.
  • osmotic devices comprising drug in a mixture with excipients, optionally including osmotically active component(s), within the compartment are known in the art. Although effective for many drugs, the release rate in these devices often declines over time and complete delivery of the drug load may not occur.
  • a more sophisticated type of osmotic device comprises two component layers within the compartment formed by the semipermeable wall. One component layer comprises drug in a mixture with excipients, optionally including osmotically active component(s), that will form a deliverable drug formulation within the compartment and the second component layer comprises osmotically active component(s) but does not contain drug.
  • the osmotically active component(s) in the second component layer typically comprise osmopolymerys) having relatively large molecular weights and which exhibit "swelling" as fluid is imbibed such that release of these components through the drug formulation exit means does not occur.
  • the second component layer is referred to as a "push" layer since, as fluid is imbibed, the osmopolymer(s) swell and push against the deliverable drug formulation of the first component layer to thereby facilitate release of the drug formulation at a substantially constant rate.
  • the devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units.
  • Examples of multiple units include multilayer tablets and capsules containing tablets, beads, granules, etc.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using coating or compression processes or in a multiple unit system, such as a capsule, containing extended and immediate release beads,
  • Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as any of many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders.
  • Extended release tablets containing wax materiais are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In a congealing method, the drug is mixed with a wax material and either spray-congealed or congealed, screened, and processed.
  • Transdermal dosage forms are particularly useful for timed-release and sustained-release of active agents.
  • Transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos.
  • transdermal dosage form is a diffusion-driven transdermal system (particularly in the form of a patch) using either a fluid reservoir or a drug-in-adhesive matrix system.
  • Other transdermal dosage forms include, but are not limited to, topical gels, lotions, ointments, transmucosal systems and devices, and iontophoretic (electrical-diffusion) delivery systems. See, for example, U.S. Pat. No. 4,626,539 to Aungst et al., which discloses a pharmaceutical composition purportedly useful for transdermal delivery of an opioid to a mammalian circulation system; U.S. Pat. No.
  • U.S. Pat. No. 5,804,215 to Cubbage et al. discloses a disposal system for a transdermal patch containing a medicament comprising an adhesive coated, flexible, tear-resistant substrate. The used transdermal patch allegedly adheres to the substrate in order to encapsulate and deter access to the transdermal patch. Rubber-based adhesives are disclosed as being preferred.
  • the modified release formulations may also be administered adjunctively with other active compounds such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics or other dopamine agonists, including but not limited to Requip IR (ropinirole), Stalevo (carbidopa, levodopa, entacapone), COMtan (entacapone), Eldepryyl (selegiline), Neupro (rotigotine), and Azilect (rasagaline), electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics.
  • active compounds such
  • the compounds of the present invention can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • adjunctive administration is meant simultaneous administration of the compounds, in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of the compounds.
  • a preferred method for preparing extended release tablets is by compressing a drug-containing blend, e.g., blend of granules, prepared using a direct blend, wet- granulation, or dry- granulation process.
  • Extended release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant.
  • tablets are preferably manufactured using compression rather than molding.
  • a preferred method for forming extended release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants.
  • a drug-containing blend may be prepared by using wet-granulation or dry-granulation processes.
  • Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
  • a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like.
  • the admixture is used to coat a bead core such as a sugar sphere (or so-called "non-pareil”) having a size of approximately 60 to 20 mesh.
  • An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolido ⁇ e, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads.
  • excipients such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolido ⁇ e, talc, magnesium stearate, a disintegrant, etc.
  • the present invention provides a method for treating a neurodegenerative disease by administering a therapeutically effective amount of RPPX.
  • the RPPX may be formulated as a modified release pharmaceutical or therapeutic composition by combining with one or more pharmaceutically acceptable carriers.
  • Embodiments include modified release pharmaceutical or therapeutic compositions that may be administered orally, preferably as a solid oral dose, and more preferably as a solid oral dose that may be a capsule or tablet.
  • the modified release pharmaceutical or therapeutic composition is formulated in tablet or capsule form for use in oral administration routes.
  • the compositions and amounts of non-active ingredients in such a formulation may depend on the amount of the active ingredient, and on the size and shape of the tablet or capsule. Such parameters may be readily appreciated and understood by one of skill in the art.
  • the therapeutically effective amount of RPPX may be effective as an inhibitor of oxidative stress, an inhibitor of lipid peroxidation or in detoxification of oxygen radicals, or as an inhibitor of cell death pathways.
  • the therapeutically effective amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 1,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day.
  • the therapeutically effective amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day, In some embodiments, the therapeutically effective amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiment, the therapeutically effective amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the dosage may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day.
  • the therapeutically effective amount of RPPX may be from about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, preferably from about 300 mg to about 1,500 mg, or more preferably from about 500 mg to about 1 ,000 mg.
  • the therapeutically effective amount of RPPX may be from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1 ,000 mg, from about 600 mg to about 1 ,000 mg, or from 450 mg to about 1,000 mg.
  • the therapeutically effective amount of RPPX is from about 600 mg to about 900 mg.
  • the embodiment may have a chira ⁇ purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95% and more preferably at least 99.99%.
  • the chiral purity for the R(+) enantiomer of pramipexole may be 100%.
  • the present invention further provides a method of treating an acute neurodegenerative disease in a patient in need thereof, comprising administering to the patient a daily dose amount of about 50 mg to about 5,000 mg of RPPX.
  • the present invention provides use of a daily dose amount of about 50 mg to about 5,000 mg of RPPX for the preparation of medicament for use in a method of treatment of an acute neurodegenerative disorder in a patient.
  • the present invention provides a daily dose amount of about 50 mg to about 5,000 mg of RPPX for use of in method of treatment of an acute neurodegenerative disorder in a patient.
  • the acute neurodegenerative disease is selected from stroke, neutrotauma, acute metabolic dysfunction, sequelae from cerebral seizure, status epilepticus, and acute encephalitis,
  • the patient is a naive patient.
  • the daily dose amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1 ,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the daily dose amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day.
  • the daily dose amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiment, the daily dose amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day, In some embodiments, the daily dose amount may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day. In some embodiments, the daily dose amount of RPPX is from about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1 ,500 mg, or from about 500 mg to about 1 ,000 mg.
  • the daily dose amount of RPPX is from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1 ,000 mg.
  • the daily dose amount of RPPX is from about 600 mg to about 900 mg. In some embodiments, the daily dose amount is from about 500 mg to about 1 ,000 mg of RPPX. In some embodiments, daily dose amount is from about 50 mg to about 5,000 mg of RPPX. In some embodiments, the daily dose amount is from about 100 mg to about 3,000 mg of RPPX. In some embodiments, daily dose amount is from about 200 mg to about 3,000 mg of RPPX. In some embodiments, daily dose amount is from about 300 mg to about 1,500 mg of RPPX, In some embodiments, daily dose amount is from about 500 mg to about 1 ,000 mg of RPPX.
  • the chiral purity for RPPX is 99.5%, or greater. In some embodiments, the chiral purity for RPPX is 99.6%, or greater. In some embodiments, the chirai purity for RPPX is 99.7%, or greater. In some embodiments, the chiral purity for RPPX is 99.8%, or greater. In some embodiments, the chiral purity for the RPPX is 99.9%, or greater. In some embodiments, the chiral purity for the RPPX is 99.95%, or greater. In some embodiments, the chiral purity for the RPPX is 99.99% or greater.
  • the daily dose amount further comprises a no observable adverse effect level amount of PPX.
  • the no observable effective dose amount of PPX is an below 4.5 mg, below 1.5 mg, or below 0.15 mg per day.
  • the daily dose amount further comprises a noneffective dose amount of PPX.
  • the non-effective dose amount of PPX is an amount that does not exceed a total dose of 1 ,0 mg per day.
  • the non-effective dose amount of PPX is an amount that does not exceed a total dose of 0.75 mg/day, 0.5 mg/day, 0.25 mg/day, or 0.125 mg/day.
  • the noneffective dose mount of PPX does not exceed a total dose of 0.125 mg/day.
  • the daily dose amount is about 100 mg to about 3,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 200 to about 3,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 300 to about 1 ,500 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 500 mg to about 1,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 100 mg to 3,000 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • the daily dose amount is from about 200 mg to about 3,000 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • the daily dose amount is from about 300 to about 1,500 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • JOOl 8Oj In some embodiments of the methods of the invention, the daily dose amount is from about 500 mg to about 1,000 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • the RPPX in each of the method embodiments described herein is administered as a modified release pharmaceutical composition.
  • the modified release pharmaceutical composition is a tablet.
  • the modified release pharmaceutical composition is a capsule.
  • the modified release pharmaceutical composition comprises a pharmaceutically acceptable carrier.
  • the present invention further provides a method of treating a chronic neurodegenerative disease in a patient in need thereof, comprising administering to the patient a daily dose amount of about 50 mg to about 5,000 mg of RPPX.
  • the present invention provides use of a daily dose amount of about 50 mg to about 5,000 mg of RPPX for the preparation of medicament for use in a method of treatment of a chronic neurodegenerative disorder in a patient.
  • the present invention provides a daily dose amount of about 50 mg to about 5,000 mg of RPPX for use of in method of treatment of a chronic neurodegenerative disorder in a patient.
  • the chronic neurodegenerative disease is selected from primary neurodegenerative disease, Huntington's Chorea, metabolically induced neurological damage, senile dementia of Alzheimer's type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, hepatic encephalopathy, and chronic encephalitis.
  • primary neurodegenerative disease Huntington's Chorea
  • metabolically induced neurological damage senile dementia of Alzheimer's type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral s
  • the patient is a naive patient.
  • the daily dose amount of RPPX may be from about 0.01 mg/kg/day to about 10,000 mg/kg/day, from about 1 mg/kg/day to about 1,000 mg/kg/day, from about 0.1 mg/kg/day to about 1,000 mg/kg/day, from about 1 mg/kg/day to about 1 ,000 mg/kg/day, from about 1,000 mg/kg/day to about 10,000 mg/kg/day, or from about 1 mg/kg/day to about 100 mg/kg/day. In some embodiments, the daily dose amount of RPPX may be from about 3 mg/kg/day to about 70 mg/kg/day. In some embodiments, the daily dose amount of RPPX may be from about 7 mg/kg/day to about 40 mg/kg/day.
  • the daily dose amount of RPPX may be from about 3 mg/kg/day to about 50 mg/kg/day. In some embodiments, the daily dose amount may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/day to 600 mg/day. In some embodiments, the daily dose amount of RPPX is from about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, from about 300 mg to about 1,500 mg, or from about 500 mg to about 1,000 mg.
  • the daily dose amount of RPPX is from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1 ,000 mg.
  • the daily dose amount of RPPX is from about 600 mg to about 900 mg. In some embodiments, the daily dose amount is from about 500 mg to about 1 ,000 mg of RPPX. In some embodiments, daily dose amount is from about 50 mg to about 5,000 mg of RPPX. In some embodiments, daily dose amount is from about 100 mg to about 3,000 mg of RPPX. In some embodiments, daily dose amount is from about 200 mg to about 3,000 mg of RPPX. In some embodiments, daily dose amount is from about 300 mg to about 1,500 mg of RPPX. In some embodiments, the daily dose amount is from about 500 mg to about 1,000 mg of RPPX.
  • the chiral purity for RPPX is 99.5%, or greater. In some embodiments, the chiral purity for RPPX is 99.6%, or greater. In some embodiments, the chiral purity for RPPX is 99.7%, or greater, In some embodiments, the chiral purity for RPPX is 99.8%, or greater. In some embodiments, the chiral purity for the RPPX is 99.9%, or greater. In some embodiments, the chiral purity for the RPPX is 99.95%, or greater. In some embodiments, the chiral purity for the RPPX is 99.99% or greater.
  • the daily dose amount further comprises a no observable adverse effect level amount of PPX.
  • the no observable effective dose amount of PPX is an below 4.5 mg, below 1,5 mg, or below 0.15 mg per day.
  • the daily dose amount farther comprises a noneffective dose amount of PPX.
  • the non-effective dose amount of PPX is an amount that does not exceed a total dose of 1.0 mg per day. In some embodiments, the non-effective dose amount of PPX is an amount that does not exceed a total dose of 0.75 mg/day, 0.5 mg/day, 0.25 mg/day, or 0.125 mg/day. In some embodiments, the noneffective dose mount of PPX does not exceed a total dose of 0.125 mg/day.
  • the daily dose amount is about 100 mg to about 3,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 200 to about 3,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 300 to about 1 ,500 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 500 mg to about 1 ,000 mg of RPPX and the chiral purity for the RPPX is 99.95% or greater.
  • the daily dose amount is from about 100 mg to 3,000 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • the daily dose amount is from about 200 mg to about 3,000 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX.
  • the daily dose amount is from about 300 to about 1,500 mg of RPPX and the daily dose amount further comprises less than about 0.05 mg of PPX. (00197 ⁇ In some embodiments of the methods of the invention, the daily dose amount is from about 500 mg to about 1,000 mg of RPPX and the daily dose amount fitrther comprises less than about 0.05 mg of PPX.
  • the RPPX in each of the method embodiments described herein is administered as a modified release pharmaceutical composition.
  • the modified release pharmaceutical composition is a tablet.
  • the modified release pharmaceutical composition is a capsule.
  • the modified release pharmaceutical composition comprises a pharmaceutically acceptable carrier.
  • the present invention provides a kit comprising one or more modified release pharmaceutical compositions comprising RPPX and instructions for administering or prescribing the one or more pharmaceutical compositions, comprising a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of at least about 50 mg to about 5,000 mg of RPPX to a patient.
  • kits comprising one or more modified release pharmaceutical compositions according to any of the previous embodiments of the compositions described herein, or any combination thereof, and instructions for administering or prescribing the one or more modified release pharmaceutical compositions, comprising a direction to administer or prescribe the one or more modified release pharmaceutical compositions according to the embodiments of the methods described herein, or any combination thereof.
  • kits of the invention may have a chiral purity for RPPX of at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%, preferably at least 99.95% and more preferably at least 99.99%.
  • the chirai purity for the R(+) enantiomer of pramipexole may be 100%.
  • the chiral purity for the RPPX is 99.9% or greater.
  • the chirai purity for the RPPX is 99.95% or greater.
  • the chiral purity for the RPPX is 99.99% or greater.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of RPPX of from about 0.1 mg/kg/day to about 1 ,000 mg/kg/day or from about 1 mg/kg/day to about 100 mg/kg/day.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of RPPX of from about 3 mg/kg/day to about 70 mg/kg/day.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of RPPX of from about 7 mg/kg/day to about 40 mg/kg/day. In some embodiments, the instructions comprise a direction to administer or prescribe the one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of RPPX of from about 50 mg to about 5,000 mg, from about 100 mg to about 3,000 mg, preferably from about 300 mg to about 1 ,500 mg, or more preferably from about 500 mg to about 1 ,000 mg.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of RPPX of from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000 mg, from about 200 mg to about 5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg to about 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg to about 5,000 mg, from about 200 mg to about 3,000 mg, from about 250 mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about 400 mg to about 3,000 mg, from 450 mg to about 3.000 mg, from about 100 mg to about 1,000 mg, from about 200 mg to about 1,000 mg, from about 250 mg to about 1 ,000 mg, from about 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg, from about 600 mg to about 1,000 mg, or from 450 mg to about 1 ,000 mg.
  • the starting daily dose amount of RPPX is from about 600 mg to about 5,000 mg, from about 100 mg
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 mg to about 3,000 mg of RPPX to a patient. In some embodiments, instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 mg to about 3,000 mg of RPPX to a patient. In some embodiments, the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of from about 300 to about 1 ,500 mg of RPPX to a patient. In some embodiments, the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 to about 1 ,000 mg of RPPX to a patient.
  • the direction further results in administration of a non-effective dose amount of PPX.
  • the non-effective dose amount of PPX is an amount that does not exceed a total dose of 1.0 mg/day. In more preferred embodiments, the non-effective dose amount of PPX is an amount that does not exceed a total dose of 0.75 mg/day, 0.5 mg/day, 0.25 mg/day, and preferably 0.125 mg/day. In some embodiments, the non-effective dose amount is less than about 0.125 mg of PPX.
  • the direction further results in administration of a no adverse effect level (NOAEL) dose amount of PPX.
  • NOAEL no adverse effect level
  • the no observable effective dose amount of dose of PPX may be preferably below 4.5 mg, preferably below 1.5 mg, or more preferably below 0.15 mg.
  • the no observable adverse effect level dose amount is less than about 0.05 mg per day.
  • the NOAEL dose amount of PPX is an amount that does not exceed 0.0007 mg/kg per unit dose.
  • the direction further results in administration of less than about 4.5 dopaminergic activity equivalents per day.
  • the direction further results in administration of less than about 1.5 dopaminergic activity equivalents per day.
  • the direction further results in administration of less than about 0,15 dopaminergic activity equivalents per day.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 mg to 3,000 mg of RPPX to a patient; and the chiral purity for the RPPX is 99.95% or greater.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 mg to about 3,000 mg of RPPX to a patient; and the chiral purity for the RPPX is 99.95% or greater.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 300 mg to about 1,500 mg of RPPX to a patient; and the chiral purity for the RPPX is 99.95% or greater.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 mg to about 1 ,000 mg of RPPX to a patient; and the chiral purity for the RPPX is 99.95% or greater.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 mg to 3,000 mg of RPPX and less than about 0.05 mg of PPX to a patient.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 mg to 3,000 mg of RPPX and less than about 0.05 mg of PPX to a patient.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 300 mg to 1,500 mg of RPPX and less than about 0.05 mg of PPX to a patient.
  • the instructions comprise a direction to administer or prescribe the one or more modified release pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 mg to 1,000 of RPPX and less than about 0.05 mg of PPX to a patient.
  • the modified release pharmaceutical or therapeutic compositions of the invention may be prepared, packaged, sold in bulk, as a single unit dose, or as multiple unit doses.
  • the compositions may be formulated to be administered orally, ophthalmically, intravenously, intramuscularly, intra-arterially, mtrameduiarry, intrathecally, transdermal Iy, subcutaneously, intraperitoneally, intravesicularly, intranasally, enterally, topically, sublingually, or rectally.
  • the modified release compositions of the invention may be administered orally, preferably as a solid oral dose, and more preferably as a solid oral dose that may be a capsule or tablet.
  • the modified release compositions of the present invention may be formulated as tablets for oral administration.
  • the compounds of the present invention can be administered in the conventional manner by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, intravesicularly, by inhalation, by depot injections, or by implants.
  • modes of administration for the compounds of the present invention can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
  • the doses of the RPPX which may be administered to a patient in need thereof may range between about 0.1 mg/kg per day and about 1,000 mg/kg per day.
  • the route of administration may include oral, sublingual, transdermal, rectal, or any accessible parenteral route.
  • One of ordinary skill in the art will understand and appreciate the dosages and timing of the dosages to be administered to a patient in need thereof.
  • the doses and duration of treatment may vary, and maybe based on assessment by one of ordinary skill in the art based on monitoring and measuring improvements in neuronal and non-neuronal tissues. This assessment may be made based on outward physical signs of improvement, such as increased muscle control, or on internal physiological signs or markers.
  • the doses may also depend on the condition or disease being treated, the degree of the condition or disease being treated and further on the age and weight of the patient.
  • Specific modes of administration will depend on the indication.
  • the selection of the specific route of administration and the dose regimen may be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical response.
  • the amount of compound to be administered may be that amount which is therapeutically effective.
  • the dosage to be administered may depend on the characteristics of the subject being treated, e.g., the particular animal or human subject treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).
  • a preferable route of administration of the modified release compositions of the present invention may be oral, with a more preferable route being in the form of tablets, capsules, lozenges and the like,
  • the compositions of the present invention may be formulated as tablets for oral administration.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active compound in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active compound until after passage of the stomach (enteric coating).
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylce ⁇ lulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).
  • a film coating e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone
  • an enteric coating e
  • a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active drug substance).
  • Modified release pharmaceutical formulations containing the compounds of the present invention and a suitable carrier may also be any number of solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jeilies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder; comprising an effective amount of a polymer or copolymer of the present invention.
  • the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, di s integrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, di s integrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Oilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co,, New York (19
  • the compounds of the present invention can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • the compounds can be administered by continuous infusion over a period of about 15 minutes to about 24 hours.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the modified release compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-ceilulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores can be provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added.
  • AU formulations for oral administration should be in dosages suitable for such administration.
  • compositions cart take the form of tablets, flash melts or lozenges formulated in any conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotelraftuoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotelraftuoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotelraftuoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotelraftuoroethane, carbon dioxide or other suitable gas.
  • the compounds of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g,, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the present invention can also be formulated as a depot preparation.
  • Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the present invention for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
  • compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
  • the compounds of the present invention can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • active ingredients such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt reaction product displays a high chemical purity and an increased optical purity over the reactants, which may be due to limited solubility of the 2-amino-4,5,6,7-tetrahydro- ⁇ -(propylamino)benzothiazole salt in the polar solvents of the reaction mixture.
  • the RPPX is prepared by dissolving a diamine of formula 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole in an organic solvent, reacting the diamine with a propyl sulfonate or a propyl halide under conditions sufficient to generate and precipitate the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt, and recovering the 2 ⁇ amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt.
  • the propyl sulfonate may be propyl tosylate.
  • the propyl halide may be propyl bromide
  • the 2-amino-4,5,6,7-tetrahydro-6 ⁇ (propylamino)benzothiazole salt reaction product of this process displays a high chemical purity and an increased optical purity over the reactants.
  • the increased optical purity may be due to limited solubility of the 2 ⁇ amino-4, 5,6,7- tetrahydro-6-(propylamino)benzothiazole salt reaction product in the polar solvents of the reaction mixture.
  • the diamine may be an R(+) diamine, or a mixture of the R(+) and an S diamine.
  • the chemical purity of the final 2-amino-4, 5,6,7- tetrahydro-6-(propylamino)benzothiazole salt may be at least about 97% or greater, preferably 98% or greater, more preferably 99% or greater.
  • the R(+) enantiomers of the 2- amino-4,5,6,7-tetrahydro-6-(pro ⁇ ylamino)benzothiazole salt generated using this process are generated from starting diamines which may be at least 55% optically pure, preferably 70% optically pure, and more preferably greater than 90% optically pure.
  • the final 2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product may be enriched to 99.6% optical purity or greater, 99.7% optical purity or greater, preferably 99.8% optically purity or greater, and more preferably 99.9% optical purity or greater, 99.95% optical purity or greater, 99.99% optical purity or greater.
  • the optical purity may be 100%.
  • the organic solvent may be a polar aprotic solvent such as tetrahydofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, or hexamethylphosphoric triamide.
  • the organic solvent may also be a low molecular weight alcohol such as ethanol, 1-propanol, or n-butanol.
  • the organic solvent may be any combination of the polar aprotic solvents and low molecular weight alcohols.
  • the organic solvent may have a water content of from about 0 to about 10 volume percent.
  • the solvents used in the practice of this invention are standard ACS grade solvents.
  • the propyl sulfonate or a propyl halide may be added at about LO to about 2.0 molar equivalents of the diamine.
  • the conditions sufficient to generate and precipitate the 2-amino-4,5,6,7-tetrahydro-6-( ⁇ ropylamino)benzothiazole salt may comprise heating the dissolved diamine at an elevated temperature, adding the propyl sulfonate or propyl halide which may be dissolved in di-isoproplyethylamine and an organic solvent to form a mixture, and stirring the mixture for about 4 hours.
  • the di- isoproplyethylamine may be added to the reaction with the diamine, and the propyl sulfonate or propyl halide may be dissolved in an organic solvent to form a mixture, which may be added to the reaction with stirring over about 4 hours.
  • the elevated temperature of the reaction may be below the boiling temperature of the reaction, specifically, below the boiling temperature of the organic solvent(s) of the reaction mixture.
  • the elevated temperature may be lower than about 125°C, preferably lower than about 100[d], and more preferably about 95[d] or lower.
  • the times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature.
  • the conditions sufficient to generate and precipitate the 2-amino-4,5,6,7-tetrahydro-6-(propylammo)benzothiazole salt may comprise using di methyl formam id e as the organic solvent, heating the dissolved diamine at an elevated temperature, adding the propyl sulfonate or propyl halide which is dissolved in dimethylformamide to form a mixture, and stirring the mixture for about 4 hours.
  • the elevated temperature of the reaction may be below the boiling temperature of the reaction, specifically, below the boiling temperature of the organic solvent(s) of the reaction mixture.
  • the elevated temperature may be lower than about 125[d], preferably lower than about 100[d], and more preferably about 75[d] or lower.
  • the times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature.
  • the conditions sufficient to generate and precipitate the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt comprise using dimethylformamide as the organic solvent and heating the dissolved diamine at an elevated temperature.
  • the di- isoproplyethylamine may be added to the reaction with the diamine, and the propyl sulfonate or propyl halide may be dissolved in dimethylformamide to form a mixture, which may be added to the reaction with stirring for about 4 hours.
  • the elevated temperature of the reaction may be below the boiling temperature of the reaction, specifically, below the boiling temperature of the organic solvent(s) of the reaction mixture.
  • the elevated temperature may be lower than about 125[d], preferably lower than about 100 ⁇ C, and more preferably about 65°C or lower.
  • the times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature.
  • Embodiments of the process further comprise cooling the reaction to a temperature of about room temperature, about 25[d], and stirring the reaction for about 2 hours.
  • the process may further involve filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol, and drying the precipitate under vacuum.
  • the 2- amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt reaction product of this process may display an increased optical purity over the reactants.
  • the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole sulfonate or halide salt can be reacted with concentrated HCl in an organic solvent, such as an alcohol, at a temperature of from about 0 to about 5[d].
  • an organic solvent such as methyl tert-butyl ether (MTBE)
  • MTBE methyl tert-butyl ether
  • the RPPX dihydrochloride product may be recovered from the reaction mixture by filtering, washing with an alcohol and vacuum drying.
  • the reaction condition which may be sufficient to generate the 2-amino- 4,5,6, 7-tetrahydro-6-(propylamino)benzothiazo ⁇ e product may include heating the dissolved diamine of formula II to an elevated temperature with continuous stirring.
  • the elevated temperature is preferably less than the melting point of the chosen organic solvent, lower than about 125°C, preferably lower than about 100[d], and more preferably about 95°C.
  • a solution of propyl sulfonate or propyl halide, which is dissolved in di-isoproplyethylamine and an organic solvent to form a mixture, is added slowly over a period of several hours. This reaction mixture may then be stirred at temperature for an additional period of time such as, for example, about 4 hours.
  • the times necessary for the reaction may vary with the identities of the reactants and solvent system, and with the chosen temperature, and would be understood by one of skill in the art.
  • the di-isoproplyethylamine may be added to the reaction with the diamine, and the propyl sulfonate or propyl halide may be dissolved in an organic solvent to form a mixture, which may be added to the reaction with stirring over a period of several hours.
  • This reaction mixture may then be stirred at temperature for an additional period of time such as, for example, at least 4 hours.
  • the time necessary for the reaction to run to completion may vary with the identities of the reactants and solvent system, and with the chosen temperature, and would be understood by one of skill in the art.
  • the reaction conditions which are sufficient to generate the 2-amino-4 > 5,6,7- tetrahydro-6-(propylamino)benzothiazole product may include using dimethylformamide as the organic solvent, and heating the dissolved diamine of formula II to an elevated temperature with continuous stirring.
  • the elevated temperature is preferably less than the melting point of the chosen organic solvent, lower than about 125[d], preferably lower than about 100[d], and more preferably about 75[d].
  • a solution of propyl sulfonate or propyl halide, which is dissolved in dimethylformamide, may be added slowly over a period of several hours.
  • This reaction mixture may then be stirred at temperature for an additional period of time such as, for example, about 4 hours.
  • the time necessary for the reaction to run to completion may vary with the identities of the reactants and solvent system, and with the chosen temperature, and would be understood by one of skill in the art.
  • the reaction includes using dimethylformamide as the organic solvent for dissolution of the diamine.
  • the diamine of formula II may then be heated to an elevated temperature with continuous stirring.
  • the elevated temperature is preferably less than the melting point of the chosen organic solvent, lower than about 125[d]. preferably lower than about 100[d], and more preferably about 65[d].
  • a solution of propyl sulfonate or propyl halide, preferably about 1.25 molar equivalents, may be dissolved in dimethylformamide, preferably about 10 volumes, and di-isoproplyethylainine, preferably about 1.25 molar equivalents, to form a mixture.
  • This mixture may be added slowly over a period of several hours to the heated diamine. This reaction mixture may then be stirred at temperature for an additional period of time such as, for example, about 4 hours.
  • the di- isoproplyethylamine may be added to the reaction with the diamine, and the propyl sulfonate or propyl halide may be dissolved in dimethylformamide to form a mixture, which may be added to the reaction with stirring over a period of several hours.
  • This reaction mixture may then be stirred at temperature for an additional period of time such as, for example, about 4 hours.
  • the time necessary for the reaction to run to completion may vary with the identities of the reactants and solvent system, and with the chosen temperature, and would be understood by one of skill in the art.
  • (propylamino)benzofhiazole product may include cooling the reactions disclosed above to a temperature of about 25[d], and stirring the reactions for a period of time such as, for example, about 2 hours.
  • the purification may further include filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol, and drying the precipitate under vacuum.
  • the final products of the reaction may be analyzed by high pressure liquid chromatography (HPLC) for chemical and chiral purity.
  • HPLC high pressure liquid chromatography
  • the sulfonate or halide salts of 2-amino-4,5,6,7-tetrahyd ⁇ o-6- (pro ⁇ ylamino)benzothiazole may be converted to an HCl salt using a concentrated solution of HC! in ethanol.
  • a /J-TSA 2-ammo-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt may be re-dissolved in an alcohol, such as ethanol, and the mixture may be cooled to between about 0 and about 5[d] with continuous stirring.
  • a concentrated HCl may then be added, followed by a solvent such as methyl tert-butyl ether (MTBE), and the mixture may be stirred for an hour at between about 0 and about 5[d].
  • MTBE methyl tert-butyl ether
  • the reaction mixture may then be filtered, washed with an MTBE/ alcohol solution, and dried under vacuum.
  • the final product is 2- amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazoIe dihydrochloride.
  • a detailed example of this synthesis may be found in Example 8.
  • An alternate method for conversion of the sulfonate or halide salts of 2- amino-4,5,6,7-tetrahydro-6-( ⁇ ropylamino)benzothiazole to an HCl salt involves the use of a concentrated solution of HCl and isopropyl acetate (IPAC).
  • IPAC isopropyl acetate
  • a sulfonate or halide salt of 2- amino-4,5,6,7-tetrahydro-6-(propylarmno)benzothiazole may be taken up in IPAC and cooled to 15°C.
  • the sulfonate or halide salts of 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole may alternatively be converted to the free base form of 2-amino- 4,5.6,7-tetrahydro ⁇ 6-(propylamino)benzothiazole.
  • A/?-TSA 2 ⁇ amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole salt may be dissolved in dichloromethane (DCM) and water. The resulting solution may then by brought to a pH of about 11-12 using NaOH.
  • aqueous phase may be extracted with DCM, dried over magnesium sulfate (MgSCi), filtered over Celite® and concentrated.
  • MgSCi magnesium sulfate
  • Celite® Celite®
  • the concentrated residue may be re-dissolved in MTBE and stirred as a slurry for several hours.
  • the solids may then be filtered, washed with MTBE, and dried under vacuum at a temperature of about 35°C.
  • the final product is 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole free base.
  • a detailed example of this synthesis may be found in Example 10.
  • the sulfonate or halide salts of 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole may alternatively be converted to the free base form of 2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole by a second process, in this second process, the/?-TSA salt of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole is dissolved in water and cooled to a temperature of about 10[d]. This slurry is basified by addition of NaOH, diluted with brine, and extracted several times in DCM. The combined organic phases are then washed with brine, dried over MgSO 4 , filtered and concentrated to dryness. A detailed example of this synthesis may be found in Example 11.
  • the free base form of 2-amino-4,5,6,7-tetrahydro ⁇ 6- (propylamino)benzothiazoie may be converted to 2-amino-4,5, ⁇ ,7-tetrahydro-6- (propylamino)benzothiazole dihydrochloride by bubbling HCl gas into a cooled solution of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole free base in IPAC.
  • the free base form of 2-amino-4,5,6,74etrahydro ⁇ 6- (propylamino)benzothiazole may be converted to 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole dihydrochloride by mixing with concentrated HCl at room temperature overnight.
  • 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole dihydrochloride by mixing with concentrated HCl at room temperature overnight.
  • the free base form of 2-amino-4,5, ⁇ ,7-tetrahydro-6- (propylamino)benzothiazole may be converted to 2-amino ⁇ 4,5, ⁇ ,7-tetrahydro- ⁇ - (propylamino)benzothiazole fumarate by the addition of 2 molar equivalents of fumaric acid.
  • enantiomericaily pure 2-amirto-4,5, ⁇ ,7-tetrahydro-6- (propylamino)benzothiazole is triturated from an acid addition solution based on the insolubility of the enantiomers in the resulting achiral salt reagents.
  • a process for preparing an enantiomericaily pure 2-amino ⁇ 4,5,6,7-tetrahydro-6- ⁇ propylamino)ben2othiazole comprises dissolving an enantiomericaily enriched 2-ammo- 4,5,6,7 ⁇ tet ⁇ ahydro- ⁇ -(propylamino)benzothiazole in art organic solvent at an elevated temperature, adding a selected acid, cooling the reaction to room temperature, stirring the cooled reaction at room temperature for an extended time and recovering enantiomericaily pure RPPX.
  • the selected acid may be added at from about 1 molar equivalent to about 2 molar equivalents of the enantiomericaily enriched 2-amino- 4,5,6,7-tetrahydro-6 ⁇ (propylamino)benzothiazoie.
  • the selected acid is /j-toluenesulfonic acid (p-TSA) and the organic solvent is ethanol.
  • the elevated temperature may be from about 65[d] to about 85°C and the cooling occurs at a rate of about 25[d] per hour.
  • the elevated temperature may also be a temperature lower than 125[d], preferably lower than 100[d], and more preferably about 75[d]. The times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature, and may be easily appreciated by one of skill in the art.
  • recovering enantiomericaily pure 2-amino-4,5,6,7-tetrahydro-6- ( ⁇ ropylamino)benzothiazole comprises cooling the reaction to a temperature of about 25[d] and stirring the reaction for at least about 2 hours.
  • the recovery may further comprise filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol and drying the precipitate under vacuum.
  • the organic solvent may include, but is not limited to, acetonitrile, acetone, ethanol, ethyl acetate, methyl tert-butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.
  • the organic solvent is ethanol.
  • the acid may include, but is not limited to, halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid; inorganic acids such as, for example, nitric, perchloric, sulfuric and phosphoric acid; organic acids such as, for example, sulfonic acids (methanesulfonic, tritluoromethan sulfonic, ethanesulfonic, benzenesulfonic or/j-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid; and aminoacids such as aspartic or glutamic acid.
  • halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid
  • inorganic acids such as, for example, ni
  • the acid may be a mono- or di-acid, such as a di-hydrohalogenic, di-sulfu ⁇ c, di-phosphoric or di-organic acid.
  • the acid is used as an achiral reagent which is not selected on the basis of any expected or known preference for interaction with or precipitation of a specific optical isomer of the products of this disclosure.
  • the selected acid is /Moluenesulfonic acid.
  • the final chiral purity for an R(+) enantiomer of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt may be greater than 99% when the starting mixture contains 2-amino-4,5,6,7-tetrahydro-6- ( ⁇ ropylammo)benzothiazole which is at least 55% optically pure for the R(+) enantiomer, preferably 80% optically pure for the R(+) enantiomer, preferably 85% optically pure for the R(+) enantiomer, more preferably 90% optically pure for the R(+) enantiomer and most preferably 95% optically pure for the R(+) enantiomer.
  • the final chiral purity for an S(-) enantiomer of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt may be greater than 99% when the starting mixture contains 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole which is at least 55% optically pure for the S(-) enantiomer, preferably 80% optically pure for the S(-) enantiomer, preferably 85% optically pure for the S(-) enantiomer, more preferably 90% optically pure for the S(-) enantiomer and most preferably 95% optically pure for the S(-) enantiomer.
  • the chiral purity of the final 2-amino- 4,5,6,7-tetrahydro-6-(propylamino)ben7 J othiazo!e salt may preferably be 99.6% or greater, 99.7% or greater, preferably 99.8% or greater, and more preferably 99.9% or greater. In some embodiments, the chiral purity of the final 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole salt may be 100%.
  • the reaction may be cooled to room temperature at a rate of about 25°C/hour.
  • the enantiomerically pure 2-amino-4,5, ⁇ ,7-tetrahydro-6- (pro ⁇ ylamino)benzothiazole may then be recovered from the reaction solution by stirring the reaction for at least about 2 hours, filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol and drying the precipitate under vacuum.
  • the rates of cooling and the time required for the additional stirring may vary with the chosen organic solvent and acid, and may be easily appreciated by one skilled in the art. Additionally, the reaction volumes may dictate the degree of optical purification and the overall yield of the final 2- amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product. These volumes would be understood and appreciated by one of skill in the art. Examples of specific times, temperatures and volumes which enable the practice of this invention are given in the Examples.
  • the chiral purity of the 2-amino-4,5,6,7-tetrahydro- ⁇ - (propylamino)benzothiazole salt product for the R(+) enantiomer may be greater than 99% when the chiral purity of the starting 2-amino-4,5,6,7-tetrahydro- ⁇ -
  • (pr ⁇ pylammo)benzothiazole mixture for the R(+) enantiomer is greater than 55%, preferably greater than 70%, or more preferably greater than 90%.
  • the chiral purity of the final 2- amino-4,5,6 J-tetrahydro- ⁇ -(propylamino)benzothiazole salt may be 99.6% or greater, 99.7% or greater, preferably 99.8% or greater, and more preferably 99.9% or greater, more preferably 99.95% or greater, even more preferably 99.99% or greater.
  • the chiral purity of the final 2-amino-4,5, ⁇ ,7-tetrahydro-6- (propylamino)benzothiazole salt may be 100%.
  • Chirally pure 2-amino-4,5,6,7 ⁇ tetrahydro-6-(propylamino)benzothiazoIe also may be prepared by the process of trituration of a single enantiomer of 2-amino-4,5, ⁇ ,7- tetrahydro- ⁇ -( ⁇ ropylamino)benzothiazole from a mixture of RPPX and PPX by acid addition, based on insolubility of the enantiomers in the resulting achiral salt solution.
  • the process comprises dissolving an enantiomerically enriched 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzotbiazole in an organic solvent at an elevated temperature, adding from about 1.05 molar equivalents to about 2.05 molar equivalents of a selected acid, cooling the reaction to room temperature, stirring the cooled reaction at room temperature for an extended time and recovering enantiomerically pure 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole.
  • the elevated temperature of the reaction may be below the boiling temperature of the reaction, specifically, below the boiling temperature of the organic solvent(s) of the reaction mixture.
  • the elevated temperature may be lower than about 125°C, more preferably lower than about 100[d], and more preferably about 75[d].
  • the times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature, and would be appreciated by one of skill in the art,
  • the organic solvent may include, but is not limited to, acetonitrile, acetone, ethanol, ethyl acetate, methyl tert-butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.
  • the organic solvent is ethanol.
  • the acid may include, but is not limited to, halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid; inorganic acids such as, for example, nitric, perchloric, sulfuric and phosphoric acid; organic acids such as, for example, sulfonic acids (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or/7-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid; and aminoacids such as aspartic or glutamic acid.
  • halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid
  • inorganic acids such as, for example, nitric, per
  • the acid may be a mono- or di-acid, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid.
  • the acid is used as an achira) reagent which is not selected on the basis of any expected or known preference for interaction with or precipitation of a specific optical isomer of the products of this disclosure, hi a preferred embodiment, the selected acid isp-toluenesulfonic acid.
  • the reaction may be cooled to room temperature at a rate of about 25 ⁇ C/hour.
  • the chirally pure 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole may then be recovered from the reaction solution by stirring the reaction for at least about 2 hours, filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol and drying the precipitate under vacuum.
  • reaction volumes may dictate the degree of optical purification and the overall yield of the final 2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole product. These volumes would be understood and appreciated by one of skill in the art. Examples of specific times, temperatures and volumes which enable the practice of this invention are given in the Examples.
  • the chiral purity for the R(+) enantiomer of the recovered 2- amino-4,5,6,7-tetrahydr ⁇ - ⁇ -( ⁇ ropylamino)benzothiazole salt may be greater than 99% when the starting 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole material has a chiral purity for the R(+) enantiomer of greater than 55%, preferably greater than 70%, or more preferably greater than 90%.
  • the chiral purity of the final 2-amino-4,5,6,7-ietrahydro-6- (propylamino)benzothiazoJe salt for the R(+) enantiomer may be 99.6% or greater, 99.7% or greater, preferably 99.8% or greater, and more preferably 99.9% or greater, more preferably 99.95% or greater, even more preferably 99.99% or greater.
  • the chiral purity of the final 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt for the R(+) enantiomer may be 100%.
  • the process may include dissolving an enantiomerically enriched 2-amino ⁇ 4,5,6,7-tetrahydro-6-( ⁇ ropylamino)benzothiazole in an organic solvent at an elevated temperature, adding from about 1.05 equivalents to about 2.05 equivalents of a selected acid, cooling the reaction to room temperature, stirring the cooled reaction at room temperature for an extended period of time and recovering enantiomerically pure 2-amino-4,5,6,7-tetrahydro- 6-(propylamino)benzothiazole of formula I.
  • the selected acid is/»-toluenesulfonic acid (p-TSA) and the organic solvent is ethanol.
  • the elevated temperature may be from about 65[d] to about 85[d] and the cooling occurs at a rate of about 25°C per hour.
  • the elevated temperature may also be a temperature lower than 125[d], preferably lower than 100[d], and more preferably about 75[d]. The times necessary for the reaction may vary with the identities of the reactants, the solvent system and with the chosen temperature, and may be easily appreciated by one of skill in the art.
  • recovering enantiomerically pure 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole comprises cooling the reaction to a temperature of about 25[d] and stirring the reaction for at least about 2 hours.
  • the recovery may further comprise filtering the reaction to isolate a solid precipitate, washing the precipitate with an alcohol and drying the precipitate under vacuum.
  • the organic solvent may include, but is not limited to, acetonitrile, acetone, ethanol, ethyl acetate, methyl tert-butyl ether, methyl ethyl ketone, isopropyl acetate and isopropyl alcohol.
  • the organic solvent is ethanol.
  • the acid may include, but is not limited to, halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid; inorganic acids such as, for example, nitric, perchloric, sulfuric and phosphoric acid; organic acids such as, for example, sulfonic acids (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or/j-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid; and aminoacids such as aspartic or glutamic acid.
  • halogenic acids such as, for example, hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid
  • inorganic acids such as
  • the acid may be a mono- or di-acid, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid.
  • the acid is used as an achiral reagent which is not selected on the basis of any expected or known preference for interaction with or precipitation of a specific optical isomer of the products of this disclosure.
  • the selected acid is/>-toluenesulfonic acid.
  • the final chiral purity for an R(+) enantiomer of the 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole salt may be greater than 99% when the starting mixture contains 2-amino-4,5,6,7-tetrahydro-6 ⁇ (propylami ⁇ o)benzothiazole which is at least 55% optically pure for the R(+) enantiomer, preferably 80% optically pure for the R(+) enantiomer, preferably 85% optically pure for the R(+) enantiomer, more preferably 90% optically pure for the R(+) enantiomer and most preferably 95% optically pure for the R(+) enantiomer.
  • the final chiral purity for an S(-) enantiomer of the 2-amino-4,5, ⁇ ,7-tetrahydro-6-(propylamino)ben2:othiazole salt may be greater than 99% when the starting mixture contains 2 ⁇ amino-4,5,6,7-tetrahydro-6- (propy!amino)benzothiazole which is at least 55% optically pure for the S(-) enantiomer, preferably 80% optically pure for the S(-) enantiomer, preferably 85% optically pure for the S(-) enantiomer, more preferably 90% optically pure for the S(-) enantiomer and most preferably 95% optically pure for the S(-) enantiomer.
  • the chiral purity of the final 2-amino- 4,5,6,7-tetrahydro-6-( ⁇ ropyIamino)benzothiazole salt may preferably be 99.6% or greater, 99.7% or greater, preferably 99.8% or greater, and more preferably 99.9% or greater. In a more preferred embodiment, the chiral purity of the final 2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole salt may be 100%.
  • RPPX The chemical and chiral purity of the preparations of RPPX may be verified with at least HPLC, 13 C-NMR, 1 H-NMR and FTlR.
  • the RPPX may be synthesized by the method described above, which yields enantiomerically pure material.
  • the RPPX may be purified from mixtures of RPPX and PPX using a purification scheme which is disclosed in copending U.S. Provisional Application No. 60/894,829 entitled "Methods of Synthesizing and Purifying R(+) and (S)-pramipexole", filed on March 14, 2007, and U.S. Provisional Application No.
  • Condition C The reaction is performed in 10 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67[d]. The reaction is then cooled to room temperature and diluted with 8 volumes of MTBE.
  • Condition D The reaction is performed m 18 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67[d]. The reaction is then cooled to room temperature and diluted with 8 volumes of MTBE.
  • Condition E The reaction is performed in 10 volumes of DMF and 1.25 equivalents of propyl tosylate at 65-67[d]. The reaction is then cooled to room temperature with no dilution in MTBE.
  • the various synthesis reactions carried out using condition C all have chemical yields of about 50%, independent of the percentage of predominant diamine enantiomer of the starting material.
  • the volume of the organic solvent used in the synthesis reaction is increased, the chemical yield is reduced, but the chiral yield is increased.
  • condition E is the same as condition C, except that the recovery step does not incorporate dilution in MTBE.
  • the MTBE is observed to increase 2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole recovery (yield) from the synthesis reaction, but may reduce the overall chiral purity.
  • RPPX dihydrochloride is a preferred pharmaceutical salt due its high water solubility.
  • dihydrochloride may be prepared from other salts of RPPX in a one step method comprising reacting the RPPX, or RPPX salt, with concentrated HCl in an organic solvent, such as an alcohol, at a reduced temperature.
  • the reduced temperature is a temperature of from about O[d] to about 5[d].
  • An organic solvent, such as methyl tert-butyl ether, may be added, and the reaction may be stirred for an additional hour.
  • the RPPX dihydrochloride product may be recovered from the reaction mixture by filtering, washing with an alcohol and vacuum drying.
  • Each of the methods disclosed herein for the manufacture and purification of RPPX or a pharmaceutically acceptable salt thereof may be scalable to provide industrial scale quantities and yields, supplying products with both high chemical and chiral purity.
  • the enantiomerically pure RPPX may be manufactured in large batch quantities as may be required to meet the needs of a large scale pharmaceutical use,
  • EXAMPLE 1 Measurement of the dopamine receptor affinities for the R ⁇ +) and S(-) enantiomers of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole.
  • nM, 100 nM, ImM, 1OmM and 10OmM were used to displace standard reference radiolabeled dopamine agonists. These concentrations were tested in cell lines expressing select human cloned dopamine receptors (D 2S , D 3 ). Previous work in the literature and our data demonstrated no significant interaction with Dl and D5 dopamine receptors. Group results for the interaction of RPPX or PPX with each receptor are expressed as the 1C50 in Table 10.
  • a NOAEL was established at a dose level of 25 mg/lcg for the R(+) enantiomer when administered to non-na ⁇ ve dogs, while a dose level of 75 mg/kg may be considered an MTD in non-na ⁇ ve dogs.
  • a NOAEL of 0.00125 mg/kg and an MTD of 0.0075 mg/kg was found in non-na ⁇ ve dogs.
  • the NOAEL was found to be 0.25 mg/kg, which corresponds to a dose of 00125 mg/kg of the S(-) enantiomer, while the MTD is 1.5 mg/kg, which corresponds to a dose of 0.0075 mg/kg of the S(-) enantiomer.
  • the data in Table 11 demonstrate that the NOAEL and MTD for the combination composition (99.5% RPPX and 0.5% PPX) may be determined directly by the dose of the S(-) enantiomer in the composition.
  • a small (fractional percentage) contamination of a composition of RPPX by the PPX may reduce the MTD and NOEL of the composition.
  • the MTD of pramipexole was reduced from 75 mg/kg for the R(+) enantiomer to a total dose of 1.5 mg/kg of the mixed composition (a factor of 50), and the NOAEL was reduced from 25 mg/kg to 0.25 mg/kg, respectively (a factor of 100).
  • the shift in MTD and NOAEL may be predicted by the dose of the S(-) enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole in the mixture
  • the shift for any unknown mixture may be calculated based on the percentage contamination of the RPPX by the PPX, relative to the MTD and NOAEL for PPX. This indicates that any contamination of an RPPX dosing solution with PPX will have a measurable effect on these indicators of dose tolerability.
  • RPPX may be safely administered (1 ) at starting doses that are at least 2400- fold higher than the Mirapex® starting dose and (2) at steady state doses that are at least 44- fold higher than the highest recommended dose of Mirapex®.
  • the form of RPPX was RPPX dihydrochloride monohydrate.
  • the mean steady state AUC in rats at the NOAEL dose of 100 mg/kg was 61 ,299 and 61,484 h*ng/mL for males and females, respectively, and for minipigs at the NOAEL dose of 50 mg/kg was 91,812 and 131,731 h*ng/mL for males and females, respectively.
  • the mean steady state AUC in humans at a dose of 100 mg Q12H (200 mg total daily dose) was 2,574 h*ng/mL.
  • the drug has been safe, well-tolerated, and free of clinically significant adverse events in healthy adult subjects at single doses up to 300 mg and at multiple doses up to 100 mg Q12H, and the projected human exposure associated with a daily dose of 250 mg Ql 2H is expected to be greater than 13-fold lower than exposures seen at the NOAEL in male minipigs and approximately 9-fold lower than exposures seen at the NOAEL in male and female rats after 13 weeks of dosing.
  • RPPX has been studied at single daily IR doses of 50, 150 and 300 mg and twice daily IR doses of 50 and 100 mg for 414 days in healthy adult volunteers.
  • the drug has been safe and well-tolerated in both studies and there were no serious adverse events, discontinuations due to adverse events, or dose-related or clinically significant adverse events in either study.
  • the most frequent adverse events have been dizziness and headache, all of which have been mild to moderate in severity and resolved without intervention.
  • Results of this study demonstrate that single IR oral doses of 50, 150, and 300 mg RPPX are safe and well-tolerated.
  • the drug is orally bioavailable and the pharmacokinetics are linear. Absorption and elimination are not affected by a high fat/high calorie meal.
  • Table 12 Summary of pharmacokinetic parameters for RPPX after oral administration of single 50 mg. 150 mg, and 300 mg doses to health) volunteers under fasted conditions and 150 mg under fed conditions.
  • the second panel was administered a single IR dose of 100 mg, followed 48 hours later by 4V- days of multiple IR dosing (twice daily) at 100 mg Q12 hours.
  • Safety observations included vital signs, physical examination, clinical laboratory tests, FXGs, and adverse event reporting.
  • Blood samples were collected pre-dose on Day 1 and serially for 48 hours post-dose to assess the single-dose pharmacokinetics.
  • Blood samples were collected pre-dose on Days 5, 6, and 7 to confirm steady-state was achieved, and serially through 72 hours post-dose on Day 7 to assess the steady-state pharmacokinetics of RPPX.
  • Urine samples were collected for 12 hours after dosing ⁇ n Day 7 to assess urinary excretion.
  • Table 13 Summary of pharmacokinetic parameters for RPPX during oral administration of 50 mg and 100 mg LR doses on Day I 5 Q12H on Days 3 through 6, and a single dose on Day 7 to healthy volunteers under fasted conditions
  • 3- and 6-month repeat dose toxicology studies were completed at doses of 30, 100, and 300 mg/kg
  • the results of the 3-month study contain some target organ toxicity by histopathology examination at the highest dose (300 mg/kg) with no test article related deaths and no significant clinical observations outside of several incidences of convulsions in high dose rats lasting approximately 2 minutes. The animals' health did not appear to be otherwise adversely affected by these convulsions.
  • Test article- related microscopic changes were observed in the liver (minimal grade cholestasis correlating with increased total bilirubin), ileal small intestine (minimal grade mineralization), and thymus (minimal grade lymphoid depletion correlating with lower group thymus weights compared to controls).
  • the NOAEL for the 3-month study in rats is considered to be 100 mg/kg.
  • Systemic exposure (AUCo-i ⁇ st) at week 13 at the NOAEL dose of 100 mg/kg was 61,299 h*ng/mL in males and 61 ,484 h*ng/mL in females.
  • the in-life phase of the 6-month toxicology study in rats was recently completed and histopatholgic examinations are pending. There were no mortalities at any dose level between the 13-week and 26-week sacrifices.
  • the NOAEL for the 2-week study was considered to be greater than or equal to 75 mg/kg.
  • 3-, and 6-, and 9-month repeat dose studies of RPPX in minipigs were initiated at dose levels of 7.5, 25 and 75 mg/kg.
  • dose levels were reduced to 7.5, 25 and 50 mg/kg due to mortalities at the 75 mg/kg level.
  • the 3- and 6-month repeat dose studies have now been completed at the 7.5, 25 and 50 mg/kg dose levels and the 9-month repeat dose study is ongoing. No target organ toxicity by histopathology examination was identified at any dose level following animal sacrifice after 3 months of exposure.
  • the NOAEL for the 3-month study in minipigs is considered to be 50 mg/kg.
  • Exposure at steady state in rats, miniptgs, and humans is linear across ail doses studied. After 3 months of dosing, the NOAEL in rats has been determined to be 100 mg/kg; and the NOAEL in minipigs has been determined to be 50 mg/kg.
  • the mean AUC in rats at the NOAEL was 61,299 and 61 ,484 h*ng/mL for males and females, respectively, and for minipigs was 91 ,812 and 131,731 h*ng/mL for males and females, respectively.
  • the mean AUC in humans at steady state at a dose of 100 mg Ql 2H ⁇ 200 mg total daily dose) was 2,574 h*ng/mL.
  • EXAMPLE 4 Preparation of Capsules with RPPX.
  • RPPX dihydrochJoride monohydrate is filled in hard gelatin capsules with no excipients.
  • the capsules used for the drug product are #00 blue opaque gelatin capsules from Hawkins Chemical Group. Dose strengths of 50 and 500 mg are produced. Matching placebo capsules are filled with microcrystalline cellulose.
  • Capsules are prepared by weighing individual empty capsules and recording the weight (W e ). Specified amount of active drug substance are individually weighed and hand-filled into a capsule bottom using a Torpac ⁇ filling funnel.
  • Capsule tops are joined with the filled capsule bottom.
  • the filled capsules are then weighed, and the weight is recorded (W f ).
  • the calculated weight of the drug substance in the capsule (WrW e ) is recorded. If this calculated weight is within +/-5% of the nominal weight, then the capsule is cleaned, polished, and placed into and appropriately labeled container. If the calculated weight is outside of the specified range, the capsule is discarded.
  • the free-base weight per capsule (free-base weight per mg of capsule contents multiplied by fill weight) is 90% to 100% of the calculated label claim. Total impuritie are ⁇ 2%.
  • the appearance is a blue capsule containing white to off-white powder.
  • EXAMPLE 4B Preparation of Tablets with RPPX.
  • Capsules with 125 mg dose strength are prepared with the composition shown in Table 17.
  • Capsules are generally prepared under conditions of 60 to 74°F and a relative humity of 30 to 60%.
  • Microcrystalline cellulose, mannitol, crospovidone, magnesium stearate, and RPPX (milled) are weighed out in the amounts shown in the column "Quantity/batch" in Table 14.
  • the microcrystalline cellulose, mannitol, crospovidone, and RPPX are then hand screened through a #20 mesh stainless steel screen and transferred to a Maxibiend V-blender with a 4 quart shell.
  • the materials are then mixed using the Maxibiend V-blender for 10 minutes.
  • the magnesium stearate is then screened using a 30 mesh stainless steel hand screen and transferred to the blender.
  • the powders are then mixed for five minutes.
  • the final blend is then emptied into a labeled, double PE-lined drum and the gross, tare, and net weights are recorded.
  • Tablets are prepared using a Minipress II B with 5 stations of 3/8" round, standard, concave tooling and gravity feed frame. The final blend is placed in the hopper and the tablet press set up is run according to the specifications in Table 15. Table 14: Tablet aud Batch Compositions
  • EXAMPLE 5 Preparatioa of RPPX ⁇ -TSA salt: Condition A: All reagents were purchased from CNH technologies, Fisher, Aldrich, GJ. Chemicals, Puritan s TCI and Spectrum and were used as provided. Proton nuclear magnetic resonance spectra were obtained on a Bruker AC 300 spectrometer at 300 MHz. HPLC analysis for chiral purity was performed on a Chiralpak ⁇ IA column (5 ⁇ M, 250 x 4.6 mm) at 3O[d] using a mobile phase of heptane/ethanol/diethylamine (80:20:2 v/v/v).
  • HPLC analysis for chemical purity was performed on a Sunfire® column (3.5 ⁇ M, 150 x 4.6 mm) at 3O[d] using two mobile phases; A - 0.5% TFA in water; and B - 0.5% TFA in methanol. A gradient of 5%B to $0%B was used to separate the diamine and pramipexole peaks. A detection wavelength of 265 run was used for both HPLC analyses.
  • a 2.0 liter, three-necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 500 ml addition funnel.
  • the flask was charged with 45 grams of R(+)-2,6 diamino-4,5,6,7-tetrahydro- benzothiazole, followed by 750 ml of n-propanol. Under continuous stirring, the mixture was heated to a temperature of 95[d] over 15 minutes generating a clear solution.
  • the addition funnel was charged with a solution of 74 grams propyl tosylate and 60 ml diisopropylethyleamme in 250 ml n-propanol. This solution was added dropwise to the 2.0 liter flask with continuous stirring over a period of 4 hours. The reaction was continued with stirring for an additional 8 hours at 95°C, after which the solution was brought to room temperature, and stirring was continued for an additional 4 hours.
  • EXAMPLE 6 Preparation of racemic pramipexole p-TSA salt: Condition A: A 250 ml, three necked flask was equipped with a magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 100 ml addition funnel. The flask was charged with 5 grams of racemic 2,6 diamino ⁇ 4,5,6,7-tetrahydro- benzothiazole, followed by 80 ml of n-propanol. Under continuous stirring, the mixture was heated to a temperature of 95[d] over 15 minutes generating a clear solution.
  • the addition funnel was charged with a solution of 10.12 grams propyl tosylate and 8.2 ml diisopropylethyleamine in 28 ml n-propanol. This solution was added dropwise to the 250 ml flask with continuous stirring over a period of 2 hours. The reaction was continued with stirring for an additional 6 hours at 95[d], after which the solution was brought to room temperature, and stirring was continued for an additional 6 hours.
  • EXAMPLE 7 Preparation of RPVXp-TSA salt: Condition C: A 12 L, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 500 ml addition funnel. The flask was charged with 250 grams of R(+)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (R(+) diamine), followed by 2 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 65°C.
  • R(+)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole R(+) diamine
  • DMF dimethyl formamide
  • the addition funnel was charged with a solution of 386.6 grams propyl tosylate (1.25 molar equivalents) and 322 ml diisopropylethyleamine (1 ,25 molar equivalents) in 500 ml DMF. This solution was added to the 12 L flask dropwise over a period of 2.0 hours. The reaction was monitored by analysis on HPLC.
  • the final weight of the dried product was 317.6 grams, representing a 56% yield.
  • HPLC was used to determine the chemical purity of the R(+)-2,6-diamino-4,5,6,7- tetrahydro-benzothiazole (PPX) as 98.4% and the chiral purity as greater than 99.8%.
  • EXAMPLE 8 Conversion of RPPX/J-TSA salt to RPPX dihydrochloride: RPPX ⁇ -TSA salt (50 grams; 0.13 mol) was taken into 150 ml absolute ethanol and cooled to between 0 and 5[d] with continuous stirring. Concentrated HCl (33 ml) was slowly added to the reaction while maintaining the temperature at between 0 and 5°C, and the mixture was stirred for an additional 15 minutes. MTBE (200 ml) was added to the mixture, and stirring was continued for an additional 1.5 hours at temperature. The reaction mixture was then filtered, washed twice with an MTBE/ethanol solution (2:1 , 2 x 50 ml wash volumes), and dried under vacuum at 30[d] overnight.
  • RPPX /J-TSA salt (10 grams; 0.026 mol) was dissolved in 200 ml IPAC and cooled to 15[d] with continuous stirring. HCl gas was bubbled into the slurry for 1 hour. The mixture was then filtered, washed with IPAC, and dried overnight under vacuum at room temperature. The final product was 6.8 grams of RPPX dihydrochloride, indicative a of 92% yield, and a 97% chemical purity as determined by HPLC.
  • EXAMPLE 10 Conversion of RPPX/>-TSA salt to RPPX free base:
  • RPPX p-TSA salt (25 grams; 0.065 mol) was dissolved in 200 ml DCM and mixed into a slurry. 10 ml of water was added and the mixture was basified with 12 mi of 6N NaOH to a pH of 11-12. The two phases were split, and the aqueous was extracted with 200 ml of DCM. The combined organic phases were dried over MgSO 4 , filtered over Celite® and concentrated. The residue was dissolved in 100 ml MTBE and slurried for several hours. The solids were then filtered, washed with MTBE and dried under vacuum at 35[d]. The final product was 9.1 grams of RPPX dihydrochloride, indicative a of 66% yield, and a 98% chemical purity as determined by HPLC.
  • EXAMPLE 11 Conversion of RPPX/>-TSA salt to RPPX free base Freebase formation was performed on a 200 gram scale.
  • a 5 L, three necked, round- bottomed flask, equipped with an over head stirrer, thermometer, and addition funnel was charged with 200 g (0.522 mol) of RPPXp-TSA salt and 3 L of water.
  • the mixture was stirred and cooled to 1O[d].
  • the slurry was basified to a pH of about 11-12 by the slow addition of 200 mi of 6 N NaOH over period of 15 min.
  • the reaction mixture was diluted with 500 ml of brine (sodium chloride dissolved in water) and extracted with 3 ⁇ 1 L of dichloromethane.
  • EXAMPLE 12 Conversion of RPPX free base to RPPX dihydrochloride: The freebase of RPPX (4.8 grams; 0.022 mol) was dissolved in 200 ml of IPAC and cooled to 15[d]. HCl gas was bubbled into the slurry for 1 hour. The mixture was then filtered, washed with IPAC and dried under vacuum at room temperature overnight. The final product was 6.4 grams of RPPX dihydrochloride, indicative a of 100% yield, and a 97% chemical purity as determined by HPLC.
  • EXAMPLE 13 Conversion of RPPX free base to RPPX dihydrochloride: The freebase of RPPX (50 grams; 0.13 mol) was dissolved in 500 ml of IPAC. Under continuous stirring, the mixture was slowly charged with 78 ml of concentrated HCl at a temperature of 25[d]. The mixture was stirred overnight at ambient conditions (-25[d]), filtered and dried under vacuum at 4O°C The final product was 68 grams of RPPX dihydrochloride, indicative a of 95% yield.
  • EXAMPLE 14 Optica! purification of RPPX using achiral acid addition: Pramipexole enantioenriched for the R(+) enantiomer (-300 mg) was dissolved in 10 ml of the chosen solvent at 75°C (see examples in Table 8; etha ⁇ ol or acetonitriJe). Complete dissolution was observed in all samples.
  • EXAMPLE 15 Industrial scale resolution of racemic diamine: A 72 L, unjacketed reactor was charged with racemic 2,6 diamino-4,5, ⁇ ,7-tetrahydro-benzothiazole (rac-diamine) (4.5 kg; 26.6 mol) and 58.5 L water, and heated as a suspension to a temperature of about 6O[d] to 65°C Resolution of the enantiomers was achieved by addition of one equivalent of (D)-(-)-Tartaric acid (3991 grams; 26.6 mol) in 4.5 L of water, after which the resulting solution was heated to a temperature of about 70°C to 75[d] and maintained at this temperature for about 1 hour. The mixture was allowed to cool to a temperature of about 2O[d] to 25°C and stirred for an additional 15 hours, after which the mixture was filtered and the solids were washed 3 X with water (6.3 L each wash).
  • rac-diamine racemic 2,6 diamino-4,5, ⁇ ,7-te
  • the wet solids which contain the R(+) enantiomer of the diamine, were charged to the reactor followed by 54 L of water, and the mixture was heated to a temperature of about 7O[d] to 75[d] for 2 hours. The mixture was allowed to cool to a temperature of about 20°C to 25[d] and stirred for 17 hours. The mixture was then filtered and the solids were washed 2 X with water (4.5 L each wash). The wet solids were transferred to a jacketed reactor and the reactor was charged with 8.1 L of water.
  • the mixture was cooled to a temperature of about O[d] to 5°C and cautiously charged with concentrated 1.625 L of HC3, followed by 1.155 L of 50% NaOH to achieve a pH of about 9-10. During the addition the temperature was maintained at about 0[d] to 5°C, and stirred for an additional hour at temperature. The resulting mixture was then filtered and the solids were washed 2 X with cold (O[d] tO 5°C) water ( 1.125 L each wash). The solids were transferred to a jacketed reactor and were reslurried once more with 4.5 L of water at O[d] to 5[d]. The solids were filtered and dried under warm air (4O[d] to 45[d]) to give 1940 grams of the product (R(+) diamine) as a white solid, with an 86% yield for the R(+) enantiomer.
  • the application presents methods for using pure compositions of RPPX in acute and chronic neurodegenerative disorders previously inaccessible to this drug and immediately at full- strength without dose-titration and at higher theoretical MTDs. Additionally, the data showing that a pure composition of RPPX can be mixed with a known amount of PPX to produce dopamine receptor agonist effects determined solely by the contribution of the (S)- enantiomer allows for the use of compositions comprising the mixture of known amounts of pure (R)- and (S)-enantiomers for use in neurodegenerative disorders amenable to both dopamine receptor agonist treatment and neuroprotection, such as PD.
  • EXAMPLE 17 - Industrial scale preparation of RPPX/>-TSA salt Condition C: A 72 liter unjacketed reactor was charged with 1.84 kg (10.87 mol) of R(+)- 2,6 diammo-4,5,6,7-tetrahydro-benzothiazole (R(+) diamine), followed by 14.7 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of between 65[d] and 68°C A solution of 2926 grams propyl tosylate and 1761 grams diisopropylethyleamine in 3.455 L DMF was added slowly over a period of 2 hours.
  • the reaction was continued at 67[d] for an additional 4 hours, after which the solution was gradually cooled to room temperature ( 18[d] to 22[d]) and stirred for an additional 15 hours.
  • the solution was diluted with 14.72 L of MTBE over a time period of 30 minutes, and stirred for an additional 1 hour.
  • the precipitated material was collected by filtration and washed with 7.32 L MTBE 7 followed by 3 washes of 3.68 L each of ethanol, and a wash with 9.2 L heptane.
  • the washed precipitated cake was dried under high vacuum at 3O[d] to 35°C.
  • the final weight of the dried product was 2090 grams, representing a 50% yield.
  • EXAMPLE 18 The following provides an exemplary simulation of the plasma concentration-time profiles of KNS-760704 that would be obtained at steady-state after administration according to various regimens based on a compartmental model that was fit to the mean data from Study KNS-760704-CLOOl, in which single 50 mg and 150 mg doses were administered to healthy volunteers, wherein the target was a trough concentration of I ⁇ M (211 ng/mL) with once-daily dosing of 300 mg RPPX as the salt (equivalent to 224 mg base) in a matrix-type formulation with substantially first-order type of release.
  • Table 17 Predicted in vivo/in vitro release profile for a once-daily controlled-release KNS- 760704 formulation.
  • the modeling predicts a Cmin of 185 ng/mL and a Cmax of 219 ng/mL, slightly under and over the 21 ⁇ ng/mL (1 ⁇ M) target trough and provides a relatively flat curve.
  • This modeling provides just one example of a particular extended release formulation.
  • Other formulations, as described herein, can be formulated to provide/maintain other targeted Cmin and Cmax measurements.
  • a formulation comprising 400 mg that may result in a Cmin of about 21 1 ng/mL (1 ⁇ M) and a Cmax of about 320 ng/mL, well below the observed Cmax of about 479 ng/mL after administration of the immediate release 150 mg formulation every 12 hours in KNS-760704-CL002.
EP08743922A 2007-03-14 2008-03-14 Modifizierte freisetzungsformulierungen von (6r)-4,5,6,7-tetrahydro-n6-propyl-2,6-benzothiazoldiamin und verwendungsverfahren Withdrawn EP2136638A4 (de)

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