Source: http://www.google.com/patents/US7815942?ie=ISO-8859-1
Timestamp: 2014-11-21 03:30:57
Document Index: 144258625

Matched Legal Cases: ['Application No. 200680005518', 'Application No. 06720975', 'Application No. 200680005518', 'Application No. 2007135169', 'Application No. 200680005518', 'Application No. 560660']

Patent US7815942 - selective irreversible inhibitor of the B-form of the enzyme monoamine ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsDisclosed are pharmaceutical preparations of R(+)-N-propargyl-1-aminoindan salts having enhanced content uniformity, processes for preparation of the compositions, and their uses....http://www.google.com/patents/US7815942?utm_source=gb-gplus-sharePatent US7815942 - selective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment of Parkinson's disease; R(+)-N-propargyl-1-aminoindan salts, in particular tartrate, esylate, mesylate, or sulfate saltsAdvanced Patent SearchPublication numberUS7815942 B2Publication typeGrantApplication numberUS 11/359,324Publication dateOct 19, 2010Filing dateFeb 22, 2006Priority dateFeb 23, 2005Fee statusPaidAlso published asCA2600011A1, EP1848402A1, EP1848402A4, US20060188581, WO2006091657A1Publication number11359324, 359324, US 7815942 B2, US 7815942B2, US-B2-7815942, US7815942 B2, US7815942B2InventorsTirtza Berger PeskinOriginal AssigneeTeva Pharmaceutical Industries, Ltd.Export CitationBiBTeX, EndNote, RefManPatent Citations (58), Non-Patent Citations (39), Referenced by (11), Classifications (18), Legal Events (2) External Links: USPTO, USPTO Assignment, Espacenetselective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment of Parkinson's disease; R(+)-N-propargyl-1-aminoindan salts, in particular tartrate, esylate, mesylate, or sulfate saltsUS 7815942 B2Abstract Disclosed are pharmaceutical preparations of R(+)-N-propargyl-1-aminoindan salts having enhanced content uniformity, processes for preparation of the compositions, and their uses.
FIELD OF THE INVENTION The present invention concerns formulations of the enantiomer R(+)-N-propargyl-1-aminoindan (referred to hereinafter as R(+) PAI or rasagiline) which is a selective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment of Parkinson's disease. The enzyme monoamine oxidase is referred to herein as MAO and the B-form thereof as MAO-B.
BACKGROUND OF THE INVENTION U.S. Pat. No. 5,532,415 discloses R(+)-N-propargyl-1-aminoindan, its preparation, and various pharmaceutically acceptable salts thereof. U.S. Pat. No. 6,126,968 discloses pharmaceutical compositions comprising R(+)PAI. R(+)PAI and salts thereof have been shown to be selective inhibitors of MAO-B, useful in treating Parkinson's disease and various other conditions.
SUMMARY OF THE INVENTION In accordance with the invention it has been surprisingly found that certain particle size distributions have a beneficial effect on the content uniformity of solid pharmaceutical compositions of R(+)PAI. Milling, as well as other methods, can be used to alter the particle size distribution (hereinafter �PSD�) of R(+)PAI in order to provide greater uniformity of content of the drug product.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts R(+)PAI mesylate particles before milling. The micrograph was prepared as a paraffin oil suspension and taken at 80� magnification.
FIG. 2 depicts R(+)PAI mesylate particles after milling. The micrograph was prepared as a paraffin oil suspension and taken at 80� magnification.
DETAILED DESCRIPTION OF THE INVENTION The subject invention provides a mixture of particles of a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan, wherein more than 90% of the total amount by volume of R(+)-N-propargyl-1-aminoindan salt particles have a size of less than 250 microns.
Such compositions may comprise the compound of R(+)PAI or pharmaceutically acceptable acid addition salts thereof, together with pharmaceutically acceptable carriers and/or excipients. In the practice of this invention, pharmaceutically acceptable salts include, but are not limited to, the mesylate, maleate, fumarate, tartrate, hydrobromide, esylate, p-tolunesulfonate, benzoate, acetate, phosphate and sulfate salts. Particles of R(+)PAI salts are referred to herein as �R(+)PAI particle� or active ingredient or the drug substance.
R(+)PAI mesylate, however, is readily soluble in water (approximately 617 mg/mL at 25� C.). Such fast dissolution behavior minimizes concerns related to gastrointestinal absorption and bioavailability. Hence, increasing solubility is not a motivating factor for comminution of R(+)PAI.
The disadvantage of comminution is illustrated by the drug Nitrofurantoin, an antibacterial drug used in the treatment of uncomplicated lower urinary-tract infections. Its absorption rate is dependent on crystal size. The macrocrystalline form of Nitrofurantoin has slower dissolution and absorption rates, produces lower serum concentrations and takes longer to achieve peak concentration in urine than the microcrystalline form (Martindale). However, an 18-year study has shown that the microcrystalline form produces negative side effects (�adverse events�) such as nausea and gastro-intestinal problems. Such negative side effects did not manifest in subjects who took a macrocrystalline form dosage. (Brumfitt, W. and J. M. T. Hamilton-Miller, J. Antimicrobial Chemotherapy 42:363-371 (1998))
�Blend uniformity,� as used herein, refers to the homogeneity of granulate including R(+)PAI particles before tablet formulation, and can represent either one sample or the average of more than one sample.
�Content uniformity,� as used herein, refers to the homogeneity of the R(+)PAI content among dosage forms, e.g. tablets, after formulation.
�Particle,� as used herein, refers to an aggregated physical unit of the R(+)PAI compound, i.e., a piece or grain of the R(+) PAI. For example, FIGS. 1 and 2 provide photographic representations of various R(+) PAI particles.
�Relative standard deviation� or �RSD,� as used herein, refers to a measurement of how precise each measurement of blend uniformity or content uniformity is, i.e., how much each individual unit deviates from the group.
EXAMPLE 1 R(+)PAI mesylate samples before milling contain large, irregular, plate-shaped particles of various sizes (See FIG. 1). PSDs of four different batches were measured before milling and after milling. The PSDs were measured using Malvern Laser Diffraction, using the Mastersizer S model. Laser diffraction relies on the fact that diffraction angle of light is inversely proportional to particle size. Properties of particles are measured and interpreted as measurements of a sphere (a sphere being the only shape that can be described by one unique number). In addition, laser diffraction calculates a particle size distribution based around volume terms, thus eliminating particle count from the determination of particle size. The Masterizer S model measures particles using a single technique and a single range setting.
EXAMPLE 2 Formulations were prepared according to the following process, using several batches of R(+)PAI with controlled PSD determined by the method used in Example 1:
s = [ ∑ ( x i - X _ ) 2 n - 1 ] 1 / 2 RSD = 100 ⁢ s X _ In the above formulae, s is the standard deviation; RSD is the relative standard deviation; x1, x2, x3 . . . xn are individual amounts of the tested samples expressed as percentages of the labeled amount of drug substance in each sample; X(bar) is the mean of the values obtained from the samples tested, expressed as a percentage of the labeled amount of drug substance in each sample; and n is the number of units tested.
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", International Journal of Pharmaceutics. vol. 154, pp. 179-183.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS7855233Jan 18, 2010Dec 21, 2010Teva Pharmaceutical Industries, Ltd.Monorasagiline citrate; salt formation; monoamine oxidase inhibitors; side effects reduction; carriers; tablets; transdermal patches; Parkinson's disease; brain disorders; nervous system disorders; neurodegenerative disease; multiple sclerosisUS7968749Jun 19, 2009Jun 28, 2011Teva Pharmaceutical Industries, Ltd.Process for preparing and drying solid rasagiline baseUS8080584Jun 9, 2009Dec 20, 2011Teva Pharmaceuticals Industries, Ltd.Delayed release rasagiline citrate formulationUS8143315Aug 17, 2007Mar 27, 2012Ratiopharm GmbhSalts of the active substance rasagilineUS8163960May 13, 2011Apr 24, 2012Teva Pharmaceutical Industries, Ltd.Process for preparing and drying solid rasagiline baseUS8188149Sep 16, 2008May 29, 2012Teva Pharmaceutical Industries, Ltd.Use of R(+)-N-propargy1-1-aminoindan to treat or prevent hearing lossUS8334409Jun 19, 2009Dec 18, 2012Teva Pharmaceutical Industries, Ltd.Process for purifying rasagiline baseUS8569379Jul 27, 2011Oct 29, 2013Teva Pharmaceutical Industries Ltd.Use of rasagiline for the treatment of olfactory dysfunctionUS8614252Jan 8, 2010Dec 24, 2013Teva Pharmaceutical Industries Ltd.Crystalline solid rasagiline baseUS8691872Jul 27, 2011Apr 8, 2014Teva Pharmaceutical Industries Ltd.Dispersions of rasagiline citrateUS8809310Feb 21, 2007Aug 19, 2014Teva Pharmaceutical Industries, Ltd.Use of rasagiline for the treatment of multiple system atrophyClassifications U.S. Classification424/489, 424/464, 514/554, 564/429, 514/467, 514/657International ClassificationC07C211/00, A01N37/30, A61K9/20, A61K9/14, A61K31/135Cooperative ClassificationA61K9/14, A61K9/2018, A61K9/2059, A61K31/205European ClassificationA61K31/205, A61K9/14, A61K9/20H4BLegal EventsDateCodeEventDescriptionApr 10, 2014FPAYFee paymentYear of fee payment: 4Feb 22, 2006ASAssignmentOwner name: TEVA PHARMACEUTICAL INDUSTRIES, LTD., ISRAELFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PESKIN, TIRTZA BERGER;REEL/FRAME:017620/0087Effective date: 20060219RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google