U.S. patent application number 14/203209 was filed with the patent office on 2014-07-10 for dispersions of rasagiline citrate.
This patent application is currently assigned to Teva Pharmaceutical Industries Ltd.. The applicant listed for this patent is David Engers, Keith Lorimer. Invention is credited to David Engers, Keith Lorimer.
Application Number | 20140194510 14/203209 |
Document ID | / |
Family ID | 45530490 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140194510 |
Kind Code |
A1 |
Lorimer; Keith ; et
al. |
July 10, 2014 |
DISPERSIONS OF RASAGILINE CITRATE
Abstract
The subject invention provides a solid dispersion of rasagiline
citrate, a composition and a process for the manufacture
thereof.
Inventors: |
Lorimer; Keith; (Lisburn,
IE) ; Engers; David; (West Lafayette, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lorimer; Keith
Engers; David |
Lisburn
West Lafayette |
IN |
IE
US |
|
|
Assignee: |
Teva Pharmaceutical Industries
Ltd.
Petach-Tikva
IL
|
Family ID: |
45530490 |
Appl. No.: |
14/203209 |
Filed: |
March 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13192082 |
Jul 27, 2011 |
8691872 |
|
|
14203209 |
|
|
|
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61400369 |
Jul 27, 2010 |
|
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Current U.S.
Class: |
514/554 ;
264/140; 264/28; 264/5; 514/657 |
Current CPC
Class: |
A61K 9/19 20130101; A61K
47/32 20130101; A61K 9/1652 20130101; A61K 9/1635 20130101; A61K
31/205 20130101; A61K 31/135 20130101; A61P 25/16 20180101 |
Class at
Publication: |
514/554 ;
514/657; 264/5; 264/140; 264/28 |
International
Class: |
A61K 47/32 20060101
A61K047/32; A61K 31/205 20060101 A61K031/205; A61K 31/135 20060101
A61K031/135 |
Claims
1. A solid dispersion of at least one polymeric pharmaceutical
excipient and rasagiline or a pharmaceutically acceptable salt
thereof.
2. The solid dispersion of claim 1, wherein the at least one
polymeric pharmaceutical excipient is a water soluble polymeric
pharmaceutical excipient.
3. The solid dispersion of claim 1 or 2, wherein the
pharmaceutically acceptable salt of rasagiline is rasagiline
citrate.
4. The solid dispersion of claim 3, wherein the rasagiline citrate
is mono-rasagiline citrate.
5. The solid dispersion of any one of claims 1-4, wherein the at
least one polymeric pharmaceutical excipient is
polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose acetate succinate, or hydroxypropyl methylcellulose
phthalate.
6. The solid dispersion of any one of claims 1-4, wherein the at
least one polymeric pharmaceutical excipient is a co-polymer.
7. The solid dispersion of claim 6, wherein the co-polymer is
polyvinylpyrrolidone-vinyl acetate or methacrylic acid-ethyl
acrylate.
8. The solid dispersion of claim 7, wherein the co-polymer is
methacrylic acid-ethyl acrylate.
9. The solid dispersion of any one of claims 1-8, wherein T.sub.g
of the solid dispersion is at least 20.degree. C. higher than that
of rasagiline or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the solid dispersion of
any one of claims 1-9.
11. A process for making the solid dispersion of any one of claims
1-9, comprising: a) combining a mixture of rasagiline free base and
the at least one polymeric pharmaceutical excipient in a solvent to
form a solution; b) adding citric acid to the solution; and c)
removing the solvent from the solution.
12. The process of claim 11, wherein the solvent is methanol,
ethanol, acetone, dichloromethane, dioxane and water, or a mixture
of at least two thereof.
13. The process of claim 11 or 13, wherein step c) is performed at
a temperature of between about 55.degree. C. and 80.degree. C. by
rotary evaporation.
14. The process of claim 11 or 12, wherein in step b) the solvent
is removed by lyophilization.
15. A process for making the solid dispersion of any one of claims
1-9, comprising: a) dissolving a mixture of rasagiline or the
pharmaceutically acceptable salt thereof, and the at least one
polymeric pharmaceutical excipient in a solvent to form a solution;
and b) removing the solvent from the solution.
16. The process of claim 15, wherein the pharmaceutically
acceptable salt of rasagiline is rasagiline citrate.
17. The process of claim 16, wherein the rasagiline citrate is
mono-rasagiline citrate.
18. The process of any one of claims 15-17, wherein the solvent is
methanol, ethanol, acetone, dichloromethane, dioxane and water, or
a mixture of at least two thereof.
19. The process of any one of claims 15-18, wherein step b) is
performed at a temperature of between about 55.degree. C. and
80.degree. C. by rotary evaporation.
20. The process of any one of claims 15-18, wherein in step b) the
solvent is removed by lyophilization.
21. A process for making the solid dispersion of any one claims
1-9, comprising: a) combining a mixture of rasagiline free base,
the at least one polymeric pharmaceutical excipient, and citric
acid; and b) grinding the mixture.
22. The process of claim 21, wherein step b) is performed by dry
milling the mixture.
23. The process of claim 21, wherein step b) is performed by wet
milling the mixture with a solvent.
24. The process of claim 23, wherein the solvent is methanol or
acetone.
25. The process of claim 21, wherein step b) is performed at a
temperature below -100.degree. C.
26. A process for making the solid dispersion of any one of claims
1-9, comprising: a) obtaining a solid mixture of rasagiline or the
pharmaceutically acceptable salt thereof, and the at least one
polymeric pharmaceutical excipient; and b) grinding the
mixture.
27. The process of claim 26, wherein the pharmaceutically
acceptable salt of rasagiline is rasagiline citrate.
28. The process of claim 27, wherein the rasagiline citrate is
mono-rasagiline citrate.
29. The process of any one of claims 26-28, wherein step b) is
performed by dry milling the mixture.
30. The process of claim any one of claims 26-28, wherein step b)
is performed by wet milling the mixture with a solvent.
31. The process of claim 30, wherein the solvent is methanol or
acetone.
32. The process of claim any one of claims 26-28, wherein step b)
is performed at a temperature below -100.degree. C.
33. A method of treating a human subject afflicted with Parkinson's
disease comprising administering to the human subject an amount of
the pharmaceutical composition of claim 10, effective to treat the
human subject.
Description
[0001] This application claims benefit of U.S. Provisional
Application No. 61/400,369, filed Jul. 27, 2010, the contents of
which are hereby incorporated by reference.
[0002] Throughout this application various publications, published
patent applications, and patents are referenced. The disclosures of
these documents in their entireties are hereby incorporated by
reference into this application in order to more fully describe the
state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133,
5,599,991, 5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061,
5,786,390, 6,316,504, 6,630,514 disclose
R(+)-N-propargyl-1-aminoindan ("R-PAI"), also known as rasagiline.
U.S. Pat. No. 6,126,968 and PCT International Application
Publication No. WO 95/11016 disclose pharmaceutical compositions
comprising rasagiline. Rasagiline has been reported to be a
selective inhibitor of the B-form of the enzyme monoamine oxidase
("MAO-B") and is useful in treating Parkinson's disease and various
other conditions by inhibition of MAO-B in the brain.
[0004] A formulation of rasagiline mesylate is approved for
treating Parkinson's disease either as monotherapy or as an adjunct
with other treatments. See, e.g. AZILECT.RTM., Physicians' Desk
Reference 2009 (PRD, 63.sup.th Edition).
[0005] AZILECT.RTM. is indicated for the treatment of the signs and
symptoms of idiopathic Parkinson's disease as initial monotherapy
and as adjunct therapy to levodopa. Rasagiline, the active
ingredient of AZILECT.RTM., is rapidly absorbed, reaching peak
plasma concentration (C.sub.max) in approximately 1 hour. The
absolute bioavailability of rasagiline is about 36%. (AZILECT.RTM.
Product Label, May 2006).
[0006] While not previously identified as a problem for rasagiline,
there remains a need for a solid dispersion of rasagiline with
polymeric pharmaceutical excipients that exhibits suitable handling
properties.
SUMMARY OF THE INVENTION
[0007] The subject invention provides a solid dispersion of at
least one polymeric pharmaceutical excipient and rasagiline or a
pharmaceutically acceptable salt thereof.
[0008] The subject invention also provides a pharmaceutical
composition comprising the solid dispersion described herein.
[0009] The subject invention further provides a process for making
the solid dispersion described herein, comprising: [0010] a)
dissolving a mixture of rasagiline or the pharmaceutically
acceptable salt thereof, and the at least one polymeric
pharmaceutical excipient in a solvent to form a solution; and
[0011] b) removing the solvent from the solution.
[0012] The subject invention yet further provides a process for
making the solid dispersion described herein, comprising: [0013] a)
obtaining a solid mixture of rasagiline or the pharmaceutically
acceptable salt thereof, and the at least one polymeric
pharmaceutical excipient; and [0014] b) grinding the mixture.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1: Cyclic Differential Scanning calorimetry (DSC)
thermogram of Rasagiline citrate, sample size 3.43 mg, 20.degree.
C./min.
[0016] FIG. 2: Modulated Differential Scanning calorimetry (MDSC)
thermogram of Rasagiline citrate, sample size 4.00 mg, 2.degree.
C./min.
[0017] FIG. 3: Trending of glass transition temperature (T.sub.q)
by varying polymer content
DETAILED DESCRIPTION OF THE INVENTION
[0018] The subject invention provides a solid dispersion of at
least one polymeric pharmaceutical excipient and rasagiline or a
pharmaceutically acceptable salt thereof.
[0019] In an embodiment of the solid dispersion, the at least one
polymeric pharmaceutical excipient is a water soluble polymeric
pharmaceutical excipient.
[0020] In another embodiment of the solid dispersion, the
pharmaceutically acceptable salt of rasagiline is rasagiline
citrate.
[0021] In yet another embodiment of the solid dispersion, the
rasagiline citrate is mono-rasagiline citrate.
[0022] In yet another embodiment of the solid dispersion, the at
least one polymeric pharmaceutical excipient is
polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose acetate succinate, or hydroxypropyl methylcellulose
phthalate.
[0023] In yet another embodiment of the solid dispersion, the at
least one polymeric pharmaceutical excipient is a co-polymer.
[0024] In yet another embodiment of the solid dispersion, the
co-polymer is polyvinylpyrrolidone-vinyl acetate or methacrylic
acid-ethyl acrylate.
[0025] In yet another embodiment of the solid dispersion, the
co-polymer is methacrylic acid-ethyl acrylate.
[0026] In yet another embodiment of the solid dispersion, T.sub.g
of the solid dispersion is at least 20.degree. C. higher than that
of rasagiline or a pharmaceutically acceptable salt thereof.
[0027] The subject invention also provides a pharmaceutical
composition comprising the solid dispersion described herein.
[0028] The subject invention further provides a process for making
the solid dispersion of rasagiline citrate described herein,
comprising: [0029] a) combining a mixture of rasagiline free base
and the at least one polymeric pharmaceutical excipient in a
solvent to form a solution; [0030] b) adding citric acid to the
solution; and [0031] c) removing the solvent from the solution.
[0032] The subject invention further provides a process for making
the solid dispersion of rasagiline citrate described herein,
comprising: [0033] a) dissolving a mixture of rasagiline or the
pharmaceutically acceptable salt thereof, and the at least one
polymeric pharmaceutical excipient in a solvent to form a solution;
and [0034] b) removing the solvent from the solution.
[0035] In an embodiment of the process, the pharmaceutically
acceptable salt of rasagiline is rasagiline citrate.
[0036] In another embodiment of the process, the rasagiline citrate
is mono-rasagiline citrate.
[0037] In an embodiment of the process, the solvent is methanol,
ethanol, acetone, dichloromethane, dioxane and water, or a mixture
of at least two thereof.
[0038] In another embodiment of the process, step b) is performed
at a temperature of between about 55.degree. C. and 80.degree. C.
by rotary evaporation.
[0039] In yet another embodiment of the process, in step b) the
solvent is removed by lyophilization.
[0040] The subject invention yet further provides a process for
making the solid dispersion of rasagiline citrate described herein,
comprising: [0041] a) combining a mixture of rasagiline free base,
the at least one polymeric pharmaceutical excipient, and citric
acid; and [0042] b) grinding the mixture.
[0043] The subject invention yet further provides a process for
making the solid dispersion of rasagiline citrate described herein,
comprising: [0044] a) obtaining a solid mixture of rasagiline or
the pharmaceutically acceptable salt thereof, and the at least one
polymeric pharmaceutical excipient; and [0045] b) grinding the
mixture.
[0046] In an embodiment of the process, the pharmaceutically
acceptable salt of rasagiline is rasagiline citrate.
[0047] In another embodiment of the process, the rasagiline citrate
is mono-rasagiline citrate.
[0048] In yet another embodiment of the process, step b) is
performed by dry milling the mixture.
[0049] In yet another embodiment of the process, step b) is
performed by wet milling the mixture with a solvent.
[0050] In yet another embodiment of the process, the solvent is
methanol or acetone.
[0051] In yet another embodiment of the process, step b) is
performed at a temperature below 0.degree. C.
[0052] In yet another embodiment of the process, step b) is
performed at a temperature below -10.degree. C.
[0053] In yet another embodiment of the process, step b) is
performed at a temperature below -25.degree. C.
[0054] In yet another embodiment of the process, step b) is
performed at a temperature below -50.degree. C.
[0055] In yet another embodiment of the process, step b) is
performed at a temperature below -100.degree. C.
[0056] In yet another embodiment of the process, step b) is
performed at a temperature below -150.degree. C.
[0057] The subject invention yet further provides a method of
treating a human subject afflicted with Parkinson's disease
comprising administering to the human subject an amount of the
pharmaceutical composition of claim 8, effective to treat the human
subject.
[0058] By any range disclosed herein, it is meant that all
hundredth, tenth and integer unit amounts within the range are
specifically disclosed as part of the invention. Thus, for example,
0.01 mg to 50 mg means that 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . .
0.9; and 1, 2 . . . 49 mg unit amounts are included as embodiments
of this invention.
[0059] Citric acid is a weak organic acid, and is triprotic.
Therefore, the rasagiline citrate described herein may exist in
mono-, di- or tri-rasagiline citrate form or a mixture thereof.
[0060] As used herein, an example of an immediate release
formulation of rasagiline is an AZILECT.RTM. Tablet containing
rasagiline mesylate.
[0061] As used herein, a polymer is a large molecule composed of
repeating structural units typically connected by covalent chemical
bonds.
[0062] As used herein, a "pharmaceutically acceptable" carrier or
excipient is one that is suitable for use with humans and/or
animals without undue adverse side effects (such as toxicity,
irritation, and allergic response) commensurate with a reasonable
benefit/risk ratio.
[0063] As used herein, a "pharmaceutically acceptable salt" of
rasagiline includes citrate, tannate, malate, mesylate, maleate,
fumarate, tartrate, esylate, p-toluenesulfonate, benzoate, acetate,
phosphate and sulfate salts. For the preparation of
pharmaceutically acceptable acid addition salts of the compounds of
the invention, the free base can be reacted with the desired acids
in the presence of a suitable solvent by conventional methods.
[0064] Rasagiline can also be used in its free base form. A process
of manufacture of the rasagiline free base is described in POT
publication WO 2008/076348, the contents of which are hereby
incorporated by reference.
[0065] As used herein, an "isolated" compound is a compound that
has been separated from the crude reaction mixture in which it
formed by an affirmative act of isolation. The act of isolation
necessarily involves separating the compound from the other known
components of the crude reaction mixture, with some impurities,
unknown side products and residual amounts of the other known
components of the crude reaction mixture permitted to remain.
Purification is an example of an affirmative act of isolation.
[0066] As used herein, a composition that is "free" of a chemical
entity means that the composition contains, if at all, an amount of
the chemical entity which cannot be avoided following an
affirmative act intended to separate the chemical entity and the
composition.
[0067] As used herein, a "glass transition temperature (T.sub.g)"
of a solid is the temperature where the solid goes from a rigid
state to a flexible state. At T.sub.g, a polymer undergoes a phase
transition from a hard, glass-like state to a flexible, rubber-like
state. The T.sub.g temperature values listed herein were determined
based upon half-height of the step change or "S" shape curve seen
in DSC data.
[0068] As used herein, a polymer is a large molecule composed of
repeating structural units typically connected by covalent chemical
bonds.
[0069] As used herein, a "solid dispersion" is a drug-containing
pharmaceutical bulk substance in which the drug is dispersed in a
pharmaceutical excipient such as a polymer, a co-polymer, or a
mixture thereof.
[0070] Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate oral dosage forms of
the present invention are described, e.g., in U.S. Pat. No.
6,126,968 to Peskin et al., issued Oct. 3, 2000. Techniques and
compositions for making dosage forms useful in the present
invention are described, for example, in the following references:
7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,
Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et
al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd
Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack
Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical
Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in
Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones,
James McGinity, Eds., 1995); Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences,
Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate
Carriers: Therapeutic Applications: Drugs and the Pharmaceutical
Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the
Gastrointestinal Tract (Ellis Horwood Books in the Biological
Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S.
Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the
Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.
Rhodes, Eds.).
[0071] The pharmaceutical dosage forms may be prepared as
medicaments to be administered orally, parenterally, rectally or
transdermally. Suitable forms for oral administration include
tablets, compressed or coated pills, dragees, sachets, hard or soft
gelatin capsules, sublingual tablets, syrups and suspensions; for
parenteral administration the invention provides ampoules or vials
that include an aqueous or non-aqueous solution or emulsion; for
rectal administration the invention provides suppositories with
hydrophilic or hydrophobic vehicles; for topical application as
ointments; and for transdermal delivery the invention provides
suitable delivery systems as known in the art.
[0072] Tablets may contain suitable binders, lubricants,
disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents, melting agents, stabilizing agents,
solubilizing agents, antioxidants, buffering agent, chelating
agents, fillers and plasticizers. For instance, for oral
administration in the dosage unit form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as gelatin, agar,
starch, methyl cellulose, dicalcium phosphate, calcium sulfate,
mannitol, sorbitol, microcrystalline cellulose and the like.
Suitable binders include starch, gelatin, natural sugars such as
corn starch, natural and synthetic gums such as acacia, tragacanth,
or sodium alginate, povidone, carboxymethylcellulose, polyethylene
glycol, waxes, and the like. Antioxidants include ascorbic acid,
fumaric acid, citric acid, malic acid, gallic acid and its salts
and esters, butylated hydroxyanisole, editic acid. Lubricants used
in these dosage forms include sodium oleate, sodium stearate,
sodium benzoate, sodium acetate, stearic acid, sodium stearyl
fumarate, talc and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum,
croscarmellose sodium, sodium starch glycolate and the like,
suitable plasticizers include triacetin, triethyl citrate, dibutyl
sebacate, polyethylene glycol and the like.
[0073] One type of oral dosage forms of the present invention
relates to delayed release formulations. Such formulations may be
comprised of an acid resistant excipient which prevents the dosage
form or parts thereof from contacting the acidic environment of the
stomach. The acid resistant excipient may coat the rasagiline in
the form of an enteric coated tablet, capsule, or gelatin capsule.
Enteric coating, in the context of this invention, is a coating
which prevents the dissolution of an active ingredient in the
stomach. Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate such delayed release
formulations are described, e.g., in International Application
Publication No. WO 06/014973, hereby incorporated by reference in
its entirety.
[0074] Another type of oral dosage forms of the present invention
relates to fast disintegrating formulations which provide a means
to avoid the absorption of rasagiline in the stomach, and to
eliminate the need for swallowing tablets, by absorption of
rasagiline into the body before reaching the stomach. Such
absorption of rasagiline can be accomplished by contact with the
buccal, sublingual, pharyngeal and/or esophageal mucous membranes.
To accomplish this, the fast disintegrating formulations were
designed to rapidly disperse within the mouth to allow maximum
contact of rasagiline with the buccal, sublingual, pharyngeal
and/or esophageal mucous membranes. Specific examples of
pharmaceutically acceptable carriers and excipients that may be
used to formulate such fast disintegrating formulations are
described, e.g., in International Application Publication No. WO
03/051338, hereby incorporated by reference in its entirety.
[0075] Other pharmaceutical compositions of the present invention
include transdermal patches. Transdermal patches are medicated
adhesive patches placed on the skin to deliver a time-released dose
of medication through the skin and into the bloodstream. A wide
variety of pharmaceuticals can be delivered through transdermal
patches. Some pharmaceuticals must be combined with other
substances, for example alcohol, to increase their ability to
penetrate the skin. Transdermal patches have several important
components, including a liner to protect the patch during storage,
the drug, adhesive, a membrane (to control release of the drug from
the reservoir), and a backing to protect the patch from the outer
environment. The two most common types of transdermal patches are
matrix and reservoir types. (Wikipedia; and Remington, The Science
and Practice Pharmacy, 20.sup.th Edition, 2000)
[0076] In reservoir type patches, a drug is combined with a
non-volatile, inert liquid, such as mineral oil, whereas in matrix
type patches a drug is dispersed in a lipophilic or hydrophilic
polymer matrix such as acrylic or vinylic polymers. Adhesive
polymers, such as polyisobutylene, are used to hold the patch in
place on the skin. (Stanley Scheindlin, (2004) "Transdermal Drug
Delivery: PAST, PRESENT, FUTURE," Molecular Interventions,
4:308-312)
[0077] The major limitation to transdermal drug-delivery is the
intrinsic barrier property of the skin. Penetration enhancers are
often added to transdermal drug formulations in order to disrupt
the skin surface and cause faster drug delivery. Typical
penetration enhancers include high-boiling alcohols, diols, fatty
acid esters, oleic acid and glyceride-based solvents, and are
commonly added at a concentration of one to 20 percent (w/w).
(Melinda Hopp, "Developing Custom Adhesive Systems for Transdermal
Drug Delivery Products," Drug Delivery)
[0078] In all of its aspects, the present invention provides
pharmaceutical dosage forms useful for treating a condition
selected from the group consisting of: Parkinson's disease (PD),
brain ischemia, stroke, head trauma injury, spinal trauma injury,
neurotrauma, neurodegenerative disease, neurotoxic injury, nerve
damage, dementia, Alzheimer's type dementia, senile dementia,
depression, memory disorders, hyperactive syndrome, attention
deficit disorder, Multiple Sclerosis (MS), schizophrenia, affective
illness, Amyotrophic Lateral Sclerosis, Restless Legs Syndrome
(RLS), hearing loss, Multiple System Atrophy (MSA), Glucoma,
modifying Parkinson's disease, and Progressive Supranuclear Palsy
(PEP), but with a reduced risk of peripheral MAO inhibition that is
typically associated with administration of rasagiline with known
oral dosage forms.
[0079] A conventional method for the manufacture of a solid
dispersion relates to a fusion process which is characterized by
melting a drug substance and a polymeric pharmaceutical excipient
together at elevated temperature and, then, cooling the melt to
solidify. Another conventional method for the manufacture of a
solid dispersion relates to a solvent process which is
characterized by dissolving a drug substance and a polymeric
pharmaceutical excipient in an appropriate solvent and, then,
removing the solvent. Additional method for the manufacture of a
solid dispersion relates to mixing a drug substance and a polymeric
pharmaceutical excipient through milling.
[0080] Generally, a phase-separated dispersion will exhibit two
T.sub.g values, whereas a molecular dispersion will exhibit a
single T.sub.g.
[0081] The subject invention is also intended to include all
isotopes of atoms occurring on the compounds disclosed herein.
Isotopes include those atoms having the same atomic number but
different mass numbers. By way of general example and without
limitation, isotopes of hydrogen include tritium and deuterium.
Isotopes of carbon include C-13 and C-14.
[0082] It will be noted that any notation of a carbon in structures
throughout this application, when used without further notation,
are intended to represent all isotopes of carbon, such as .sup.12C,
.sup.13C, or .sup.14C. Furthermore, any compounds containing
.sup.13C or .sup.14C may specifically have the structure of any of
the compounds disclosed herein.
[0083] It will also be noted that any notation of a hydrogen in
structures throughout this application, when used without further
notation, are intended to represent all isotopes of hydrogen, such
as .sup.1H, .sup.2H, or .sup.3H. Furthermore, any compounds
containing .sup.2H or .sup.3H may specifically have the structure
of any of the compounds disclosed herein.
[0084] Isotopically-labeled compounds can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described in the Examples disclosed
herein using an appropriate isotopically-labeled reagents in place
of the non-labeled reagents employed.
[0085] This invention will be better understood from the
experimental details which follow. However, one skilled in the art
will readily appreciate that the specific methods and results
discussed are merely illustrative of the invention as described
more fully in the claims which follow thereafter.
Experimental Details
[0086] A solid dispersion screen was carried out using rasagiline
citrate and pharmaceutical excipients of polymers. Dispersions were
prepared using several techniques including rotary evaporation from
solution, cryogrinding dry components and lyophilization. Samples
were analyzed by modulated Differential Scanning calorimetry (DSC)
to determine glass transition temperatures (T.sub.g). A slight
excess of citric acid was used in most dispersions i.e. 0.7:1 mol
of rasagiline: citric acid.
[0087] The pharmaceutical excipients of polymers used in the
following example are listed in the table below:
TABLE-US-00001 Excipient Abbreviation polyvinylpyrrolidone- PVP-VA
vinyl acetate polyvinylpyrrolidone PVP K-29/32 polyvinylpyrrolidone
PVP K-90 hydroxypropyl HPMC methylcellulose hydroxypropyl HPMC-AS
methylcellulose- acetate succinate hydroxypropyl HPMC-P
methylcellulose- phthalate methacrylic acid Eudragit ethyl acrylate
L-100 copolymer
[0088] These pharmaceutical excipients of polymers each exhibits
characteristics as listed in the following table.
TABLE-US-00002 Excipient Observation.sup.a Eudragit L-100 small
white particles, no B/E HPMC small rod-like fragments, B/E HPMC-AS
small particles, some B/E HPMC-P small, irregular fragments, B/E
PVP K-29/32 small particles, B/E PVP K-90 small particles, B/E
.sup.aObservations by light microscopy. B = birefringence, E =
extinction.
Example 1
Preparation of Mono-Rasagiline Citrate Salt
[0089] In the following experiment, rasagiline base was mixed with
citric acid (1:1 mol:mol) and then methanol was added to the
mixture. After stirring and complete dissolution of solids, the
solution was evaporated under vacuum in rotary evaporator at bath
temperature 60.degree. C. The resulting foamy substance was dried
under vacuum to obtain mono-rasagiline citrate.
TABLE-US-00003 TABLE 1 Preparation of Mono-Rasagiline Citrate Salt
Sample Solvent/ No Conditions.sup.a Observations Analysis.sup.b
Result 1 MeOH/RE foamy HSM At 40.degree. C., @60.degree. C.,
substance solids vacuum become gel- dried like, all become gel at
80.degree. C. cyclic T.sub.g = 18.degree. C. DSC Modulated T.sub.g
= 16.degree. C. DSC .sup.aRE = rotary evaporation, .sup.bHSM =
hotstage microscopy, DSC = differential scanning calorimetry.
Example 2
Solid Dispersion of Rasagiline Citrate Prepared by Rotary
Evaporation
[0090] The experiments conducted in this example are listed below
in Table 2. In each of the experiments, rasagiline free base,
excipient, and citric acid were combined and mixed in the
corresponding solvent. A solid dispersion was prepared from the
mixture by rotary evaporation of the solvent at conditions listed
in Table 2 below.
TABLE-US-00004 TABLE 2 Exp. Excipient.sup.a No.* Solvent.sup.b
Conditions.sup.d Observation.sup.e Eudragit 1 EtOH RE @70.degree.
C. glassy solids, some which show L-100 extinction (1:1) vac. dried
glassy solids Eudragit 2.sup.c MeOH RE @65.degree. C., handleable
white powder, glassy L-100 vac. dried fragments, a few extinguish
(70:30) Eudragit 3.sup.c MeOH RE @60.degree. C., white solid,
stored @ -13.degree. C. L-100 vac. dried (75:25) HPMC 4
MeOH:H.sub.2O did not -- (1:1) dissolve, sample discarded HPMC 5
MeOH:DCM RE @60.degree. C., gel formed, plastic-like film (75:25)
vac. dried after vac dried w/B, stored @ -13.degree. C. HPMC 6
MeOH:H.sub.2O sample did -- (70:30) not dissolve HPMC-AS 7 MeOH:ACN
RE @80.degree. C. foamy subtance, very sticky (1:1) vac. dried gel
HPMC-AS 8.sup.c Acetone:MeOH RE @55.degree. C., many solids clung
to side of (70:30) vac. dried vial, scraped down solids are
handleable and off-white. Glassy fragments, no B/E HPMC-AS 9.sup.c
MeOH:DCM RE @60.degree. C., white foam, dry white powder (75:25)
vac. dried when dried HPMC-P 10 Acetone:H.sub.2O RE @50.degree. C.
foam with solid particles (1:1) dispersed, became gel HPMC-P 11
MeOH:DCM RE @60.degree. C., white foam, white powder when (75:25)
vac. dried dried HPMC-P 12.sup.c Acetone:DCM RE @55.degree. C.,
tacky white solids, glassy (90:10) vac. dried fragments PVP-VA 13
EtOH RE @70.degree. C. glassy solids, slightly sticky (1:1) to
spatula, no B/E under microscope vac. dride glassy solids 14.sup.c
DCM -- sample did not dissolve PVP-VA 15.sup.c Acetone:MeOH RE
@55.degree. C., handleable white solids, glassy (70:30) vac. dried
fragments, no B/E PVP-VA 16.sup.c Acetone:DCM RE @55.degree. C.,
fine white powder, easily (90:10) vac. dried handled, unifom glassy
fragments PVP 17 Acetone:EtOH RE @60.degree. C. foamy substance,
gel like K-29/32 vac. dried glassy material, became powder (1:1)
when touched with spatula. Glassy solids under microscope, no B/E
PVP 18 Acetone:MeOH RE @60.degree. C., vac white sticky solid, no
B/E, dry K-29/32 dried white solid when dried, stored @ (75:25)
-13.degree. C. PVP K-90 19 Acetone:EtOH RE @70.degree. C. glassy
solids, no B/E (1:1) PVP K-90 20.sup.c DCM:MeOH RE @50.degree. C.,
handleable white powder, glassy (70:30) vac. dried fragments, few
extinguish PVP K-90 21.sup.c MeOH:acetone RE @60.degree. C., white
foam, no B/E, dy white (75:25) vac. dried solid when dried, stored
@ -13.degree. C. PVP K-90 22.sup.c Acetone:DCM RE @55.degree. C.,
tacky white solids, glassy (90:10) vac. dried fragments *the molar
ratio of rasagiline:citric acid is 1:1 unless indicated otherwise
.sup.aExcipient: Rasagiline ratio (weight/weight) .sup.bExcipient
and Rasagiline dissolved in solvent, followed by addition of citric
acid in a 1:1 molar ratio. .sup.c0.7:1 molar ratio of
rasagiline:citric acid .sup.dRE = rotary evaporation.
.sup.eobservations by light microscopy. B = birefringence, E =
extinction
Example 3
Solid Dispersion of Rasagiline Citrate Prepared by Grinding
[0091] The experiments conducted in this example are listed below
in Table 3, In each of the experiments, rasagiline free base,
excipient, and citric acid were combined and mixed. A solid
dispersion was prepared from the mixture by dry milling, wet
milling, or cryo-grinding the mixture at conditions listed in Table
3 below.
TABLE-US-00005 TABLE 3 Exp. Excipient.sup.a No.* Conditions
Observation.sup.c HPMC .sup. 1.sup.b dry milled, 30 Hz, white
powder, solids present (60:40) 15 minutes with, B/E, no single
phase 2 wet milled w/ fine white powder and sticky acetone, 30 Hz,
10 solids, fragments with B/E minutes present HPMC 3 cryogrind
grind 2 small white particles, no B/E (70:30) minutes, 5 cycles,
rate = 10 HPMC-P 4 cryogrind grind 2 small white particles, no B/E
(1:1) minutes, 3 cycles, rate = 10 HPMC-P 5 cryogrind grind 2 small
white particles, approx (70:30) minutes, 5 cycles, same size,
shape, no B/E rate = 10 PVP-VA .sup. 6.sup.b dry milled, 30 Hz,
white powder, solids present (1:1) 15 minutes with B/E, pockets of
differing morphology 7 wet milled w/ MeOH, fine white powder and
sticky 30 Hz, 10 minutes solids, pockets of birefringent material
PVP-VA 8 cryogrind grind 2 white fine particles with no (70:30)
minutes, 5 cycles, B/E rate = 10 PVP 9 cryogrind grind 2 small
white particles approx K-29/32 minutes, 5 cycles, same size, no B/E
(70:30) rate = 10 PVP K-90 10.sup.b cryogrind grind 2 white fine
powder. Appears as (60:40) minutes, 5 cycles, single phase with
same size, rate = 10 morphology *the molar ratio of
rasagiline:citric acid is 1:1 unless indicated otherwise
.sup.aExcipient: Rasagiline ratio (weight/weight) .sup.b0.7:1 molar
ratio of Rasagiline:citric acid .sup.cobservations by light
microscopy. B = birefringence, E = extinction
Example 4
Solid Dispersion of Rasagiline Citrate Prepared by
Lyophilization
[0092] The experiments conducted in this example are listed below
in Table 4. In each of the experiments, rasagiline free base,
excipient, and citric acid were combined and mixed in the
corresponding solvent. A solid dispersion was prepared from the
mixture by lyophilization at conditions listed in Table 4
below.
TABLE-US-00006 TABLE 4 Excipient.sup.a Exp. No. Solvent Conditions
Observation HPMC-P 1.sup.b dioxane lyophilize fluffy white powder
(7:3) overnight HPMC-AS 2.sup.b dioxane lyophilize fluffy white
powder (7:3) overnight HPMC-P 3.sup.b dioxane- lyophilize fluffy
white powder (7:3) water overnight (1:1) PVP-VA 4.sup.b dioxane-
lyophilize fluffy white powder (7:3) water overnight (1:1)
.sup.aExcipient: Rasagiline ratio (weight/weight) .sup.b0.7:1 molar
ratio of Rasagiline:citric acid
Example 5
Analysis of Dispersions of Rasagiline Citrate
[0093] Samples of dispersion of rasagiline citrate obtained in
Examples 2-4 were analyzed and the results are summarized in Table
5 below.
TABLE-US-00007 TABLE 5 Excipient.sup.a Sample No. Prep Method.sup.b
Analysis Result T.sub.g calc.sup.c Eudragit .RTM. L 1.sup.d RE MDSC
T.sub.g = 15.degree. C. 60.degree. C. 100 (1:1) Eudragit .RTM. L 2
RE MDSC T.sub.g = 19.degree. C. 82.degree. C. 100 (30:70) HPMC 3
cryomill MDSC T.sub.g = 32.degree. C., 106.degree. C. (30:70)
126.degree. C. HPMC-AS 4 RE MDSC T.sub.g = 17.degree. C. 90.degree.
C. (30:70) 100.degree. C. HPMC-AS 5 lyophilization MDSC T.sub.g =
17.degree. C. 90.degree. C. (30:70) HPMC-P 6.sup.d cryomill MDSC
T.sub.g = 25.degree. C. 69.degree. C. (1:1) HPMC-P 7 RE MDSC
T.sub.g = 8.degree. C. 103.degree. C. (25:75) HPMC-P 8
lyophilization MDSC T.sub.g = 29.degree. C. 96.degree. C. (30:70)
HPMC-P 9 cryomill MDSC T.sub.g = 27.degree. C. 96.degree. C.
(30:70) HPMC-P 10.sup.d RE MDSC -- 127.degree. C. (10:90) PVP
K-29/32 11.sup.d RE MDSC T.sub.g = 3.degree. C. 75.degree. C. (1:1)
PVP K-29/32 12 cryomill MDSC T.sub.g = 29.degree. C. 106.degree. C.
(30:70) PVP K-29/32 13 lyophilization MDSC T.sub.g = 30.degree. C.
106.degree. C. (30:70) PVP K-29/32 14 RE MDSC T.sub.g = 17.degree.
C. 106.degree. C. (25:75) PVP K-90 15.sup.d RE MDSC T.sub.g =
18.degree. C. 78.degree. C. (1:1) PVP K-90 16 RE MDSC T.sub.g =
34.degree. C. 111.degree. C. (30:70) PVP K-90 17 cryomill MDSC
T.sub.g = 39.degree. C. 94.degree. C. (40:60) PVP K-90 18 RE MDSC
-- 151.degree. C. (10:90) PVP-VA 19.sup.d RE MDSC T.sub.g =
16.degree. C., 56.degree. C. (1:1) 77.degree. C. PVP-VA 20 RE MDSC
T.sub.g = 38.degree. C., 76.degree. C. (30:70) PVP-VA 21
lyophilization MDSC T.sub.g = 22.degree. C., 76.degree. C. (30:70)
PVP-VA 22 cryomill MDSC T.sub.g = 26.degree. C., 76.degree. C.
(30:70) .sup.aRasagiline: excipient weight ratio listed in
parentheses. .sup.bRE = rotary evaporation. .sup.cT.sub.g value for
ideal dispersion calculated using Fox equation. .sup.d1:1 molar
ratio of Rasagiline:citric acid. All other samples contain slight
excess of citric acid
Example 6
Stressing of Dispersions of Rasagiline Citrate
[0094] Stability of the dispersions of rasagiline citrate obtained
in Examples 2-4 was studied at the conditions listed in Table 6
below. The results are also summarized in Table 6 below.
TABLE-US-00008 TABLE 6 Sample Excipient.sup.a No. Conditions.sup.b
Duration Observation.sup.c Eudragit 1 75% RH 2 hours no change
L-100 4 hours no change (70:30) 6 hours no change 8 hours no change
24 hours pooling of solids, needles present 5 days slight pooling
of solids w/ moisture HPMC-AS 2 75% RH 2 hours no change (70:30) 4
hours no change 6 hours no change 8 hours no change 24 hours
pooling of solids w/ moisture 5 days pooling of solids w/ moisture
HPMC-P 3 75% RH 2 hours no change (70:30) 4 hours no change 6 hours
no change 8 hours pooling of solids 24 hours pooling of solids w/
moisture 5 days deliquesced PVP K-29/32 4 75% RH 2 hours no change
(70:30) 4 hours pooling of solids 6 hours pooling of solids 8 hours
pooling of solids 24 hours deliquesced PVP K-90 5 75% RH 2 hours no
change (70:30) 4 hours no change 6 hours no change 8 hours no
change 24 hours deliquesced PVP-VA 6 75% RH 2 hours no change
(70:30) 4 hours no change 6 hours pooling of solids 8 hours pooling
of solids 24 hours deliquesced Rasagiline 7 75% RH 2 hours pooling
of solids Citrate 4 hours deliquesced 6 hours deliquesced 8 hours
deliquesced 24 hours deliquesced HPMC-P 8 75% RH 1 day solids
pooling (1:1) together with moisture PVP-VA 9 75% RH 1 day solids
deliquesced (70:30) PVP K-90 10 75% RH 1 day slight pooling of
(70:30) moisture around solids .sup.apolymer: drug weight ratio
listed in parentheses. .sup.bRH = relative humidity.
.sup.cObservations made visually using light microscopy.
Example 7
Additional Preparation of Solid Dispersion of Rasagiline
Citrate
[0095] In Examples 2-4, rasagiline citrate was formed in-situ by
combining rasagiline free base, excipient, and citric acid in the
preparation of solid dispersion of rasagiline citrate.
Alternatively, the solid dispersion of rasagiline citrate can be
prepared by obtaining rasagiline citrate salt first. The rasagiline
citrate can be obtained by reacting rasagiline free base with
citric acid in the presence of a suitable solvent by conventional
methods, e.g. the process described in Example 1.
[0096] The rasagiline citrate obtained can then be mixed with the
excipient listed in Table 2 to prepare the solid dispersion of
rasagiline citrate by the rotary evaporation as described in
Example 2. The rasagiline citrate obtained can also be mixed with
the excipient listed in Table 3 to prepare the solid dispersion of
rasagiline citrate by dry milling, wet milling, or cryo-grinding as
described in Example 3. The rasagiline citrate obtained can further
be mixed with the excipient listed in Table 4 to prepare the solid
dispersion of rasagiline citrate by lyophilization as described in
Example 4.
Discussion of Examples 1-6
[0097] The plasticizing effect of water as well as the low T.sub.g
of rasagiline citrate has generally resulted in dispersions with
low T.sub.g values. T.sub.g of mono-rasagiline citrate was
.about.17.degree. C. by DSC.
[0098] Most of the solid dispersions of rasagiline citrate prepared
appeared to be phase-separated by MDSC. In addition, T.sub.g of
some of the solid dispersions of rasagiline citrate prepared was
not observed due to decomposition of rasagiline at elevated
temperatures.
[0099] Dispersions containing PVP K90 and PVP-VA have shown the
largest increase in T.sub.g with high polymer loadings but both
deliquesced when stressed under high relative humidity for 1
day.
[0100] All solid dispersions of rasagiline citrate prepared using
methods described in Examples 2-4 have resulted in handleable white
powders.
[0101] As T.sub.g can be impacted by technique used to generate
dispersions, dispersions were prepared by different methods. For
most polymers, little difference in T.sub.g was noted with
different methods of preparation. However, for HPMC-P an increase
in T.sub.g of .about.20.degree. C. was observed for a lyophilized
sample compared with a sample prepared by rotary evaporation.
[0102] Preparation of solid dispersions involving HPMC was
difficult due to the low solubility of HPMC in most solvents. A
dispersion was prepared by cryogrinding but it did not exhibit a
T.sub.u much higher than that of the rasagiline base.
[0103] Solid dispersions of rasagiline citrate prepared were
stressed at 75% relative humidity over a period of 24 hours and
were compared with rasagiline citrate alone. All solid dispersions
except for PVP K-29/32 and PVP-VA showed no moisture accumulation
for the first 6 hours by visual inspection. After 6 hours, pooling
of moisture was observed in some samples and deliquescence was
observed in some samples after 24 hours.
[0104] Dispersions containing Eudragit L-100 and HPMC-AS showed no
change after 24 hours. All dispersions showed greater stability
than rasagiline citrate alone, which was fully deliquesced after 4
hours.
[0105] T.sub.4 of varying polymer loadings was also studied. As
shown in FIG. 3, three dispersions showed a significant increase of
T.sub.g with increasing loading of polymers: dispersions containing
PVP K-29/32, PVP-VA, and PVP-K90.
[0106] Stability of dispersions under high relative humility was
also studied. The results showed that dispersions containing
Eudragit L-100 were the most stable and dispersions containing PVP
K-29/32 were the least stable. The relative ranking of stability is
as follows: Eudragit L-100>HPMC-AS>PVP
K-90>HPMCP>PVP-VA>PVP K-29/32.
* * * * *