U.S. patent application number 13/145989 was filed with the patent office on 2012-01-05 for delayed release rasagiline formulation.
Invention is credited to Rachel Cohen, Anton Frenkel, Tamas Koltai, Daniella Licht, Muhammad Safadi, Marina Zholkovsky.
Application Number | 20120003310 13/145989 |
Document ID | / |
Family ID | 42354337 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120003310 |
Kind Code |
A1 |
Safadi; Muhammad ; et
al. |
January 5, 2012 |
DELAYED RELEASE RASAGILINE FORMULATION
Abstract
Disclosed are formulations of rasagiline base which are designed
to delay release of rasagiline while maintaining specific
pharmacokinetic properties. Also, disclosed are rasagiline citrate
salt and the use and process of manufacture thereof.
Inventors: |
Safadi; Muhammad; (Nazareth,
IL) ; Licht; Daniella; (Givat-Shmuel, IL) ;
Cohen; Rachel; (Hadera, IL) ; Frenkel; Anton;
(Netanya, IL) ; Koltai; Tamas; (Netanya, IL)
; Zholkovsky; Marina; (Bat-Yam, IL) |
Family ID: |
42354337 |
Appl. No.: |
13/145989 |
Filed: |
January 21, 2010 |
PCT Filed: |
January 21, 2010 |
PCT NO: |
PCT/US10/00174 |
371 Date: |
September 15, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61205833 |
Jan 23, 2009 |
|
|
|
Current U.S.
Class: |
424/465 ;
424/400; 514/554; 514/657 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61P 25/00 20180101; A61P 25/28 20180101; C07C 211/42 20130101;
A61P 25/24 20180101; A61K 9/2018 20130101; A61K 9/2886 20130101;
A61K 9/2059 20130101; A61P 25/16 20180101; A61K 9/2846 20130101;
C07C 2602/08 20170501; A61K 9/2013 20130101; A61P 9/10 20180101;
A61P 25/18 20180101; A61K 9/2893 20130101; A61K 31/135 20130101;
C07C 59/265 20130101 |
Class at
Publication: |
424/465 ;
424/400; 514/657; 514/554 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61P 25/16 20060101 A61P025/16; A61K 9/28 20060101
A61K009/28; A61K 9/00 20060101 A61K009/00; A61K 31/205 20060101
A61K031/205 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 2009 |
US |
12455976 |
Jun 9, 2009 |
US |
12456001 |
Jun 9, 2009 |
US |
12456029 |
Jun 9, 2009 |
US |
12456031 |
Jan 18, 2010 |
US |
12689044 |
Claims
1-6. (canceled)
7. A method of treating a human subject afflicted with Parkinson's
disease comprising administering to the human subject while the
human subject is in a fed state a stable oral dosage form
comprising a core having at least one pharmaceutically acceptable
excipient and rasagiline base, rasagiline citrate, or a mixture of
rasagiline base and rasagiline citrate; and an acid resistant
pharmaceutically acceptable coating.
8. The method of claim 7, wherein the rasagiline base is
crystalline rasagiline base.
9. The method of claim 7, wherein the core of the dosage form
consists essentially of at least one pharmaceutically acceptable
excipient and rasagiline citrate.
10. The method of claim 7, wherein in the dosage form the at least
one pharmaceutically acceptable excipient in the core is at least
one anti-oxidant.
11. The method of claim 10, wherein in the core of the dosage form
the anti-oxidant is citric acid.
12. The method of claim 7, wherein in the core of the dosage form
the at least one pharmaceutically acceptable excipient in the core
is at least one disintegrant.
13. The method of claim 12, wherein in the dosage form the
disintegrant is present in the core at an amount between 0.5% and
20% by weight.
14. The method of claim 12, wherein the disintegrant is
pre-gelatinized starch.
15. The method of claim 7, wherein the dosage form is less than 150
mg by weight.
16. The method of claim 9, wherein the content of rasagiline
citrate in the dosage form is 0.74 mg to 3.63 mg.
17. The method of claim 9, wherein the dosage form, in addition to
the rasagiline citrate, comprises mannitol, colloidal silicon
dioxide, starch NF, pregelatinized starch, stearic acid, talc,
hypromellose, methacrylic acid ethyl acrylate copolymer, talc extra
fine, and triethyl citrate.
18. The method of claim 17, wherein in the dosage form the content
of rasagiline is 1.0 mg and the dosage form comprises 45.0 mg of
mannitol, 0.4 mg of aerosil, 5.0 mg of starch NF, 20.0 mg of
pregelatinized starch, 1.5 mg of stearic acid, 1.5 mg of talc, 3.5
mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate
copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra
fine.
19. The method of claim 17, wherein in the dosage form the content
of rasagiline is 0.5 mg and the dosage form comprises 45.5 mg of
mannitol, 0.4 mg of aerosil, 5.0 mg of starch NF, 20.0 mg of
pregelatinized starch, 1.5 mg of stearic acid, 1.5 mg of talc, 3.5
mg of hypromellose, 4.0 mg of methacrylic acid ethyl acrylate
copolymer, 0.8 mg of triethyl citrate, and 1.9 mg of talc extra
fine.
20. The method of claim 18, wherein the dosage form further
comprises 2.0 mg of a color coating agent.
21. The method of claim 7, wherein the core of the dosage form is
in the form of a tablet.
22. The method of claim 7, wherein the acid resistant
pharmaceutically acceptable coating of the dosage form comprises
methacrylic acid-ethyl acrylate copolymer (1:1) and a
plasticizer.
23. The method of claim 22, wherein in the acid resistant
pharmaceutically acceptable coating the ratio of methacrylic
acid-ethyl acrylate copolymer (1:1) to plasticizer is between 10 to
1 and 2 to 1.
24. The method of claim 23, wherein in the acid resistant
pharmaceutically acceptable coating the ratio of methacrylic
acid-ethyl acrylate copolymer (1:1) to plasticizer is about 5 to
1.
25. The method of claim 24, wherein the plasticizer is triethyl
citrate.
26. The method of claim 22, wherein the acid resistant
pharmaceutically acceptable coating of the dosage form further
comprises talc.
27. The method of claim 7, wherein the acid resistant
pharmaceutically acceptable coating of the dosage form is between
3% and 12% by weight of the dosage form.
28. The method of claim 27, wherein the acid resistant
pharmaceutically acceptable coating of the dosage form is about 8%
by weight of the dosage form.
29. The method of claim 7, wherein the acid resistant
pharmaceutically acceptable coating of the dosage form comprises
two coating layers.
30. The method of claim 29, wherein the inner one of the two
coating layers comprises hypromellose.
31. The method of claim 7, wherein the dosage form releases between
80 and 100% of rasagiline when placed in a basket apparatus in 500
mL of buffered aqueous media at a pH of 6.8 at 37.degree. C. at 75
revolutions per minute for 20 minutes.
31-37. (canceled)
38. The method of claim 7, wherein the dosage form when ingested by
a human subject in a fed state provides an AUC value of rasagiline
which is greater than that of the corresponding amount of
rasagiline ingested as an immediate release formulation.
39. (canceled)
40. (canceled)
41. The method of claim 7, wherein the dosage form when ingested by
a human subject in a fed state provides a C.sub.max of rasagiline
which is greater than that of the corresponding amount of
rasagiline ingested as an immediate release formulation.
42-64. (canceled)
65. The method of claim 7, wherein the subject suffers from delayed
gastric emptying.
66-68. (canceled)
69. The method of claim 19, wherein the dosage form further
comprises 2.0 mg of a color coating agent.
Description
[0001] The application claims priority of U.S. Ser. Nos.
12/689,044, filed Jan. 18, 2010; 12/455,976, filed Jun. 9, 2009;
12/456,001, filed Jun. 9, 2009; 12/456,029, filed Jun. 9, 2009; and
12/456,031, filed Jun. 9, 2009; and U.S. Provisional Application
No. 61/205,833, filed Jan. 23, 2009, the contents of each 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.
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] U.S. Pat. No. 6,126,968 discloses pharmaceutical
formulations comprising rasagiline. 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 a commercially available rasagiline mesylate
immediate release formulation indicated for the treatment of the
signs and symptoms of idiopathic Parkinson's disease as initial
monotherapy and as adjunct therapy to levodopa. The current
marketed formulation of rasagiline (Azilect.RTM.) is rapidly
absorbed, reaching peak plasma concentration (t.sub.max) in
approximately 1 hour. The absolute bioavailability of rasagiline is
about 36%. (AZILECT.RTM. Product Label, May 2006).
[0006] There are, however, several concerns associated with the
commercially available form of rasagiline mesylate. For example, a
concern in using monoamine oxidase ("MAO") inhibitors is the risk
of hypertensive crises, often called the "cheese effect." (Simpson,
G. M. and White K. "Tyramine studies and the safety of MAOI drugs."
J Clin Psychiatry. 1984 July; 45 (7 pt 2): 59-91.) This effect is
caused by inhibition of peripheral MAO. A high concentration of
peripheral MAO is found in the stomach.
[0007] Another concern in Parkinson's disease patients is that many
patients suffer from delayed gastric emptying (Pfeiffer, R. F. and
Quigley, E. M. M. "Gastrointestinal motility problems in patients
with Parkinson's disease: Epidemiology, pathophysiology, and
guidelines for management," CNS-Drugs, 1999, 11(6): 435-448; Jost,
W. H., "Gastrointestinal motility problems in patients with
Parkinson's disease: Effects of antiparkinsonian treatment and
guidelines for management", Drugs and Aging, 1997, 10(4): 249-258).
Delayed gastric emptying (prolonged gastric residence) can be a
cause of increased inhibition of peripheral MAO, and can contribute
to the cheese effect.
[0008] There is also a concern regarding the potential for
formation of alkyl mesylates during the treatment of the free base
of a drug substance with MSA if any residues of short-chain
alcohols are present. (Snodin D., "Residues of genotoxic alkyl
mesylates in mesylate salt drug substances: Real or imaginary
problems?" Rugulatory Toxicology and Pharmacology, Vol. 45, 2006,
pages 79-90).
[0009] Efforts to address such concerns and to improve the
commercially available form of rasagiline mesylate are described in
the literature. For example, PCT International Application
Publication No. WO 2006/057912 describes orally disintegrating
rasagiline compositions; PCT International Application Publication
No. WO 2006/014973 discloses delayed release rasagiline
compositions; PCT International Application Publication No. WO
2008/076348 discloses a crystalline solid form of the rasagiline
base; PCT International Application Publication No. WO 2008/076315
discloses the tannate salt of rasagiline. Other efforts to make
certain improvements are described in PCT International Application
Publication No. WO 2008/019871 and in PCT International Application
Publication No. WO 2008/131961.
[0010] However, the previous efforts did not disclose formulations
as described herein, in particular formulations using solid
rasagiline base described herein. The previous efforts also did not
disclose the citrate salt of rasagiline or the advantages of
formulations using the citrate salt of rasagiline, described
herein.
SUMMARY OF THE INVENTION
[0011] The subject invention provides a stable oral dosage form
comprising a core having a production process-resulting form of
rasagiline and at least one pharmaceutically acceptable excipient;
and an acid resistant pharmaceutically acceptable coating, the
production process comprising [0012] a) preparing the core by
admixing rasagiline base, citric acid and/or malic acid, and a
pharmaceutically acceptable excipient; and [0013] b) coating the
core with the acid resistant pharmaceutically acceptable
coating.
[0014] The subject invention also provides a stable oral dosage
form comprising a core having rasagiline base, rasagiline citrate,
rasagiline malate, or a mixture of at least two of rasagiline base,
rasagiline citrate, and rasagiline malate, and at least one
pharmaceutically acceptable excipient; and an acid resistant
pharmaceutically acceptable coating.
[0015] The subject invention further provides a method of treating
a patient suffering from Parkinson's disease comprising
administering to the patient the dosage form described herein.
[0016] The subject invention yet further provides rasagiline
citrate.
[0017] The subject invention yet further provides a composition
comprising the rasagiline citrate described herein and a
carrier.
[0018] The subject invention yet further provides a process for
manufacture of the rasagiline citrate or the composition describe
herein, comprising: [0019] a) combining a solution of citric acid
with rasagiline base to form a first mixture; [0020] b) adding a
solvent to the first mixture to form a second mixture; [0021] c)
completely removing liquid from the second mixture; and [0022] d)
recovering the rasagiline citrate or preparing the composition.
[0023] The subject invention yet further provides a process for
manufacture of the composition described herein, comprising: [0024]
a) obtaining rasagiline citrate in isolated form; and [0025] b)
admixing the rasagiline citrate with a carrier.
[0026] The subject invention yet further provides a method of
treating a human subject afflicted with 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
(PSP), comprising administering to the human subject an amount of
the rasagiline citrate or the composition described herein
effective to treat the human subject.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The subject invention provides a stable oral dosage form
comprising a core having a production process-resulting form of
rasagiline and at least one pharmaceutically acceptable excipient;
and an acid resistant pharmaceutically acceptable coating, the
production process comprising [0028] a) preparing the core by
admixing rasagiline base, citric acid and/or malic acid, and a
pharmaceutically acceptable excipient; and [0029] b) coating the
core with the acid resistant pharmaceutically acceptable
coating.
[0030] In yet another embodiment of the dosage form, step a) of the
process comprises preparing a wet granulate of the rasagiline base,
citric acid and/or malic acid, and a pharmaceutically acceptable
excipient.
[0031] In yet another embodiment of the dosage form, step a) of the
process further comprises: [0032] i) drying the wet granulate to
form a dry granulate, [0033] ii) milling the dry granulate to form
particles, and [0034] iii) admixing the particles with at least one
lubricant.
[0035] In yet another embodiment of the dosage form, in step iii)
of the process the lubricant is talc or stearic acid, or a
combination thereof.
[0036] In yet another embodiment of the dosage form, in step i) of
the process the wet granulate is dried in a fluid bed dryer under
inlet air temperature of 40.degree. C. to 50.degree. C., and under
outlet air temperature of not greater than 37.degree. C.
[0037] In yet another embodiment of the dosage form, in step i) of
the process the inlet air temperature is 45.degree. C.
[0038] In yet another embodiment of the dosage form, in step ii) of
the process the dry granulate is milled through an oscillating
granulator.
[0039] In yet another embodiment of the dosage form, step a) of the
process further comprises a step of forming the core by
compression.
[0040] In yet another embodiment of the dosage form, in step a) of
the process the core is prepared by admixing rasagiline base,
citric acid, and a pharmaceutically acceptable excipient.
[0041] In yet another embodiment of the dosage form, in step a) of
the process the core is prepared by admixing rasagiline base, malic
acid, and a pharmaceutically acceptable excipient.
[0042] In yet another embodiment of the dosage form, in step a) of
the process the core is prepared by admixing rasagiline base,
citric acid and malic acid, and a pharmaceutically acceptable
excipient.
[0043] The subject invention also provides a stable oral dosage
form comprising a core having rasagiline base, rasagiline citrate,
rasagiline malate, or a mixture of at least two of rasagiline base,
rasagiline citrate, and rasagiline malate, and at least one
pharmaceutically acceptable excipient; and an acid resistant
pharmaceutically acceptable coating.
[0044] In an embodiment of the dosage form, the rasagiline base
described herein is crystalline rasagiline base.
[0045] In an embodiment of the dosage form, the dosage form
comprises a core having rasagiline citrate and at least one
pharmaceutically acceptable excipient; and an acid resistant
pharmaceutically acceptable coating.
[0046] In another embodiment of the dosage form, the dosage form
comprises a core having rasagiline malate and at least one
pharmaceutically acceptable excipient; and an acid resistant
pharmaceutically acceptable coating.
[0047] In yet another embodiment of the dosage form, the dosage
form when ingested by a human subject provides an AUC value of
rasagiline of 80-130% of that of the corresponding amount of
rasagiline ingested as an immediate release formulation.
[0048] In yet another embodiment of the dosage form described
herein, the dosage form upon administration to a human subject
provides an AUC value of rasagiline of 80-125% of that of the
corresponding amount of rasagiline ingested as an immediate
released formulation.
[0049] In yet another embodiment of the dosage form described
herein, the dosage form when ingested by a human subject in a fed
state provides an AUC value of rasagiline which is greater than
that of the corresponding amount of rasagiline ingested as an
immediate release formulation.
[0050] In yet another embodiment of the dosage form described
herein, the dosage form when ingested by a human subject provides a
C.sub.max of rasagiline 80-145% of that of the corresponding amount
of rasagiline ingested as an immediate release formulation.
[0051] In yet another embodiment of the dosage form described
herein, the dosage form when ingested by a human subject provides a
C.sub.max of rasagiline of 80-125% of that of the corresponding
dosage of rasagiline ingested as an immediate release
formulation.
[0052] In yet another embodiment of the dosage form described
herein, the dosage form when ingested by a human subject in a fed
state provides a C.sub.max of rasagiline which is greater than that
of the corresponding amount of rasagiline ingested as an immediate
release formulation.
[0053] In yet another embodiment of the dosage form, the core
further comprises at least one anti-oxidant.
[0054] In yet another embodiment of the dosage form, the
anti-oxidant is citric acid.
[0055] In yet another embodiment of the dosage form, the
anti-oxidant is malic acid.
[0056] In yet another embodiment of the dosage form, the
anti-oxidant is citric and malic acid.
[0057] In yet another embodiment of the dosage form described
herein, the core is in the form of a tablet.
[0058] In yet another embodiment of the dosage form, the core
further comprises at least one disintegrant.
[0059] In yet another embodiment of the dosage form, the
disintegrant is present in the core at an amount between 0.5% and
20% by weight.
[0060] In yet another embodiment of the dosage form, the
disintegrant is pre-gelatinized starch.
[0061] In yet another embodiment of the dosage form described
herein, the acid resistant coating layer comprises methacrylic
acid-ethyl acrylate copolymer (1:1) and a plasticizer.
[0062] In yet another embodiment of the dosage form, in the acid
resistant coating layer the ratio of methacrylic acid-ethyl
acrylate copolymer (1:1) to plasticizer is between 10 to 1 and 2 to
1.
[0063] In yet another embodiment of the dosage form, in the coating
the ratio of methacrylic acid-ethyl acrylate copolymer (1:1) to
plasticizer is about 5 to 1.
[0064] In yet another embodiment of the dosage form, the
plasticizer is triethyl citrate.
[0065] In yet another embodiment of the dosage form, the acid
resistant coating layer further comprises talc.
[0066] In yet another embodiment of the dosage form, the acid
resistant coating is between 3% and 12% by weight of the dosage
form.
[0067] In yet another embodiment of the dosage form, the acid
resistant coating is about 8% by weight of the dosage form.
[0068] In yet another embodiment of the dosage form, the acid
resistant coating comprises two coating layers.
[0069] In yet another embodiment of the dosage form, the inner one
of the two coating layers comprises hypromellose.
[0070] In yet another embodiment of the dosage form, the dosage
form is less than 150 mg by weight.
[0071] In yet another embodiment of the dosage form, the dosage
form in addition to the rasagiline base and citric acid and/or
malic acid, comprises mannitol, colloidal silicon dioxide, starch
NF, pregelatinized starch, stearic acid, talc, hypromellose,
methacrylic acid ethyl acrylate copolymer, talc extra fine, and
triethyl citrate.
[0072] In yet another embodiment of the dosage form described
herein, the content of rasagiline citrate is 0.74 mg to 3.63
mg.
[0073] In yet another embodiment of the dosage form, the dosage
form in addition to the rasagiline citrate, comprises mannitol,
colloidal silicon dioxide, starch NF, pregelatinized starch,
stearic acid, talc, hypromellose, methacrylic acid ethyl acrylate
copolymer, talc extra fine, and triethyl citrate.
[0074] The dosage form of claim 23, comprising 0.66 mg to 3.05 mg
of rasagiline malate.
[0075] In yet another embodiment of the dosage form, the dosage
form in addition to the rasagiline malate comprises mannitol,
colloidal silicon dioxide, starch NF, pregelatinized starch,
stearic acid, talc, hypromellose, methacrylic acid ethyl acrylate
copolymer, talc extra fine, and triethyl citrate.
[0076] In yet another embodiment of the dosage form described
herein, the content of rasagiline is 1.0 mg.
[0077] In yet another embodiment of the dosage form, the dosage
form comprises 79.8 mg of mannitol, 0.6 mg of colloidal silicon
dioxide, 10.0 mg of starch NF, 20.0 mg of pregelatinized starch,
2.0 mg of stearic acid, 2.0 mg of talc, 4.8 mg of hypromellose,
6.25 mg of methacrylic acid-ethyl acrylate copolymer, 1.25 mg of
triethyl citrate, and 3.1 mg of talc extra fine.
[0078] In yet another embodiment of the dosage form, the dosage
form comprises 67.8 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of
starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic
acid, 2.0 mg of talc, 4.8 mg of hypromellose, 4.0 mg of methacrylic
acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9
mg of talc extra fine.
[0079] In yet another embodiment of the dosage form, the dosage
form comprises 45.0 mg of mannitol, 0.4 mg of aerosil, 5.0 mg of
starch NF, 20.0 mg of pregelatinized starch, 1.5 mg of stearic
acid, 1.5 mg of talc, 3.5 mg of hypromellose, 4.0 mg of methacrylic
acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9
mg of talc extra fine.
[0080] In yet another embodiment of the dosage form described
herein, the content of rasagiline is 0.5 mg.
[0081] In yet another embodiment of the dosage form, the dosage
form comprises 80.3 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of
starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic
acid, 2.0 mg of talc, 4.8 mg of hypromellose, 6.25 mg of
methacrylic acid ethyl acrylate copolymer, 1.25 mg of triethyl
citrate, and 3.1 mg of talc extra fine.
[0082] In yet another embodiment of the dosage form, the dosage
form comprises 68.3 mg of mannitol, 0.6 mg of aerosil, 10.0 mg of
starch NF, 20.0 mg of pregelatinized starch, 2.0 mg of stearic
acid, 2.0 mg of talc, 4.8 mg of hypromellose, 4.0 mg of methacrylic
acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9
mg of talc extra fine.
[0083] In yet another embodiment of the dosage form, the dosage
form comprises 45.5 mg of mannitol, 0.4 mg of aerosil, 5.0 mg of
starch NF, 20.0 mg of pregelatinized starch, 1.5 mg of stearic
acid, 1.5 mg of talc, 3.5 mg of hypromellose, 4.0 mg of methacrylic
acid ethyl acrylate copolymer, 0.8 mg of triethyl citrate, and 1.9
mg of talc extra fine.
[0084] In yet another embodiment of the dosage form described
herein, the dosage form further comprises 2.0 mg of a color coating
agent.
[0085] In yet another embodiment of the dosage form, the dosage
form comprises releases between 80 and 100% of rasagiline when
placed in a basket apparatus in 500 mL of buffered aqueous media at
a pH of 6.8 at 37.degree. C. at 75 revolutions per minute for 20
minutes.
[0086] In yet another embodiment of the dosage form, the total
amount of non-polar impurities is less than 0.3 wt % relative to
the amount of rasagiline.
[0087] In yet another embodiment of the dosage form, the amount of
N-(2-chloroallyl)-1(R)-aminoindan in the dosage form is less than
20 ppm relative to the amount of rasagiline.
[0088] In yet another embodiment of the dosage form, the amount of
N-(2-chloroallyl)-1(R)-aminoindan in the dosage form is less than 4
ppm relative to the amount of rasagiline.
[0089] In yet another embodiment of the dosage form, the dosage
form comprises when ingested by a human subject achieves MAO-B
inhibition substantially the same as that of the corresponding
dosage of rasagiline ingested as an immediate release
formulation.
[0090] The subject invention yet further provides rasagiline
citrate.
[0091] In an embodiment of the rasagiline citrate, the rasagiline
citrate is isolated rasagiline citrate or is substantially
pure.
[0092] In another embodiment of the rasagiline citrate described
herein, the rasagiline citrate is amorphous.
[0093] In yet another embodiment of the rasagiline citrate
described herein, the rasagiline citrate is mono-rasagiline
citrate.
[0094] In yet another embodiment of the rasagiline citrate
described herein, the rasagiline content in the rasagiline citrate
is between 42% and 52% by weight based on the total weight of the
rasagiline citrate.
[0095] By a range between 42% and 52%, it is meant that all tenth
and integer percentages within the range are specifically disclosed
as part of the invention. Thus, 43%, 44%, . . . , 50%, 51% and
42.1%, 42.2%, . . . , 51.8%, 51.9% are included as embodiments of
this invention.
[0096] In yet another embodiment of the rasagiline citrate
described herein, the water content in the rasagiline citrate as
determined by Karl Fischer analysis is less than 5%, less than 4%,
less than 3%, less than 2%, or less than 1%.
[0097] The subject invention yet further provides a composition
comprising the rasagiline citrate described herein and a
carrier.
[0098] In an embodiment of the composition, the composition further
comprises rasagiline base.
[0099] In another embodiment of the composition described herein,
the rasagiline base is present in an amount of less than 5%, less
than 4%, less than 3%, less than 2%, or less than 1%, based on the
total rasagiline content of the composition.
[0100] In yet another embodiment of the composition described
herein, the rasagiline base present in the composition is
crystalline rasagiline base.
[0101] In yet another embodiment of the composition described
herein, the composition is free of rasagiline base.
[0102] In yet another embodiment of the composition described
herein, the rasagiline content present in the form of rasagiline
citrate is more than 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%,
or 99% of the total rasagiline content in the composition.
[0103] In yet another embodiment of the composition described
herein, the composition is a pharmaceutical composition and the
carrier is a pharmaceutically acceptable carrier.
[0104] In yet another embodiment of the composition described
herein, the composition is in the form of an oral dosage form.
[0105] In yet another embodiment of the composition described
herein, the composition is in the form of a tablet.
[0106] In yet another embodiment of the composition described
herein, the composition further comprises stearic acid.
[0107] In yet another embodiment of the composition described
herein, the composition is in the form of a transdermal patch.
[0108] In yet another embodiment of the composition described
herein, the rasagiline citrate is mixed with a polymer.
[0109] The subject invention yet further provides a process for
manufacture of the rasagiline citrate or the composition described
herein, comprising: [0110] a) combining a solution of citric acid
with rasagiline base to form a first mixture; [0111] b) adding a
solvent to the first mixture to form a second mixture; [0112] c)
completely removing liquid from the second mixture; and [0113] d)
recovering the rasagiline citrate or preparing the composition.
[0114] In an embodiment of the process, the solvent added in step
b) is acetone.
[0115] In another embodiment of the process described herein, in
step c) the liquid is removed at ambient temperature and at reduced
pressure.
[0116] The subject invention yet further provides a process for
manufacture of the composition described herein, comprising: [0117]
a) obtaining rasagiline citrate in isolated form; and [0118] b)
admixing the rasagiline citrate with a carrier.
[0119] The subject invention yet further provides a method of
treating a human subject afflicted with 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
(PSP), comprising administering to the human subject an amount of
the dosage form described herein or the composition described
herein effective to treat the human subject.
[0120] In an embodiment of the method, the subject suffers from
delayed gastric emptying.
[0121] In another embodiment of the method, the administration step
is to the human subject in a fed state.
[0122] Each of the embodiments described herein can be combined
with any other embodiment disclosed herein.
[0123] 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.
[0124] As used herein, an example of an immediate release
formulation of rasagiline is an AZILECT.RTM. Tablet containing
rasagiline mesylate.
[0125] As used herein, a polymer is a large molecule composed of
repeating structural units typically connected by covalent chemical
bonds.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] As used herein, "about" in the context of a numerical value
or range means.+-.10% of the numerical value or range recited or
claimed.
[0130] 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.
[0131] An immediate release formulation of rasagiline is
AZILECT.RTM. Tablets which contain rasagiline (as the mesylate), a
propargylamine-based drug indicated for the treatment of idiopathic
Parkinson's disease. It is designated chemically as:
1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-, (1R)-,
methanesulfonate.
[0132] MAO inhibitors that selectively inhibit MAO-B are largely
devoid of the potential to cause the "cheese effect". Nonetheless,
the possibility exists that delayed gastric emptying of R-PAI may
contribute to this phenomenon. Therefore, a goal in developing the
formulations of the current invention was to develop a delayed
release, enteric coated formulation comprising rasagiline in an
amount equivalent to 1 mg of rasagiline base which would release
the active ingredient in the duodenum and/or the jejunum, past the
stomach.
[0133] During the development of the formulations of the current
invention, it was determined that the formulations should meet the
criteria of bioequivalence to the known, immediate release
rasagiline mesylate formulations (as disclosed in example 1, for
example) in a single dose bio-equivalence study in healthy
subjects. These criteria include similarity of C.sub.max and
AUC.sub.0-t (area under the curve) within the range of 80-125%
within a 90% confidence interval between the new formulations and
the known, immediate release formulations. The difference between
the two formulations should be evident in bioequivalence studies as
a difference in t.sub.max. In other words, the mean pharmacokinetic
profile of the formulations of the current invention should
substantially match the mean pharmacokinetic profile of the
formulations of the known immediate release formulation, with the
exception of the t.sub.max which should be greater for the delayed
release formulation than for the immediate release formulation.
[0134] The reason for attempting to match the mean C.sub.max and
AUC.sub.0-t of the known immediate release formulation (i.e. to
formulate a delayed release formulation that is bioequivalent) is
that the efficacy of the immediate release formulation has been
proven, and it is likely that the efficacy of the formulation
relates to its mean C.sub.max and/or AUC. (Arch Neurol. 2002;
59:1937-1943.)
[0135] In order to reach this target, development was directed
toward enteric coated tablets having a quickly disintegrating core
with an enteric coating which allows release of the rasagiline in a
very specific range of pH. This specific pH range would prevent the
formulation from releasing rasagiline in the stomach, and would
allow the formulation to release rasagiline quickly under the
physiological conditions of the intestine.
[0136] In PCT International Application Publication No. WO
2006/014973, delayed release rasagiline mesylate pharmaceutical
formulations were disclosed. In the disclosed formulations (Example
1, 2 and 4) methacrylic acid-ethyl acrylate copolymer (1:1) 30%
dispersion, known as Eudragit.RTM. L-30 D-55 was used. As evident
from WO 2006/014973, these formulations were indeed delayed-release
formulations as shown by their dissolution profiles and by the
in-vivo data, however, their pharmacokinetic profile, in terms of
mean C.sub.max did not match the pharmacokinetic profile of the
immediate release rasagiline mesylate formulations.
[0137] The excipient methacrylic acid-ethyl acrylate copolymer
(1:1) 30% dispersion, known as Eudragit.RTM. L-30 D-55, used in the
above-mentioned publication WO 2006/014973, when applied as an
aqueous dispersion either on tablets or on spheres prevents
dissolution of the coated composition at low acidic pH. The
structure of this polymer is as follows:
##STR00001##
[0138] The ratio of the free carboxyl groups to the ester groups is
approximately 1:1. The average molecular weight is approximately
250,000.
[0139] When this excipient is used in an aqueous dispersion or in
an organic solution and formed into a film coating of a
pharmaceutical formulation, it is intended to dissolve at a pH of
about 5.5. (Aqueous Polymeric Coatings for Pharmaceutical Dosage
Forms; Second Edition, Revised and Expanded. Ed. James W. McGinity,
1997.) Without wishing to be bound by any theory, it is possible
that these prior art formulations began to dissolve in lower pH in
the stomach, perhaps in the presence of food which can raise the pH
in the stomach, and continued to dissolve over a prolonged period
of time in the duodenum and the jejunum. The prolonged dissolution
period could explain why the C.sub.max of these prior art
formulations was significantly lower than the C.sub.max of the
immediate release formulations to which they were compared.
[0140] In general, the release process encompasses three major
steps:
1. Transport to the site where the pH is high enough to initiate
release from the dosage form; 2. Dissolution of the coating; and 3.
Disintegration and release of the drug from the core.
[0141] For highly soluble compounds the third step is the most
crucial. In contrast, for enteric coated pellets for which emptying
occurs gradually, not all at once, the first step has a major
influence on the PK profile. As pellets empty at different times,
they reach the second step at different time points as well.
Therefore the PK profile is a superimposition of multiple "mini" PK
profiles.
[0142] The delayed release compositions of the current invention
are intended to withstand pH conditions of 6.0 and are intended to
release the active ingredient only above that pH. This specific pH
was chosen in order to attempt to minimize any possible dissolution
of the pharmaceutical compositions of the invention in the stomach
in fed condition and to allow rapid dissolution of the
pharmaceutical compositions of the invention after the stomach in
the duodenum and/or the jejunum. The ability of a pharmaceutical
formulation to enter the duodenum before releasing rasagiline and
subsequently releasing the rasagiline rapidly after the stomach
provides a pharmacokinetic profile, and specifically a C.sub.max
and AUC.sub.0-t, similar to that of the known immediate release
formulation.
[0143] Achieving the goal of a delayed-release pharmaceutical
formulation in which the C.sub.max is similar to the corresponding
immediate-release formulation is not trivial to achieve. In
general, when delayed release formulations are compared to their
immediate release counterparts in bio-studies, the C.sub.max of the
delayed release formulations are lower than the C.sub.max in the
corresponding immediate release formulations. (Mascher, et al.
Arneimittelforschung. 2001; 51(6): 465-9. Behr, et al. J. Clin
Pharmacol. 2002; 42(7): 791-7.)
[0144] In addition, the instant invention provides a solution to
the problem of peripheral MAO inhibition by providing
pharmaceutical dosage forms comprising rasagiline which are adapted
to inhibit the release or absorption of rasagiline in the stomach
(i.e. delay the release of rasagiline until at least a portion of
the dosage form has traversed the stomach). This avoids or
minimizes absorption of rasagiline in the stomach, thereby avoiding
or minimizing the potential cheese effect.
[0145] The pharmaceutical dosage form 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, hard or soft gelatin capsule.
Enteric coating, in the context of this invention, is a coating
which prevents the dissolution of an active ingredient in the
stomach. This is determined by measuring the dissolution of the
pharmaceutical dosage form in acidic solution, as defined by USP
methods. Even in enteric pharmaceutical dosage forms, some of the
dosage form may dissolve in the stomach; however, the dosage form
may still be considered enteric according to USP standards.
[0146] 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
(PSP), but with a reduced risk of peripheral MAO inhibition that is
typically associated with administration of rasagiline with known
oral dosage forms.
[0147] 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.).
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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 of Pharmacy, 20.sup.th Edition, 2000)
[0153] 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)
[0154] 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)
[0155] The basket-type apparatus used in this invention is the
apparatus 1 described in the United States Pharmacopeia, 29th
Edition (2006), chapter 711. The apparatus is constructed as
follows:
[0156] The assembly consists of the following: a covered vessel
made of glass or other inert, transparent material; a motor; a
metallic drive shaft; and a cylindrical basket. The vessel is
partially immersed in a suitable water bath of any convenient size
or placed in a heating jacket. The water bath or heating jacket
permits holding the temperature inside the vessel at 37.+-.0.5
during the test and keeping the bath fluid in constant, smooth
motion. No part of the assembly, including the environment in which
the assembly is placed, contributes significant motion, agitation,
or vibration beyond that due to the smoothly rotating stirring
element. Apparatus that permits observation of the specimen and
stirring element during the test is preferable. The vessel is
cylindrical, with a hemispherical bottom and with one of the
following dimensions and capacities: for a nominal capacity of 1 L,
the height is 160 mm to 210 mm and its inside diameter is 98 mm to
106 mm; for a nominal capacity of 2 L, the height is 280 mm to 300
mm and its inside diameter is 98 mm to 106 mm; and for a nominal
capacity of 4 L, the height is 280 mm to 300 mm and its inside
diameter is 145 mm to 155 mm. Its sides are flanged at the top. A
fitted cover may be used to retard evaporation. The shaft is
positioned so that its axis is not more than 2 mm at any point from
the vertical axis of the vessel and rotates smoothly and without
significant wobble. A speed-regulating device is used that allows
the shaft rotation speed to be selected and maintained at the rate
specified in the individual monograph, within .+-.4%. Shaft and
basket components of the stirring element are fabricated of
stainless steel type 316 or equivalent.
[0157] Unless otherwise specified in the individual monograph, use
40-mesh cloth. A basket having a gold coating 0.0001 inch (2.5
.mu.m) thick may be used. The dosage unit is placed in a dry basket
at the beginning of each test. The distance between the inside
bottom of the vessel and the basket is maintained at 25.+-.2 mm
during the test.
[0158] Due to the sensitivity of rasagiline base to UV radiation
and light in general, during the preparation of formulations
described in the following examples, it is recommended to perform
the process in a low UV radiation environment, preferably in an
environment without any UV radiation.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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
Example 1
Rasagiline Immediate Release Tablets
[0164] Rasagiline immediate release tablets were prepared using the
ingredients listed in Table 1.
TABLE-US-00001 TABLE 1 Per Tablet Per Tablet (mg) (mg) (0.5 mg (1
mg Rasagiline Rasagiline Component Function base) base) Rasagiline
mesylate 0.78 1.56 Mannitol Filler 79.62 159.24 Aerosil Flowing 0.6
1.2 Agent Starch NF Binder 10.0 20.0 Starch, Pregelatinized
Disintegrant 10.0 20.0 (Starch STA-RX 1500) Talc Lubricant 2.0 4.0
Stearic Acid Lubricant 2.0 4.0 Total core Tablet 105 210 Weight
[0165] Rasagiline mesylate, mannitol, half of the colloidal silicon
dioxide, starch and pregelatinized starch were mixed in a Diosna
P-800 mixer for about 5 minutes. Water was added and the mixture
was mixed further. The granulate was dried and the remainder of the
colloidal silicon dioxide was added. The granulate was ground in a
Frewitt mill and stearic acid and talc were added. The granulate
was mixed for five minutes in a tumbler and was tableted.
Example 2
Rasagiline Base Tablet Cores
[0166] An attempt was made to formulate tablet cores which would
have a pharmacokinetic profile (C.sub.max and AUC) resembling that
of the immediate release formulation of example 1.
[0167] A process for preparing crystalline rasagiline base is
disclosed in U.S. Patent Application Publication No. 2008/0161408
(and which corresponds to WO 2008/076348). In particular, the
document describes a process for manufacture of crystalline
rasagiline base which comprises: a) dissolving a salt of
R(+)-N-propargyl-1-aminoindan in water to form a solution; b)
cooling the solution to a temperature of about 0-15.degree. C.; c)
basifying the solution to a pH of about 11 to form a suspension;
and d) obtaining the crystalline rasagiline base from the
suspension.
[0168] Five preliminary formulations of rasagiline base as API were
prepared using standard tableting technique based on rasagiline
immediate release formulation of Example 1. Different reagents were
added in order to stabilize the API within the formulation.
TABLE-US-00002 TABLE 2 Compositions of rasagiline base tablet
cores: Composition 1 Composition 2 Composition 3 Composition 4
Composition 5 Rasagiline Rasagiline Rasagiline Rasagiline
Rasagiline base base base base base Citric Acid Maleic Acid
Succinic Acid Malic Acid BHT Mannitol Mannitol Mannitol Mannitol
Mannitol USP/EP USP/EP USP/EP USP/EP USP/EP Colloidal Colloidal
Colloidal Colloidal Colloidal Silicon Silicon Silicon Silicon
Silicon Dioxide Dioxide Dioxide Dioxide Dioxide Pregelatinized
Pregelatinized Pregelatinized Pregelatinized Pregelatinized Starch
Starch Starch Starch Starch Starch NF/EP Starch NF/EP Starch NF/EP
Starch NF/EP Starch NF/EP Stearic Acid Stearic Acid Stearic Acid
Stearic Acid Stearic Acid Talc Talc Talc Talc Talc
[0169] Each composition was produced in lab scale batches of
.about.500 tablets using laboratory equipment with non-GMP lot of
API.
[0170] Stability results of all five formulations (final mixtures)
were put on short-term stability studies at accelerated and room
temperature conditions. Stability results, content of each
formulation and dissolution results of tablets compressed using
single punch are presented in the tables below.
TABLE-US-00003 Composition 1 Raw 2 wks 2 wks 1 mo Mg/tab Materials
Time 0 25.degree. C. 40.degree. C. 40.degree. C. Assay stability
results (%) 0.82 Citric Acid 101.6% 94.2% 94.8% 98.0% Water 1.00
Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 Stability
Results - Level of Impurity (%) 10.0 Starch NF/EP 20.0 Starch STA-
Total <0.04 <0.04 <0.1 <0.2 RX 1500 Impurity (DL) (DL)
(QL) (QL) 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.42 Total
weight
TABLE-US-00004 Composition 2 Raw Time 2 wks 2 wks 1 mo Mg/tab
Materials 0 25.degree. C. 40.degree. C. 40.degree. C. Assay
stability results (%) 0.7 Maleic 82.3 84.6 79.8 80.8 Acid Water
1.00 Rasagiline base 80.0 Manitol Stability Results - USP/EP Level
of Impurity (%) 0.3 Aerosil 200 10.0 Starch Total <0.1 0.1 0.4
0.8 NF/EP Impurity (QL) 20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0
Stearic Acid 2.0 Talc 116.3 Total weight
TABLE-US-00005 Composition 3 Raw 2 wks 2 wks 1 mo Mg/tab Materials
Time 0 25.degree. C. 40.degree. C. 40.degree. C. Assay stability
results (%) 0.7 Succinic 102.9 99.4 100.6 101.9 Acid Water 1.00
Rasagiline Stability Results - base Level of Impurity (%) 80.0
Manitol USP/EP 0.3 Aerosil Total 0.4 0.4 0.6 1.2 200 Impurity 10.0
Starch NF/EP 20.0 Starch STA-RX 1500 0.3 Aerosil 200 2.0 Stearic
Acid 2.0 Talc 116.3 Total weight
TABLE-US-00006 Composition 4 Raw Time 2 wks 2 wks 1 mo Mg/tab
Materials 0 25.degree. C. 40.degree. C. 40.degree. C. Assay
stability results (%) 0.8 Malic Acid 103.4 101.5 101.5 102.2 Water
1.00 Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil Stability
Results - 200 Level of Impurity (%) 10.0 Starch NF/EP 20.0 Starch
Total <0.04 <0.04 <0.1 <0.2 STA-RX Impurity (DL) (DL)
(QL) (QL) 1500 0.3 Aerosil 200 2.0 Stearic Acid 2.0 Talc 116.4
Total weight
TABLE-US-00007 Composition 5 Raw Time 2 wks 2 wks 1 mo Mg/tab
Materials 0 25.degree. C. 40.degree. C. 40.degree. C. Assay
stability results (%) Ethanol 67.8 65.7 48.5 31.9 95% 0.02 BHT 1.00
Rasagiline Stability Results - base Level of Impurity (%) 80.0
Manitol USP/EP 0.3 Aerosil Total <0.1 <0.1 2.9 5.7 200
Impurity (QL) (QL) 10.0 Starch NF/EP 20.0 Starch STA-RX 1500 0.3
Aerosil 200 2.0 Stearic Acid 2.0 Talc 115.62 Total weight
Dissolution Results (% in 0.1N HCl)
TABLE-US-00008 [0171] 5 min 10 min 15 min Composition 1 85 99 100
Composition 2 49 82 90 Composition 3 62 98 103 Composition 4 59 100
107 Composition 5 70 70 70
Dissolution Results (% in Phosphate Buffer pH 6.8)
TABLE-US-00009 [0172] 5 min 10 min 15 min Composition 1 78 92 94
Composition 2 40 77 82 Composition 3 59 98 101 Composition 4 59 95
102 Composition 5 70 70 70
Discussion:
[0173] Compositions 1 and 4, which contain antioxidants Citric and
Malic acids respectively, gave the best stability results and
satisfactory dissolution profile. Therefore, they were chosen for
future development.
Example 3
Preparation of Delayed Release Enteric Coated Tablet with Citric
Acid
[0174] In this example, rasagiline base delayed release enteric
coated tablet containing citric acid was prepared.
[0175] Rasagiline citrate was identified as having formed in the
tablet which was prepared as described in this example.
Example 3a
1.0 mg Rasagiline Base, 117 mg Core Tablet Weight (Formulation
I)
TABLE-US-00010 [0176] TABLE 3a Composition of rasagiline base
delayed release enteric coated tablet Per Tablet Component Function
(mg) Core tablets Rasagiline Base Drug Substance 1.0 Citric Acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 79.84 Colloidal Silicon
Flowing Agent 0.6 Dioxide Starch NF Binder 10.0 Starch,
Pregelatinized Disintegrant 20.0 (STA-RX .RTM. 1500) Talc Lubricant
2.0 Stearic Acid Lubricant 2.0 Total Core Tablet 117.0 Weight
Subcoating Pharmacoat .RTM. 606 Coating Agent 4.8 (Hypromellose
USP) Granules Purified Water Processing Agent Coating Suspension
Eudragit .RTM. L-30D-55 Coating Agent 6.250* Talc USP Extra Fine
Lubricant 1.25 Triethyl citrate Plasticizer 3.1 Purified Water
Processing Agent Total Tablet Weight 132.4 *Dry substance remaining
on the core.
I. Dry Mixing:
[0177] Mannitol, half amount of Aerosil, Pregelatinized Starch and
Starch NF were placed in a high shear granulating mixer and were
premixed for 1 minute mixing at mixer speed I, followed by 1 minute
mixing at mixer speed I and chopper I.
II. Wet Granulation:
[0178] Citric acid solution was prepared using 320 g of citric
acid, in purified water in a weight ratio of approximately 1:10.6
to 1:6.
[0179] Rasagiline Base was added with stirring for approximately 15
minutes. The stirring was continued until a clear solution was
observed. The solution was added into a high shear granulating
mixer and the content was mixed for approximately 2 minutes at
mixer speed II and chopper II. An extra amount of water was added
into the high shear granulating mixer, and the solution was mixed
for two more minutes at mixer speed II and chopper II.
[0180] The wet granulate was discharged into a fluid bed dryer
trolley at mixer speed I.
III. Fluid Bed Drying:
[0181] The material from step II was dried in a fluid bed dryer
under inlet air temperature of 45.degree. C. (40.degree. to
50.degree. C.) and outlet air temperature of maximum 37-38.degree.
C.
IV. Milling:
[0182] The dry granulate and the residual amount of Aerosil were
milled through an oscillating granulator with screen 0.6 mm into a
storage container.
[0183] The milled granulate was further weighed.
V. Final Blending:
[0184] Stearic Acid and Talc were sieved through a 50 mesh screen
and were transferred to the Y-cone/Bin. [0185] 1. The mixture was
mixed for 5 minutes. [0186] 2. The final blend was obtained and the
percentage yield was determined. [0187] 3. The final blend was
stored in a container using an inner transparent polyethylene bag
and an outer black polyethylene bag. Two Silica gel pillows were
placed between the two polyethylene bags. [0188] 4. Samples were
taken for a Blend Uniformity test.
VI. Tablet Compression:
[0189] A tablet compression machine (FETTE 1200) was set up with
the designated punches 6.0 mm.
[0190] The in-process control testing for tablets included average
weight, individual weight, thickness, hardness, friability and
disintegration.
[0191] In process control specifications for Rasagiline Base DR 1
mg tablets is:
TABLE-US-00011 Parameter Minimum Target Maximum Average weight (mg)
111 117 123 Individual weight (mg) 111 117 123 Thickness (mm) 3.3
3.6 3.9 Hardness (SCU) 7 9 11 Friability (%) -- -- 1.0
Disintegration (minutes) -- -- 5
[0192] The tablets were weighed and the percentage yield was
calculated.
VII. Sub-Coating:
[0193] Tablet cores were first coated with hypromellose (Pharmacoat
6066) as a pre-coating, followed by coating with Methacrylic
Acid-Methyl Methacrylate Copolymer [1:1] (Eudragit.RTM. L-30D-55,
30% dispersion of Eudragit.RTM. L100-55) to prevent any possible
interaction between the Rasagiline base in the core and the
Eudragit L polymer.
1. Preparation of Pharmacoat 606.RTM. Solution:
[0194] Hypromellose USP solution was prepared using hypromellose,
in purified water in a weight ratio of approximately 1:10.
2. Pre Heating:
[0194] [0195] The tablet cores were placed in an (Ohara) Coater
coating pan. The tablets were heated under inlet air temperature of
50.degree. C. (45.degree. to 55.degree. C.) and outlet air
temperature of 45-50.degree. C.
3. Spraying Process:
[0195] [0196] The tablet cores were sprayed with hypromellose
solution in the Ohara Coater coating pan. The inlet air temperature
was 50.degree. C.; the outlet air temperature was 35.degree. C. The
pan speed was set to 16 rpm (can vary from 14 to 18 rpm). Spraying
rate was 15-35 gr/min. The tablets were dried for 1 hour with inlet
air temperature of 45.degree. C. (temperature range is 40.degree.
C.-50.degree. C.).
VIII. Enteric Coating:
1. Preparation of Enteric Coating Dispersion of Eudragit.RTM.
L100-55:
[0196] [0197] Triethyl citrate was mixed with water for 15 minutes.
The Talc Extra fine was added into the Triethyl citrate and water
dispersion in an Ultraturax within 10 minutes. Eudragit L100-55 30%
dispersion was added to Triethyl citrate/talc dispersion, filtered
and stirred.
2. Pre Heating:
[0197] [0198] The precoated tablets were placed in an Ohara Coater
coating pan. The tablets were heated under inlet air temperature of
50.degree. C. (45.degree. to 55.degree. C.) and outlet air
temperature of 45.degree. C. (40.degree. to 50.degree. C.).
3. Spraying Process:
[0198] [0199] The tablets were sprayed with the dispersion in an
Ohara coater pan. The inlet air temperature was in the range of
40.degree. C.-50 the outlet air temperature was in the range of
30-40.degree. C. The pan speed was set to 16 rpm in range of 14-18
rpm, and the spraying rate was 5-20 gr/min. The tablets were dried
for 2 hours. The inlet air temperature was 50.degree. C. on minimum
pan speed.
[0200] EUDRAGIT.RTM. L 100-55 contains an anionic copolymer based
on methacrylic acid and ethyl acrylate. It is also known as
methacrylic acid copolymer, type C. The ratio of the free carboxyl
groups to the ester groups is approx. 1:1. The average molecular
weight is approx. 250,000.
##STR00002##
Example 3b
1.0 mg Rasagiline Base, 76 mg Core Tablet Weight (Formulation
III)
[0201] This formulation was prepared using similar steps as
described in Example 3a.
TABLE-US-00012 TABLE 3b composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 1.0 Citric acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.0 Aerosil Flowing
Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant
1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 3.5 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF
Plasticizer 0.8 Purified Water Processing Agent Total Tablet Weight
86.3 *Dry substance remaining on the core.
Example 3c
0.5 mg Rasagiline Base, 117 mg Core Tablet Weight
[0202] This formulation was prepared using similar steps as
described in Example 3a.
TABLE-US-00013 TABLE 3c composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 0.5 Citric acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 80.34 Aerosil Flowing
Agent 0.6 Starch NF Binder 10.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 2.0 Stearic Acid Lubricant
2.0 Total Core Tablet 117.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 4.8 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NF
Plasticizer 1.25 Purified Water Processing Agent Total Tablet
weight 132.4 *Dry substance remaining on the core.
Example 3d
0.5 mg Rasagiline Base, 76 mg Core Tablet Weight
[0203] This formulation was prepared using similar steps as
described in Example 3a.
TABLE-US-00014 TABLE 3d composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 0.5 Citric acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.5 Aerosil Flowing
Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant
1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 3.5 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF
Plasticizer 0.8 Purified Water Processing Agent Total Tablet Weight
86.2 *Dry substance remaining on the core.
Example 4
Dissolution Results of Tablets Prepared According to Example 3a
[0204] The tablets prepared according to Example 3a were tested for
dissolution profile in various media according to USP procedures.
The data below represents average for 4 tablets.
[0205] The % rasagiline released in the following tables is
relative to a standard which is 1 mg rasagiline.
Tablet Cores:
[0206] Dissolution Profile (% Rasagiline Released)--0.1N HCl, 75
rpm, 37.degree. C.
TABLE-US-00015 10 min 20 min 30 min 45 min 1 101 102 102 103 2 105
106 105 106 3 104 105 105 105 4 106 106 107 107 % Mean 104 105 105
105
Dissolution Profile (% Rasagiline Released)--Phosphate Buffer, 75
rpm, 37.degree. C.
TABLE-US-00016 10 min 20 min 30 min 45 min 1 98 99 99 99 2 100 101
101 102 3 99 100 100 101 4 96 96 97 97 % Mean 98 99 99 100 % RSD
1.9 2.0 2.0 2.2
Sub-Coated Tablets:
[0207] Dissolution Profile (% Rasagiline Released)--0.1N HCl, 75
rpm, 37.degree. C.
TABLE-US-00017 10 min 20 min 30 min 45 mm 1 105 105 106 106 2 109
109 109 109 3 103 104 104 104 4 103 104 103 104 % Mean 105 105 105
106 % RSD 2.5 2.3 2.3 2.3
Coated Tablets:
[0208] The dissolution profile of the coated tablets in 0.1N HCl
was acceptable according to USP specification for delayed release
(enteric coated) articles, 29th edition, Chapter 724, showing less
than 10% release after 120 minutes.
Dissolution Profile (% Rasagiline Released)--Phosphate Buffer pH
5.8
TABLE-US-00018 [0209] 10 min 20 min 30 min 40 min 60 min 90 min %
Mean 0 0 0 0 0
Dissolution Profile (% Rasagiline Released)--Phosphate Buffer pH
6.4
TABLE-US-00019 [0210] 10 min 20 min 30 min 40 min 60 min 90 min %
Mean 0 35 93 96 96 96 % RSD 2.2 1.3 1.3 1.2
Dissolution Profile (% Rasagiline Released)--Phosphate Buffer pH
6.8
TABLE-US-00020 [0211] 10 min 20 min 30 min 40 min 60 min 90 min %
Mean 11 92 95 95 94 94 % RSD 3.7 1.6 1.6 1.5 1.6
Discussion:
[0212] The tablets prepared according to Example 3a do not begin
the release of rasagiline at a pH lower than 6.0. At a pH of 6.8,
there is a rapid release of rasagiline and within approximately 20
minutes, above 90% of the rasagiline is released from the
formulation.
[0213] During the development of the formulations of the current
invention, it was determined that the formulations should meet the
criteria of bioequivalence to the known, immediate release
rasagiline mesylate formulations (as disclosed in example 1) in a
single dose bio-equivalence study in healthy subjects. These
criteria include similarity of C.sub.max and/or AUC.sub.0-t (area
under the curve) within the range of 80-125% within a 90%
confidence interval between the new formulations and the known,
immediate release formulations. The difference between the two
formulations should be evident in bioequivalence studies as a
difference in t.sub.max. In other words, the mean pharmacokinetic
profile of the formulations of the current invention should match
substantially the mean pharmacokinetic profile of the formulations
of the immediate release formulation, with the exception of the
t.sub.max which should be greater for the delayed release
formulation than for the immediate release formulation.
[0214] The reason for attempting to match the mean C.sub.max and
AUC.sub.0-t of the known immediate release formulation (i.e. to
formulate a delayed release formulation that is bioequivalent) is
that the efficacy of the immediate release formulation has been
proven, and it is likely that the efficacy of the formulation
relates to its mean C.sub.max and/or AUC. (Arch Neurol. 2002;
59:1937-1943.)
[0215] In order to reach this target, development was directed
toward delayed release enteric coated tablets having a quickly
disintegrating core with an enteric coating which allows release of
the rasagiline in a very specific range of pH. This specific pH
range would prevent the formulation to release rasagiline in the
stomach in fed condition, and would allow the formulation to
release rasagiline quickly under the physiological conditions of
the intestine after the stomach.
[0216] Although the tablets of Example 3a were coated with an
enteric coating comprising Methacrylic Acid Ethyl Acrylate
copolymer, as were the compositions in PCT application publication
WO 2006/014973, the tablets according to Example 3a were capable of
withstanding pH of 6.0 and below, whereas the composition in WO
2006/014973 were not.
[0217] The difference in dissolution profiles stems from the fact
that the core's formulation contained high amount of disintegrant
and the enteric film has a lower ratio of polymer to plasticizer is
used in the compositions of the invention. The ratio of polymer to
plasticizer between 10:1 and 2:1, and specifically 5:1, allows for
enhanced in vitro dissolution profiles.
[0218] The dissolution profile of the formulation of Example 3a
allows the composition to have enhanced pharmacokinetic properties,
similar to the currently marketed immediate release
formulations.
Example 5
Stability Results of Tablets Prepared According to Example 3a
[0219] Stability of enteric coated tablets produced using
formulations containing citric acid was tested under different
storage conditions. The results are summarized below.
Stability Results (Accelerated Conditions):
[0220] The dissolution profile of the enteric coated tablets in
0.1N HCl was acceptable according to USP specification for delayed
release (enteric coated) articles, 29th edition, Chapter 724,
showing less than 10% release after 120 minutes.
[0221] The following table shows that dissolution profile for
enteric coated tablets after different period of storage.
Dissolution Profile of Coated Tablets--Phosphate Buffer pH 6.8,
37.degree. C.
TABLE-US-00021 [0222] Storage Dissolution Profile after Different
Period Period of Storage (% rasagiline released) (months) 10 min 20
min 30 min 40 min 60 min 90 min 0 11 92 95 95 96 96 1 28 95 96 96
97 97 2 12 97 98 98 98 99 3 35 101 103 103 104 104
[0223] The % rasagiline released in the above table is relative to
a standard which is 1 mg rasagiline.
[0224] The following tables show that analytical results for
different batches of the enteric coated tablets under various
storage conditions.
Coated Tablets--Batch 1
TABLE-US-00022 [0225] Conditions Assay % Total impurities (%) T = 0
101.5 <DL 40.degree. C., 1 Mo 101.1 <DL 75 RH 2 Mo 105.4 0.3%
3 Mo 104.5 0.4% 4 Mo 100.9 0.4% 25.degree. C., 1 Mo 104.7 <DL 60
RH 3 Mo 106.2 <DL
Coated Tablets--Batch 2
TABLE-US-00023 [0226] Conditions Assay % Total impurities (%) T = 0
98.6 <DL 40.degree. C., 1 Mo 99.1 0.05% 75 RH 2 Mo 96.3 0.1% 3
Mo 95.6 0.2% 4 Mo 96.6 0.3% 30.degree. C., 1 Mo 99.8 <DL 65 RH 2
Mo 98.4 <DL 3 Mo 96.5 <DL 25.degree. C., 1 Mo 98.4 <DL 60
RH 2 Mo 95.8 <DL 3 Mo 96.2 <DL
Coated Tablets--Batch 3
TABLE-US-00024 [0227] Conditions Assay % Total Impurities (%) T = 0
100.3 <DL 40.degree. C., 1 Mo 100.3 <DL 75 RH 40.degree. C.,
2 Mo 102.0 <DL 75 RH 40.degree. C., 3 Mo <0.28 75 RH
30.degree. C., 3 Mo <0.08 65 RH 25.degree. C., 1 Mo 101.2 <DL
60 RH 25.degree. C., 2 Mo 102.1 <DL 60 RH 25.degree. C., 3 Mo
<0.08 60 RH
N-(2-chloroallyl)-1(R)-aminoindan (2-Cl-AAI) Impurities
TABLE-US-00025 Batch No. 2-C1-AAI Content, % 1 LT 0.00004 2 LT
0.00004
Example 6
Preparation of Rasagiline Base Delayed Release Enteric Coated
Tablets with Malic Acid
Example 6a
1 mg Rasagiline Base, 117 mg Core Tablet Weight
TABLE-US-00026 [0228] TABLE 6a composition of rasagiline-base
delayed release enteric coated tablet Per Tablet Component Function
(mg) Core tablets Rasagiline base Drug Substance 1.0 Malic acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 80.0 Aerosil Flowing
Agent 0.6 Starch NF Binder 10.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX .RTM. 1500) Talc Lubricant 2.0 Stearic Acid
Lubricant 2.0 Total Core Tablet 117.2 Weight Subcoating Pharmacoat
.RTM. 606 Coating Agent 4.8 (Hypromellose USP) Granules Purified
Water Processing Agent Coating Suspention Eudragit .RTM. L-30D-55
Coating Agent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl
citrate NF Plasticizer 1.25 Purified Water Processing Agent Total
Tablet Weight 132.6 *Dry substance remaining on the core.
I. Dry Mixing:
[0229] Mannitol, half amount of Aerosil, Starch Pregelatinized and
starch NF are placed into a high shear granulating mixer and are
premixed for 1 minute mixing at mixer speed I, followed by 1 minute
mixing at mixer speed II and chopper II.
II. Wet Granulation:
[0230] Malic acid solution was prepared using malic acid in
purified water in the ratio of approximately 1:10.6 to 1:6.
[0231] Rasagiline Base was added with stirring for approximately 15
minutes. The stirring was continued until a clear solution was
observed.
[0232] The solution was added into a high shear granulating mixer
and was mixed for approximately 2 minute mixing at mixer speed II
and chopper II. An extra amount of water was added into the high
shear granulating mixer, and the solution was mixed for two more
minutes at mixer speed II and chopper II.
[0233] The wet granulate was discharged to a fluid bed dryer
trolley at mixer speed I.
III. Fluid Bed Drying:
[0234] The material was dried in a fluid bed dryer under inlet air
temperature of 45.degree. C. (40.degree. to 50.degree. C.) and
outlet air temperature of maximum 37-38.degree. C.
IV. Milling:
[0235] The dry granulate was milled with the residual amount of
Aerosil through an oscillating granulator with screen 0.6 mm into
storage container.
[0236] The milled granulate is weighed.
V. Final Blending:
[0237] 1. Stearic Acid and Talc were sieved through a 50 mesh
screen and transferred to the Y-cone or Bin. 2. The mixture was
mixed for 5 minutes. 3. The final blend was stored in a container
using an inner transparent polyethylene bag and an outer black
polyethylene bag. Two Silica gel pillows were placed between the
two polyethylene bags. 4. Samples were taken for a Blend Uniformity
test.
VI. Tablet Compression:
[0238] The compressing tablet machine was set up with the
designated punches 6.0 mm. The diameter of the punch may change
+/-10%.
[0239] The in-process control testing for tablets includes average
weight, individual weight, thickness, hardness, friability and
disintegration.
[0240] In process control specifications for the Rasagiline Base DR
1 mg tablet cores are:
TABLE-US-00027 Parameter Minimum Target Maximum Avarage weight 111
117 123 (mg) (121 Actual) Individual weight 111 117 123 (mg)
Tickness (mm) 3.3 3.6 3.9 (3.7 Actual) Hardness (SCU) 7 9 11 (10
Actual) Friability (%) -- -- 1.0 Disintegration -- -- 5
(minutes)
[0241] The tablet cores are weighed and the percentage yield is
calculated.
VII. Sub-Coating:
[0242] Tablet cores were first coated with hypromellose (Pharmacoat
606) as a pre-coating, followed by Methacrylic Acid-Methyl
Methacrylate Copolymer [1:1] (Eudragit.RTM. L30D-55, 30% dispersion
of Eudragit.RTM. L100-55) to prevent any possible interaction
between the Rasagiline base in the core and the Eudragit L
polymer.
1. Preparation of Pharmacoat 606 Solution:
[0243] Pharmacoat 606 (hypromellose USP) solution was prepared
using Pharmacoat 606 in purified water in a weight ratio of
1:10.
2. Pre Heating:
[0243] [0244] The tablet cores are place in an Ohara Coater coating
pan the tablets was heated under inlet air temperature of
50.degree. C. (45.degree. to 55.degree. C.) and outlet air
temperature of 40.degree. to 50.degree. C.
3. Spraying Process:
[0244] [0245] The tablet cores were sprayed with solution in an
Ohara Coater coating pan. The inlet air temperature was 50.degree.
C. (in the range of 40-50.degree. C.); the outlet air temperature
was in range of 30-40.degree. C. The pan speed was set to 16 rpm in
the range of 14-18 rpm; spraying rate was 15-35 gr/min. The tablets
were dried for 1 hour with inlet air temperature of 45.degree. C.
(in the range of 40-50.degree. C.)
VIII. Enteric Coating:
[0246] The Rasagiline subcoated drug product tablet formulation
described in previous section was used for the enteric coated.
1. Preparation of Eudragit.RTM. L100-55 Dispersion:
[0247] Triethyl citrate was mixed with the water for 15 min. The
Talc Extra fine was added into the Triethyl citrate and water
dispersion in an Ultraturax within 10 minutes. [0248] Eudragit.RTM.
L100-55 was added to Triethyl citrate/talc dispersion, filtered and
stirred to the continuation of the process.
2. Pre Heating:
[0248] [0249] The tablet cores are place in an Ohara Coater coating
pan the tablets was heated under inlet air temperature of
50.degree. C. (45.degree. to 55.degree. C.) and outlet air
temperature of 45.degree. C. (40.degree. to 50.degree. C.).
2. Spraying Process:
[0249] [0250] The tablets were sprayed with the dispersion in an
Ohara coater pan. The inlet air temperature was 45.degree. C.; the
outlet air temperature was 35.degree. C. (in range of 30-40.degree.
C.). The pan speed was set to 16 rpm (in the range of 14-18 rpm),
and the spraying rate was 5-20 gr/min. The tablets were dried for 2
hours; with inlet air temperature of 50.degree. C. (in the range of
45-55.degree. C.), on minimum pan speed.
Example 6b
1.0 mg Rasagiline Base, 76 mg Core Tablet Weight
[0251] This formulation was prepared using similar steps as
described in example 6a.
TABLE-US-00028 TABLE 6b composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 1.0 Malic acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.0 Aerosil Flowing
Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant
1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 3.5 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF
Plasticizer 0.8 Purified Water Processing Agent Total Tablet weight
86.2 *Dry substance remaining on the core.
Example 6c
0.5 mg Rasagiline Base, 117 mg Core Tablet Weight
[0252] This formulation was prepared using similar steps as
described in example 6a.
TABLE-US-00029 TABLE 6c composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 0.5 Malic acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 80.34 Aerosil Flowing
Agent 0.6 Starch NF Binder 10.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 2.0 Stearic Acid Lubricant
2.0 Total Core Tablet 117.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 4.8 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 6.25* Talc USP Extra Fine Lubricant 3.1 Triethyl citrate NF
Plasticizer 1.25 Purified Water Processing Agent Total Tablet
Weight 132.4 *Dry substance remaining on the core.
Example 6d
Preparation of 0.5 mg Rasagiline Base Delayed Release Enteric
Coated Tablet
[0253] In this example, a 0.5 mg rasagiline base delayed release
enteric coated tablet containing malic acid (76 mg core tablet
weight) was prepared using similar steps as described in example
6a.
TABLE-US-00030 TABLE 6d composition of rasagiline-base delayed
release enteric coated tablet Per Tablet Component Function (mg)
Core tablets Rasagiline base Drug Substance 0.5 Malic acid
Antioxidant/ 1.6 Stabilizer Mannitol Filler 45.5 Aerosil Flowing
Agent 0.4 Starch NF Binder 5.0 Starch, Pregelatinized Disintegrant
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 Stearic Acid Lubricant
1.5 Total Core Tablet 76.0 Weight Subcoating Pharmacoat .RTM. 606
Coating Agent 3.5 (Hypromellose USP) Granules Purified Water
Processing Agent Coating Suspension Eudragit .RTM. L-30D-55 Coating
Agent 4.0* Talc USP Extra Fine Lubricant 1.9 Triethyl citrate NF
Plasticizer 0.8 Purified Water Processing Agent Total Tablet weight
86.2 *Dry substance remaining on the core.
Example 7
Stability Results of Tablets Prepared According to Example 6a
[0254] Stability of enteric coated tablets produced using
formulations containing citric acid was tested under different
storage conditions. The results are summarized below.
Stability Results (Accelerated Conditions):
[0255] The dissolution profile of the enteric coated tablets in
0.1N HCl was acceptable according to USP specification for delayed
release (enteric coated) articles, 29th edition, Chapter 724,
showing less than 10% release after 120 minutes.
[0256] The following tables show that analytical results for
tablets under various storage conditions.
Tablet Cores:
TABLE-US-00031 [0257] Conditions Assay (%) Total Impurities T = 0
101.2 <DL 40.degree. C., 1 Mo 101.1 0.1 75 RH 2 Mo 98.3 0.3 3 Mo
93.3 0.5 4 Mo 93.1 0.4 30.degree. C., 1 Mo 101.4 <DL 65 RH 2 Mo
101.9 <QL 3 Mo 98.3 <QL 25.degree. C., 1 Mo 101.5 <DL 60
RH 2 Mo 102.0 <QL 3 Mo 100.3 <QL
Enteric Coated Tablets:
TABLE-US-00032 [0258] Conditions Assay % Total Impurities T = 0
98.2 <QL 40.degree. C., 75 RH 1 Mo 100.5 0.2 2 Mo 96.4 0.3 3 Mo
96.6 0.5 30.degree. C., 65 RH 1 Mo 98.2 <QL 2 Mo 100.2 <QL 3
Mo 101.0 0.1 25.degree. C., 60 RH 1 Mo 101.5 <QL 2 Mo 96.7
<QL 3 Mo 99.5 <QL
N-(2-Chloroallyl)-1(R)-aminoindan (2-Cl-AAI) Impurities
TABLE-US-00033 [0259] Batch No 2-C1-AAI Content, % 1
<0.00004
Example 8
Preparation of Rasagiline Base Tablet Cores with Citric Acid
TABLE-US-00034 [0260] Raw material mg/tablet Percentage Part I,
Granulation solution Citric acid 1.6 2.0 Rasagiline base 1 1.25
Purified Water 12.35 15.44 Part II Mannitol 48.5 60.63 Aerosil 200
0.18 0.22 Starch NF/BP 6.1 7.62 Pregelatinized starch NF/Ph. Eur
20.0 25.0 Part III Aerosil 200 0.18 0.22 Part IV Stearic acid 1.22
1.52 Talc 1.22 1.52 Total: 80.0 100
[0261] The above composition can also be used to prepare rasagiline
base tablets with malic acid by replacing the citric acid with the
same amount of malic acid.
[0262] Calculated amounts of external excipients in accordance with
actual amount of granulate:
TABLE-US-00035 mg/tablet Raw material Percentage Part III Granulate
0.18 Aerosil 200 0.22 Part IV 1.22 Stearic acid 1.52 1.22 Talc
1.52
I. Granulation solution preparation: [0263] 1. Weigh 80% of needed
amount of Purified water into glass. [0264] 2. Weigh into the same
glass Citric acid. [0265] 3. Insert stirrer into the glass and
start to stir up to complete solubility about 5-10 minutes. [0266]
4. Weigh Rasagiline base and add it into the obtained Citric acid
solution. [0267] 5. Continue stirring about 30 minutes to complete
solubility of API.
II. Granulation Preparation:
[0267] [0268] 1. Weigh Mannitol, Aerosil 200, Starch and
Pregelatinized starch and transfer all excipients to Diosna P-6
(Diosna) and mix for 1 minute with Mixer I (270 rpm). [0269] 2. Mix
the excipient for 1 addition minute with Mixer I (270 rpm) and
Chopper I (1500 rpm) [0270] 3. Add Granulation solution into the
Diosna P-6(Diosna) and mix for 2 minutes with Mixer II (540 rpm)
and Chopper II (2200 rpm). [0271] 4. Clean glass after granulation
solution with 46.563 g of Purified water and add it into the Diosna
P-6 (Diosna). [0272] 5. Mix for 2 minutes with Mixer II (540 rpm)
and Chopper II (2200 rpm). [0273] 6. Transfer obtained granulate
into the Glatt 1.1 (Fluid Bed) for drying at 37.degree. C. inlet
air up to L.O.D. NMT 1.5%.
Conditions of Drying:
Inlet: Min.--35.degree. C.; Target--50.degree. C.; Max.--55.degree.
C.
[0274] Outlet: Product temperature--37.degree. C.
Flow: Min.--25; Target--60; Max.--1000
III. Milling:
[0275] Mill granulate through 0.6 mm sieve using Frewitt.
IV. Final Blend:
[0276] 1. Weigh obtained amount of granulate. [0277] 2. Calculate
amounts of Aerosil 200, Stearic acid and Talc in accordance with
actual granulation weight. [0278] 3. Screen Aerosil 200 through 50
mesh sieve. [0279] 4. Weigh needed amount of Aerosil 200 after,
sieving. [0280] 5. Transfer milled granulate and Aerosil 200 after
sieving into the Y-cone. [0281] 6. Mix for 2 minutes. [0282] 7.
Weigh Stearic acid and Talc. [0283] 8. Screen these excipients
through 50 mesh sieve. [0284] 9. Transfer them into the Y-cone.
[0285] 10. Mix for 5 minutes.
V. Tablet Compression:
Machine: Sviac
[0286] Diameter of punch: 5.0 mm (it may be changed .+-.10%) Tablet
weight--80 mg.+-.5%
Hardness: 3-7 kP
Friability: Not More Than 1%
[0287] Disintegration: Not More Than 5 minutes
Example 9
Preparation of Rasagiline Base Tablet Cores with Malic Acid
TABLE-US-00036 [0288] Raw material mg/tablet Percentage Part I,
Granulation solution Malic acid 1.6 3.72 Rasagiline base 1 2.33
Part II Mannitol 25.8 60.0 Aerosil 200 0.1 0.24 Starch NF/BP 3.0
6.98 Pregelatinized starch NF/Ph. Eur 10.0 23.26 Part III Aerosil
200 0.1 0.23 Part IV Stearic acid 0.7 1.63 Talc 0.7 1.63 Total:
43.0 100
[0289] The above composition can also be used to prepare rasagiline
base tablets with citric acid by replacing the malic acid with the
same amount of citric acid.
I. Granulation Solution Preparation.
[0290] 1. Weigh 80% of needed amount of Purified water into glass.
[0291] 2. Weigh Malic acid and add it into the same glass. [0292]
3. Insert stirrer into the glass and start to stir up to complete
solubility about 5-10 minutes. [0293] 4. Weigh Rasagiline base and
add it into the obtained Malic acid solution. [0294] 5. Continue
stirring about 30 minutes to complete solubility of API.
II. Granulation Preparation.
[0294] [0295] 1. Weigh Mannitol, Aerosil 200, Starch and
Pregelatinized starch and transfer all excipients to Diosna P-10
(Diosna) and mix for 1 minute with Mixer I. [0296] 2. Mix the
excipient for 1 addition minute with Mixer I and Chopper I rpm.
[0297] 3. Add granulation solution into the Diosna P-10 (Diosna)
and mix for 2 minutes with Mixer II and Chopper II. [0298] 4. Add
additional Purified Water into the Diosna P-10 (Diosna) and mix for
2 minutes with Mixer II, and Chopper II. [0299] 5. Transfer
obtained granulate into the Glatt 5 (Fluid Bed) for drying at
37.degree. C. inlet air up to L.O.D. NMT 1.5%.
Conditions of Drying:
Inlet: Min.--35.degree. C.; Target--50.degree. C.; Max.--55.degree.
C.
[0300] Outlet: Product temperature--37.degree. C.
III. Milling.
[0301] Weigh and add Aerosil 200 to granulate and milled granulate
through 0.6 mm sieve using Frewitt.
IV. Final Blend.
[0302] 1. Weigh Stearic acid and Talc. [0303] 2. Screen the
excipients through 50 mesh sieve. [0304] 3. Transfer milled
granulate and sieved Stearic acid and Talc into the Y-cone. [0305]
4. Mix for 5 minutes.
V. Tablet Compression:
Machine: Sviac
[0306] Diameter of punch: 4.0 mm (it may be changed .+-.10%) Tablet
weight--43 m.+-.5%
Hardness: 3-5 kP
Friability: Not More Than 1%
[0307] Disintegration: Not More Than 5 minutes
Example 10
Preparation of Rasagiline Base Tablet Cores with Both Citric and
Malic acids
TABLE-US-00037 [0308] Raw material Mg/tablet Percentage Part I,
Granulation solution Citric acid 0.8 0.68 Malic acid 0.8 0.68
Rasagiline base 1.0 0.85 Part II Mannitol 79.8 68.2 Aerosil 200 0.3
0.26 Starch NF/BP 10.0 8.55 Pregelatinized starch NF/Ph. Eur 20.0
17.09 Part III Aerosil 200 0.3 0.26 Part IV Stearic acid 2.0 1.71
Talc 2.0 1.71 Total: 117.6 100
Calculated Amounts of External Excipients in Accordance with Actual
Amount of Granulate
TABLE-US-00038 Raw material mg/tablet Percentage Part III Granulate
Aerosil 200 0.3 0.26 Part IV Stearic acid 2.0 1.71 Talc 2.0
1.71
I. Granulation Solution 1 Preparation.
[0309] 1. weigh 80% of needed amount of Purified water into glass.
[0310] 2. Weigh into the same glass Citric acid. [0311] 3. Insert
stirrer into the glass and start to stir up to complete solubility
about 5-10 minutes. [0312] 4. weigh Rasagiline base and add it into
the obtained Citric acid solution. [0313] 5. Continue stirring
about 30 minutes to complete solubility of API.
II. Granulation Solution 2 Preparation.
[0313] [0314] 1. weigh 20% of needed amount of Purified water into
the glass. [0315] 2. Add into this glass weighed amount of Malic
acid. [0316] 3. Insert stirrer into the glass and start to stir up
to complete solubility about 5-10 minutes.
III. Granulation Preparation.
[0316] [0317] 1. Weigh Mannitol, Aerosil 200, Starch and
Pregelatinized starch and transfer all excipients to Diosna P-6
(Diosna) and mix for 1 minute with Mixer I (270 rpm). [0318] 2. Mix
the excipient for 1 addition minute with Mixer I (270 rpm) and
Chopper I (1500 rpm) [0319] 3. Add Granulation solution 1 into the
Diosna P-6 (Diosna) and mix for 2 minutes with Mixer II (540 rpm)
and Chopper II (2200 rpm). [0320] 4. Clean glass after granulation
solution 1 with Granulation solution 2 and add it into the Diosna
P-6 (Diosna). [0321] 5. Mix for 2 minutes with Mixer II (540 rpm)
and Chopper II (2200 rpm). [0322] 6. Transfer obtained granulate
into the Glatt 1.1 (Fluid Bed) for drying at 37.degree. C. inlet
air up to L.O.D. NMT 1.5%.
Conditions of Drying:
Inlet: Min.--35.degree. C.; Target--50.degree. C.; Max--55.degree.
C.
[0323] Outlet: Product temperature--37.degree. C.
Flow: Min.--25; Target--60; Max--1000
IV. Milling:
[0324] Mill obtained granulate through 0.6 mm sieve using
Frewitt.
V. Final Blend:
[0325] 1. Weigh obtained amount of granulate. [0326] 2. Calculate
amounts of Aerosil 200, Stearic acid and Talc in accordance with
actual granulation weight. [0327] 3. Screen Aerosil 200 through 50
mesh sieve. [0328] 4. Weigh needed amount of Aerosil 200 after
sieving. [0329] 5. Transfer milled granulate and Aerosil 200 after
sieving into the Y-cone. [0330] 6. Mix for 2 minutes. [0331] 7.
Weigh Stearic acid and Talc. [0332] 8. Screen these excipients
through 50 mesh sieve. [0333] 9. Transfer them into the Y-cone.
[0334] 10. Mix for 5 minutes.
VI. Tablet Compression
Machine: Sviac
[0335] Diameter of punch: 6.0 mm (it may be changed .+-.10%) Tablet
weight--117 mg.+-.5%
Hardness: 6-8 kP
Friability: Not More Than 1%
[0336] Disintegration: Not More Than 5 minutes
VII. Subcoating:
TABLE-US-00039 [0337] Mg/tablet Raw material 4.8 Pharmacoat 606
(Hypromellose USP)
Equipment: O'HARA, Peristaltic Pump
1. Preparation of Sub-Coating Solution:
[0338] Pharmacoat 606 (hypromellose USP) was added into the vessel
with 1510 g of Purified water and mixed for 30 minutes using
stirrer.
2. Preheating:
[0338] [0339] The core tablets were placed into the Pan 2.5 kg of
O'HARA Coater and preheated: [0340] Inlet air
temperature--50.degree. C. (45.degree. to 55.degree. C.) [0341]
Outlet air temperature--45.degree. C. (40.degree. to 50.degree.
C.). [0342] Difference pressure--1-50 Pa
3. Spraying Process (the Process was Continued Till Desired Tablet
Weight was Achieved):
[0342] [0343] Sub-coating solution was sprayed on the preheated
core tablets at the following conditions: [0344] Number of spray
guns--1 [0345] Nozzle bore--1 mm [0346] Distance tablet bed/spray
gun--15 cm [0347] Pan speed 10 rpm (8-12 rpm) [0348] Inlet air
temperature--50.degree. C. (45.degree. to 55.degree. C.) Outlet air
temperature--35.degree. C. (30.degree. to 40.degree. C.) Spraying
rate--10-20 g/min Difference pressure--1-50 Pa Atomizing air
pressure--30 Psi Pattern air pressure--30 Psi
4. Drying Process:
[0348] [0349] Inlet air temperature--45.degree. C. (40.degree. to
50.degree. C.) [0350] Outlet air temperature--40.degree.
C.-50.degree. C. [0351] Pan speed--5 rpm Jogging [0352] Drying
time--60 min
Example 11
Additional Rasagiline Base Enteric Coated Formulations with Citric
Acid
Example 11a
0.5 mg Rasagiline Base
[0353] This example describes 0.5 mg rasagiline base formulations
with variations in the amount of citric acid and other excipients.
These formulations have a dissolution and pharmacokinetic profile
(C.sub.max and AUC) resembling that of example 1.
TABLE-US-00040 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 0.5 0.5 0.5 0.5 Citric acid Antioxidant 1.6 or 0.8
1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler 45.5 68.3 50.5
80.3 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0 20.0
(Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic Acid
Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-55 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Triethyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 11b
1.0 mg Rasagiline Base
[0354] This example describes 1 mg rasagiline base formulations
with variations in the amount of citric acid and other excipients.
These formulations have a dissolution and pharmacokinetic profile
(C.sub.max and AUC) resembling that of example 1.
TABLE-US-00041 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 1.0 1.0 1.0 1.0 Citric acid Antioxidant 1.6 or 0.8
1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler 45.0 67.8 50.0
79.8 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10.0 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic
Acid Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-55 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Triethyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 12
Additional Rasagiline Base Enteric Coated Formulations with Malic
Acid
Example 12a
0.5 mg Rasagiline Base
[0355] This example describes 0.5 mg rasagiline base formulations
with variations in the amount of malic acid and other excipients.
These formulations have a dissolution and pharmacokinetic profile
(C.sub.max and AUC) resembling that of example 1.
TABLE-US-00042 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 0.5 0.5 0.5 0.5 Malic acid Antioxidant 1.6 or 0.8
1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler 45.5 68.3 50.5
80.3 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0 20.0
(Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic Acid
Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-55 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Triethyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 12b
1.0 mg Rasagiline Base
[0356] This example describes 1 mg rasagiline base formulations
with variations in the amount of malic acid and other excipients.
These formulations have a dissolution and pharmacokinetic profile
(C.sub.max and AUC) resembling that of example 1.
TABLE-US-00043 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 1.0 1.0 1.0 1.0 Malic acid Antioxidant 1.6 or 0.8
1.6 or 0.8 1.6 or 0.8 1.6 or 0.8 Mannitol Filler 45.0 67.8 50.0
79.8 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10.0 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic
Acid Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-55 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Trielhyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 13
Additional Rasagiline Base Enteric Coated Formulations with Both
Citric and Relic Acid
Example 13a
0.5 mg Rasagiline Base
[0357] This example describes 0.5 mg rasagiline base formulations
with variations in the amount of citric acid, malic acid, and other
excipients. These formulations have a dissolution and
pharmacokinetic profile (C.sub.max and AUC) resembling that of
Example 1.
TABLE-US-00044 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 0.5 0.5 0.5 0.5 Malic acid Antioxidant 0.8 or 0.4
0.8 or 0.4 0.8 or 0.4 1.6 or 0.8 Citric acid Antioxidant 0.8 or 0.4
0.8 or 0.4 0.8 or 0.4 1.6 or 0.8 Mannitol Filler 45.5 68.3 50.5
80.3 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10.0 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic
Acid Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-35 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Triethyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 13b
1.0 mg Rasagiline Base
[0358] This example describes 1 mg rasagiline base formulations
with variations in the amount of citric acid, malic acid, and other
excipients. These formulations have a dissolution and
pharmacokinetic profile (C.sub.max and AUC) resembling that of
example 1.
TABLE-US-00045 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug Substance 1.0 1.0 1.0 1.0 Malic acid Antioxidant 0.8 or 0.4
0.8 or 0.4 0.8 or 0.4 1.6 or 0.8 Citric acid Antioxidant 0.8 or 0.4
0.8 or 0.4 0.8 or 0.4 1.6 or 0.8 Mannitol Filler 45.0 67.8 50.0
79.8 Aerosil Flowing Agent 0.4 0.6 0.4 0.6 Starch NF Binder 5.0
10.0 5.0 10.0 Starch, Pregelatinized Disintegrant 20.0 20.0 15.0
20.0 (Starch STA-RX 1500) Talc Lubricant 1.5 2.0 1.5 2.0 Stearic
Acid Lubricant 1.5 2.0 1.5 2.0 Total Core Tablet 76.0(+/-10%)
105.0(+/-10%) 76.0(+/-10%) 117.0(+/-10%) Weight Subcoating
Pharmacoat 606 Coating Agent 3.5(+/-10%) 4.8(+/-10%) 3.5(+/-10%)
4.8(+/-10%) (Hypromellose USP) Granules Purified Water Processing
Agent Coating Suspension Eudragit L-30D-55 Coating Agent
4.0(+/-10%) 4.0(+/-10%) 4.0(+/-10%) 6.25(+/-10%) Talc USP Extra
Fine Lubricant 1.9(+/-10%) 1.9(+/-10%) 1.9(+/-10%) 3.1(+/-10%)
Triethyl citrate NF Plasticizer 0.8(+/-10%) 0.8(+/-10%) 0.8(+/-10%)
1.25(+/-10%) Purified Water Processing Agent
Example 14
Color Coated Rasagiline Base Enteric Coated Formulation with Citric
Acid
Example 14a
0.5 mg Rasagiline Base
[0359] This example describes a 0.5 mg rasagiline base formulation
containing citric acid with an extra color coating.
TABLE-US-00046 Per Tablet Component Function (mg) Core tablets
Rasagiline base Drug Substance 0.5 Citric acid Antioxidant 1.6
Mannitol Filler 80.3 Aerosil Flowing Agent 0.6 Starch,
Pregelatinized Disintegrant 20.0 (Starch STA-EX 1500) Starch NF
Binder 10.0 Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total
Core Tablet 117.0 Weight Subcoating Pharmacoat 606 Coating Agent
4.8 (Hypromellose USP) Granules Purified water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating Agent 6.25* Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat OPADRY II OY-GM-28900
Coating Agent 1-5 WHITE (catnum. 415850005) OR OPADRY II Y-30-18037
WHITE (catnum. 415880719) OR/AND Opadry fx 63f97546 silver Purified
Water Processing Agent *Dry substance remaining on the core.
Example 14b
1.0 mg Rasagiline Base
[0360] This example describes a 1 mg rasagiline base formulation
containing citric acid with an extra color coating.
TABLE-US-00047 Per Tablet Component Function (mg) Core tablets
Rasagiline base Drug Substance 1.0 Citric acid Antioxidant 1.6
Mannitol Filler 79.8 Aerosil Flowing Agent 0.6 Starch,
Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Starch NF
Binder 10.0 Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total
Core Tablet 117.0 Weight Subcoating Pharmacoat 606 Coating Agent
4.8 (Hypromellose USP) Granules Purified Water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating Agent 6.25* Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat Opadry .RTM. II 31F20721
Coating Agent 1-5 Blue OR Opadry .RTM. II 34G24627 Pink OR/AND
Opadry fx 63f97546 silver Purified Water Processing Agent *Dry
substance remaining on the core.
Example 14c
Rasagiline Base (Formulation III with Color Coating)
[0361] This example describes rasagiline base formulation
(Formulation III) containing citric acid with an extra color
coating.
TABLE-US-00048 Per Tablet per Tablet (mg) - (mg) - 0.5 mg 1.0 mg
rasagiline rasagiline Component Function formulation formulation
Core tablets Rasagiline base Drug Substance 0.5 1 Citric acid
Antioxidant 1.6 1.6 Mannitol Filler 45.5 45 Aerosil Flowing Agent
0.4 0.4 Starch NF Binder 5 5 Starch, Pregelatinized Disintegrant 20
20 (Starch STA-RX 1500) Talc Lubricant 1.5 1.5 Stearic Acid
Lubricant 1.5 1.5 Total Core Tablet 76 76 Weight Subcoating
Pharmacoat 606 Coating Agent 3.5 3.5 (Hypromellose USP) Granules
Coating Suspension Eudragit L-30D-55 Coating Agent 4 4 Talc USP
Extra Fine Lubricant 1.9 1.9 Triethyl citrate NF Plasticizer 0.8
0.8 Top coat Opadry .RTM. Coating Agent 2 2 Total Tablet Weight
88.2 88.2
Example 15
Color Coated Rasagiline Base Enteric Coated Formulation with Malic
Acid
Example 15a
0.5 mg Rasagiline Base
[0362] This example describes a 0.5 mg rasagiline base formulations
containing malic acid with an extra color coating.
TABLE-US-00049 Per Tablet Component Function (mg) Core tablets
Rasagiline base Drug Substance 0.5 Malic acid Antioxidant 1.6
Mannitol Filler 80.3 Aerosil Flowing Agent 0.6 Starch,
Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Starch NF
Binder 10.0 Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total
Core Tablet 117.0 Weight Subcoating Pharmacoat 606 Coating Agent
4.8 (Hypromellose USP) Granules Purified Water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating Agent 6.25* Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat OPADRY II OY-GM-28900
Coating Agent 1-5 WHITE (catnum. 415850005) OR OPADRY II Y-30-18037
WHITE (catnum. 415880719) OR/AND Opadry fx 63f97546 silver Purified
Water Processing Agent *Dry substance remaining on the core.
Example 15b
1.0 mg Rasagiline Base
[0363] This example describes a 1 mg rasagiline base formulations
containing malic acid with an extra color coating.
TABLE-US-00050 Per Tablet Component Function (mg) Core tablets
Rasagiline base Drug Substance 1.0 Malic acid Antibxidant 1.6
Mannitol Filler 79.8 Aerosil Flowing Agent 0.6 Starch,
Pregelatinized Disintegrant 20.0 (Starch STA-RX 1500) Starch NF
Binder 10.0 Talc Lubricant 2.0 Stearic Acid Lubricant 2.0 Total
Core Tablet 117.0 Weight Subcoating Pharmacoat 606 Coating Agent
4.8 (Hypromellose USP) Granules Purified Water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating Agent 6.25* Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat Opadry .RTM. II 31F20721
Coating Agent 1-5 Blue OR Opadry .RTM. II 34G24627 Pink OR/AND
Opadry fx 63f97546 silver Purified water Processing Agent *Dry
substance remaining on the core.
Example 16
Extraction of Rasagiline Base from Tablets
[0364] This example evaluated the amount of free Rasagiline base in
1 mg tablets of formulations with citric acid.
[0365] Rasagiline is assumed to be present in the formulation in
salt form or as free base.
[0366] Rasagiline base is a non-polar compound very soluble in
non-polar organic solvents such as hexane toluene and ethylacetate.
Therefore, free Rasagiline base could be extracted from the solid
formulation by these solvents.
[0367] Rasagiline salts are not soluble in non-polar solvents and
the probability of the extraction of rasagiline citrate with
hexane, toluene, 1-octanol or ethylacetate is very low.
[0368] Core tablets of Rasagiline base prepared using steps
described in example 9 were tested. Each tablet contained 1 mg of
Rasagiline base. Placebo tablets were used as references.
[0369] 17 core tablets, 1 mg of Rasagiline base each were crushed
and ground in mortar to homogeneous fine powder.
[0370] Each powder was mixed with 20 ml of organic solvent and
stirred with magnetic stirrer for 1 hour at room temperature in
closed glass vessel. Then the mixture was settled without stirring,
the clear liquid was decanted and a sample of the resulting extract
was filtered trough 0.2.mu. filter.
[0371] The filtered samples of the extracts were subjected to HPLC
analysis for quantity of dissolved Rasagiline. Samples of the
placebo extracts were used as control.
[0372] Maximal possible calculated concentration of Rasagiline base
in the extracts is 0.85 mg/ml (17 mg in 20 ml solvent).
[0373] The results are summarized in Table 5 below.
TABLE-US-00051 TABLE 16 Extractions of Rasagiline base from core
tablets with organic solvents Weight Achieved of concentration of
Experiment No. of tablets, Rasagiline in No. tablets g Solvent
extract, mg/ml 1 17 2.02 Toluene 0.01 2 17 2.02 n-Hexane 0.01 3 17
2.02 DCM 0.01 4 17 2.03 1-Octanol 0.01 5 17 2.02 Ethyl 0.02
acetate
Summary of Results
[0374] The experimental results in Table 16 show that the core
tablets of "Citric" formulation of Rasagiline base may contain 1 to
2 percent of the free rasagiline base extractable with non polar
solvents.
[0375] Amount of the extractable base does not depend on the
solvent type for non polar solvent as n-hexane, toluene, 1-octanol
and dichloromethane. However, more polar solvent such as
ethylacetate extracted more rasagiline base from the core
tablets.
Example 17
Clinical Study Based on Tablets According to Examples 3a and 3b
[0376] This study evaluated the bioavailability of two different
rasagiline base 1 mg enteric coated tablet formulations prepared
according to each of Examples 3a (Formulation I) and 3b
(Formulation III) verses the marketed rasagiline drug product
(Azilect.RTM. 1 mg) following a single dose administration, and to
assess the effect of food on each one of the test formulations.
[0377] This study also evaluated the safety and tolerability of
each treatment.
1. Study Design
[0378] This study was a flexible two-part protocol, each part
testing the bioavailability of a different rasagiline base 1 mg
enteric coated formulation (Formulation I or Formulation III)
against the reference product (Azilect.RTM. 1 mg).
[0379] Each part was an open-label, three-period, three-sequence,
comparative crossover study in 15 healthy males and females (5 per
sequence).
[0380] Treatment A: One Rasagiline Base 1 mg Enteric Coated Tablets
(test Formulation I or test Formulation III) in the fasted
state.
[0381] Treatment B: One Azilect.RTM. tablet (reference 1 mg
rasagiline as rasagiline mesylate) in the fasted state.
[0382] Treatment C: One Rasagiline Base 1 mg Enteric Coated Tablets
(test Formulation I or test Formulation III) following a
standardized high-fat, high-calorie meal.
[0383] The 3 treatments were administered across 3 study periods
each of which was separated by a 14-day washout interval.
[0384] Subjects were administered according to one of three
sequences to which they were randomly assigned: A-B-C, B-C-A, or
C-A-B.
[0385] In each period, subjects were confined for two overnight
stays [at least 10.5 hours prior to and until at dose
administration]. Subjects returned for an ambulatory blood sample
collection (36 hours) on Day 2.
[0386] In Part 1, Subjects 1-15 received test Formulation I or
reference, while in Part 2, Subjects 16-30 received test
Formulation III or reference. The decision to proceed with each
study part was based on the availability of the test
Formulation.
[0387] AEs, vital signs, physical examination, and clinical
laboratory tests were assessed for safety and blood samples were
taken at regular pre-defined time points throughout the study for
the measurement of rasagiline and aminoindan concentrations in
plasma.
2. Subject Selection
[0388] Thirty (30) healthy adult (.about.50%/50% male and female)
subjects were selected from non-institutionalized subjects
consisting of members of the community at large.
3. Pharmacokinetic (PK) Sampling and Analysis
[0389] A total of 80 samples (about 400 mL) were drawn from each
subject for PK purposes. Pharmacokinetic sampling occurs at the
following timepoints:
a) Treatment A (Test, Fasted):
[0390] Day 1 within 90 minutes prior to dosing (0 hour) and after
dose administration at 0.5, 0.75, 1, 1.33, 1.67, 2, 2.33, 2.67, 3,
3.33, 3.67, 4, 4.5, 5, 6, 7, 8, 9, 12, 24 and 36 hours (22
samples).
b) Treatment B (Reference, Fasted):
[0390] [0391] Day 1 within 90 minutes prior to dosing (0 hour) and
after dose administration at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3,
4, 5, 6, 7, 8, 12, 24 and 36 hours (17 samples).
c) Treatment C (Test, Fed):
[0391] [0392] Day 1 within 90 minutes prior to dosing (0 hour) and
after dose administration at 1, 1.5, 2, 2.5, 3, 3.33, 3.67, 4,
4.33, 4.67, 5, 5.33, 5.67, 6, 6.33, 6.67, 7, 7.33, 7.67, 8, 8.5, 9,
10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26 and
36 hours (41 samples).
[0393] Blood was drawn either by direct venipuncture or through an
indwelling intravenous cannula. Whenever the latter was performed,
the cannula was flushed with 1.5 mL normal saline after each
sampling. In addition, to avoid sample dilution, 1 mL blood was
discarded before the next sample (as long as the cannula was in
place). Therefore, up to 5 mL blood was collected at each time
point. The total blood volume taken per subject for pharmacokinetic
sampling was approximately 400 ml over a 4-week period.
[0394] Samples were collected into appropriate volume K2-EDTA
vacutainers. The labels for all biological sample collection and
storage containers contained, at a minimum, Protocol Number,
Sub-study number, Subject Number; Dosing Period; Dosing Day; PK
time point. Immediately following sample collection, samples were
mixed by inverting the collection tube at least 2-3 times. Samples
were cooled by an ice bath or cooling device until processed. Blood
processing occurred within 2 hours of collection: the sample was
centrifuged at approximately 2000 g and 4.degree. C. (.+-.3.degree.
C.) for about 10 minutes, the plasma transferred into appropriately
labeled duplicate polypropylene tubes, and stored at approximately
-20.degree. C. until transfer or shipment to the bioanalytical
laboratory. At least 0.7 mL of plasma was transferred into the
first polypropylene tube and the remaining plasma was transferred
to the second polypropylene tube. The time at which samples were
placed at -20.degree. C. were recorded in the study
documentation.
[0395] Actual sampling time was recorded directly in the source
data or CRF. Sample processing procedures were documented in the PK
logbook.
[0396] The rasagiline and aminoindan plasma concentrations were
measured using a validated LC/MS/MS bioanalytical method and
according to the Bioanalytical Laboratory's Standard Operating
Procedures and FDA Guidelines.
[0397] Analysis of the PK data of each sub-study was performed
separately, according to audited bioanalytical data availability.
The individual plasma concentrations of rasagiline and aminoindan
were listed, displayed graphically as appropriate and summarized
using descriptive statistics for each of the treatments.
[0398] Pharmacokinetic analysis were performed with rasagiline and
aminoindan concentration profiles using appropriate
non-compartmental methods.
[0399] The following parameters were calculated: C.sub.max,
t.sub.max, t.sub.lag, AUC.sub.t, AUC.sub..infin., t.sub.1/2, CL/F,
V/F, % AUC.sub.ext, regression coefficient of the terminal slope.
Additional PK parameters were calculated if deemed necessary. All
the PK parameters were listed and summarized using descriptive
statistics.
[0400] Statistical analysis was performed using SAS for each
substudy based on the reception of the data. For each sub-study,
bioequivalence between the test and reference formulations in the
fasted state and the food effect on the test formulation were
evaluated only for rasagiline, according to 90% confidence
intervals (CIs) of ratios of geometric means for C.sub.max,
AUC.sub.t, and AUCoo. The ratios and CI were calculated using
ANCOVA on the log-transformed data (MIXED procedure, SAS). The
conclusion regarding bioequivalence were based on the
back-transformed point estimate and CI. T.sub.max were analyzed
using nonparametric analysis (Wilcoxon Signed Rank Test).
4. Results
[0401] Tables 17a-17d below summarize testing results of this
study.
Bioequivalence Tests
[0402] The testing results showed that the delayed release
formulations tested (Formulation I and Formulation III) met the
criteria for bioequivalence to the known immediate release
formulation. Each of the C.sub.max and AUC.sub.t achieved a range
of 80-140% within a 90% confidence interval between the formulation
tested and the reference immediate release formulation.
MAO Assay:
[0403] The testing results showed MAO-B activity for formulation
prepared according to each of the Examples 3a and 3b were
comparable to the reference immediate release formulation.
[0404] The standard method was used for the enzymatic determination
of MAO: "Determination of monoamine oxidase (MAO) by an extraction
method using radiolabelled substrate in various tissues".
[0405] Briefly, fifty (50) .mu.l of homogenate were added to 100
.mu.l 0.1 M phosphate buffer (pH-7.4). After preincubation of 20
minutes at 37.degree. C., 50 .mu.l of .sup.14C-phenylethylamine
hydrochloride (10 .mu.M final concentration) were added and
incubation continued for next 20 minutes. The reaction was then
stopped by addition of citric acid 2 M.
[0406] Radioactive metabolites were extracted into toluene/ethyl
acetate (1:1 v/v.), a solution of 2,5-diphenyloxazole was added to
a final concentration of 0.4% and the metabolite content is
estimated by liquid scintillation counting.
[0407] Activity of rat brain homogenate served as standard
(positive control) to the assay.
[0408] Protein determination was performed by the Lowrey
method.
Safety and Tolerability
[0409] The testing results showed that safety and tolerability for
each treatment were acceptable.
TABLE-US-00052 TABLE 17c PK Parameters in the Fed State: t1/2 tlag
tmax Cmax AUC.sub.inf Study Formulation (h) (h) (h) (ng/mL) (ng
h/mL) Part 1 Formulation I- Mean .+-. 2.25 .+-. 1.15 1.19 .+-. 0.82
2.68 .+-. 0.80 5.078 .+-. 2.160 4.092 .+-. 1.187 Fast SD
Formulation I- Mean .+-. 2.29 .+-. 1.28 11.14 .+-. 5.88 12.31 .+-.
6.53 3.696 .+-. 2.670 3.664 .+-. 1.940 Fed SD Part 2 Formulation
III- Mean .+-. 2.12 .+-. 0.78 1.33 .+-. 0.61 2.33 .+-. 0.80 5.739
.+-. 1.406 5.073 .+-. 1.045 Fast SD Formulation III- Mean .+-. 2.90
.+-. 2.50 5.57 .+-. 1.98 6.12 .+-. 2.11 7.511 .+-. 3.448 4.995 .+-.
1.710 Fed SD
TABLE-US-00053 TABLE 17d Bioequivalence in the Fed State Single
dose fed Point Formulation estimate 90% CI Azilect .RTM. AUC 81
71-85 Cmax 49 29-50 Rasagiline Base AUC 82 68-100 Formulation I EC
Cmax 58 38-87 Rasagiline Base AUC 95 79-113 Formulation III EC Cmax
121 90-164
TABLE-US-00054 TABLE 17a PK Parameters in the Fasted State: t1/2
tmax Cmax AUC.sub.inf Study Formulation (h) (h) (ng/mL) (ng h/mL)
Part 1 AZILECT .RTM. Mean .+-. SD 1.92 .+-. 1.19 0.50 .+-. 0.24
5.790 .+-. 2.731 4.281 .+-. 1.280 Formulation I Mean .+-. SD 2.25
.+-. 1.15 2.68 .+-. 0.80 5.078 .+-. 2.160 4.092 .+-. 1.187 Part 2
AZILECT .RTM. Mean .+-. SD 2.65 .+-. 3.31 0.50 .+-. 0.21 6.22 .+-.
2.585 4.960 .+-. 1.807 Formulation III Mean .+-. SD 2.12 .+-. 0.78
2.33 .+-. 0.80 5.739 .+-. 1.406 5.073 .+-. 1.045
TABLE-US-00055 TABLE 17b Bioequivalence in the Fasted State: Single
dose fasted Point Study Formulation estimate 90% CI Part 1
Formulation I ABC 96 79-117 Cmax 88 58-133 Part 2 Formulation III
AUC 105 106-117 Cmax 99 75-130
Conclusions:
[0410] As shown in Tables 17a-17d, Formulation III meets the
requirements in both fasted and fed states. The PK parameters and
bioequivalence of Formulation III are similar to those of
Azilect.RTM..
Example 18
Preparation of Rasagiline Citrate
[0411] Solid crystalline rasagiline base used in this example was
prepared in a similar process as described below:
A) Preparation of Rasagiline Base Oil
[0412] 100.0 g of Rasagiline Tartrate was suspended in 458 ml
deionized water, 229 ml Toluene was added and 46 ml of 25% NaOH
solution was introduced at stirring. The mixture was heated to
45.degree. C., stirred at 45 C for 15 minutes and settled at this
temperature.
[0413] Two phases were separated. The lower aqueous phase
(pH=13-14) was discarded, the upper toluenic phase was washed with
140 ml deionized water. The resulting emulsion was settled, and two
phases were separated. The lower aqueous phase (pH=9-10) was
discarded. The toluenic solution was evaporated under vacuum in
evaporator.
[0414] After the solvent evaporation completion 60 ml isopropanol
was added to the residue and evaporation was continued. After
completion of the evaporation 50 ml of isopropanol was added and
distilled out under the same conditions. The residue, oil of R-PAI
base, was obtained.
B) Crystallization of Rasagiline Base
[0415] The rasagiline base oil obtained in step A) above was
dissolved in 56 ml isopropanol. The solution was cooled to
16.degree. C. and 147.5 ml of deionized water was added by portions
in 3 hr at cooling and stirring. During the addition of water
precipitation development was observed and the batch was
immediately seeded with crystalline R-PAI base.
[0416] The resulting suspension was cooled to 2.degree. C., stirred
at this temperature overnight and filtered. The solid was washed
with water and dried at room temperature under vacuum. Solid dry
R-PAI base were obtained, with a yield of 96% relative to oil
base.
[0417] This example describes the preparation and characterization
of rasagiline citrate salt. Rasagiline citrate is an attractive
drug substance. Since citric acid is a tribasic compound, there are
three possible forms of rasagiline citrate: mono-, di- and
tri-citrate. Therefore, Rasagiline citrate described herein can be
mono-rasagiline citrate, di-rasagiline citrate, or tri-rasagiline
citrate, or a mixture thereof.
[0418] Because rasagiline is a weak base and pK.sub.a values of
citric acid are 3.13, 4.76 and 6.40, it can be assumed that bonding
of 1.sup.st and 2.sup.nd rasagiline base molecules to citrate is
much more probable than bonding of the 3.sup.rd rasagiline base
molecule.
Starting Materials
[0419] Citric acid--anhydrous acid of USP grade was used for
preparation of citrate salts.
[0420] Rasagiline base--crystalline Rasagiline base prepared as
described above in this example.
Example 18a
Preparation of Rasagiline Citrate in Ethanol-Acetone
[0421] 3.02 g of Citric acid was dissolved in 10 ml absolute
ethanol at room temperature. 5.38 g rasagiline base was dissolved
in 15 ml absolute ethanol. Solution of rasagiline base was
introduced by portions into the solution of citric acid under
stirring. Significant exothermal effect was recorded during the
addition, during which the solution temperature rose from
17.degree. to 24.degree. C. during 10 minutes of addition. The
resulting clear solution was stored in freezer at -18.degree. C.
and no precipitation was observed.
[0422] Additional 2.71 g of solid Rasagiline base was added to the
above resulting clear solution. After prolonged stirring at
20-23.degree. C. the solid was dissolved and a viscous clear
solution was obtained. The resulting viscous clear solution was
stored overnight in freezer at -18.degree. C. No solid
precipitation from the solution was observed during 20 hrs in the
freezer.
[0423] The solution was evaporated under vacuum on rotary
evaporator, the resulted residue (11.2 g) of honey-like semi-solid
material was held over weekend in freezer (-18.degree. C.). No
crystallization of solid was observed.
[0424] The semi-solid material was mixed with 40 ml acetone at
stirring, no dissolution of the semi-solid material was observed
during prolonged stirring.
[0425] Absolute ethanol (3 ml) was then added to the mixture by
portions at stirring. Complete dissolution of the semi-solid
material was observed, the resulting clear solution was held
overnight in freezer.
[0426] Honey-like semi-solid material precipitated from the
acetone-ethanol solution was found on the bottom of the flask. The
solution was decanted and the precipitate was dried under vacuum
(20 mbar) for 4 hours. During the drying a stabile foam formed. The
flask with the foam was connected to high vacuum pump and dried at
2-3 mbar overnight.
[0427] The foam solidified under high vacuum. The vacuum was
disconnected and the material was broken up with spatula. 6.1 g of
white powder was obtained.
Analysis:
[0428] Assay of Rasagiline base by HPLC--60.8%
Crystallinity by XRD--Amorphous
Thermal Analysis:
[0429] DSC--Peak at 179.7.degree. C. (128 exo), TGA--LOD=1.2%
(25-100.degree. C.), cont. weight loss at T>100.degree. C.
Example 18b
Mono-Citrate Salt in Water-Acetone (Molar Ratio 1:1)
[0430] 3.02 g of Citric acid was dissolved in 4 ml deionized water.
2.69 g of Rasagiline base was added to the solution. Exothermic
effect was observed (temperature rose from 22 to 25.degree. C.),
and most of the solid was dissolved. Then the mixture was heated to
42.degree. and complete dissolution of the solid was observed. The
resulting clear viscous syrup-like solution was held in
refrigerator at +5.degree. C. overnight. No precipitation was
observed during 15 hrs.
[0431] The solution was mixed with 15 ml acetone and evaporated on
rotary evaporator under vacuum. The residue of honey-like
semi-solid material (6.29 g) was dried under vacuum (20 mbar) at
ambient temperature. A foam formed (6.11 g) during the drying and
then further dried under high vacuum (2-3 mbar).
[0432] The foam was solidified under high vacuum. The vacuum was
disconnected and the material was broken up with spatula. 5.58 g of
white powder was obtained.
Analysis:
[0433] Assay of Rasagiline base by HPLC--44.5%
Crystallinity by XRD--Amorphous
Thermal Analysis:
[0434] DSC--Peak at 188.6.degree. C. (61 exo), TGA--LOD=1.5%
(25-100.degree. C.), cont. weight loss at T>100.degree. C.
Example 18c
Di-Citrate Salt in Water-Acetone (Molar Ratio 2:1)
[0435] 3.45 g of Citric acid was dissolved in 5 ml deionized water
and pre-heated to 30.degree. C. 6.13 g of Rasagiline base was added
to the solution. Exothermic effect was observed (temperature rose
from 30 to 36.degree. C.), and the solid was dissolved. The
resulted clear viscous syrup-like solution was held in refrigerator
at +5.degree. C. overnight. No precipitation was observed during 15
hrs.
[0436] The solution was mixed with 18 ml acetone and evaporated on
rotary evaporator under vacuum. The residue of honey-like
semi-solid material (9.7 g) was dried under vacuum (20 mbar) at
ambient temperature. A foam formed during the drying and then
further dried under high vacuum (2-3 mbar).
[0437] The foam was solidified under high vacuum. The vacuum was
disconnected and the material was broken up with spatula. 8.81 g of
white powder was obtained.
Analysis:
[0438] Assay of Rasagiline base by HPLC--60.9%
Crystallinity by XRD--Amorphous
Thermal Analysis:
[0439] DSC--Peak at 180.2.degree. C. (141 exo), TGA--LOD=1.2%
(25-100.degree. C.), cont. weight loss at T>100.degree. C.
Example 18d
Tri-Citrate Salt in Water-Acetone (Molar Ratio 3:1)
[0440] 3.46 g of Citric acid was dissolved in 5 ml deionized water.
9.19 g of Rasagiline base was added to the solution. Exothermic
effect was observed (temperature rose from 22 to 27.degree. C.),
and most of the solid was dissolved. Then the mixture was heated to
46.degree. C. 0.5 ml water was added and complete dissolution of
the solid was observed. The resulting clear viscous syrup-like
solution was held in refrigerator at +5.degree. C. overnight. No
precipitation was observed during 15 hrs.
[0441] The solution was mixed with 18 ml acetone and evaporated on
rotary evaporator under vacuum. The residue of honey-like
semi-solid material (13.20 g) was dried under vacuum (20 mbar) at
ambient temperature. A foam formed during the drying (13.19 g) and
then further dried under high vacuum (2-3 mbar).
[0442] The foam was solidified under high vacuum. The vacuum was
disconnected and the material was broken up with spatula. 12.80 g
of white powder was obtained.
Analysis:
[0443] Assay of Rasagiline base by HPLC--70.6%
Crystallinity by XRD--Amorphous
Thermal Analysis:
[0444] DSC--Peak at 181.8.degree. C. (136 exo), TGA--LOD=1.3%
(25-100.degree. C.), weight loss at T>100.degree. C.
Discussion of Example 18
[0445] Experimental observations show exothermic reactions between
Rasagiline base and Citric acid in aqueous solutions. The fact that
Rasagiline base with aqueous solubility of about 2 mg/ml dissolves
in aqueous reaction solution at more than 10 wt % demonstrates
complete or near-complete conversion of the base into salt.
[0446] At the same time a fraction of the base could be extracted
from the salt solution with non-polar organic solvent as
toluene.
[0447] The preparation of mono-, di- and tri-citrate salts of
rasagiline can be calculated from molecular weights of Rasagiline
(R-PAI), Citric acid and water. The calculation results are
presented in Table 18 below. The data presented in Table 18 also
demonstrate that R-PAI content in the citrates prepared in the
examples 18a-18d conforms to the composition of hydrate salts.
TABLE-US-00056 TABLE 18 Rasagiline Citrates calculated composition
R-PAI Water content content Salt Composition MW % wt. % wt.
Mono-Citrate (R-PAIH.sup.+)CitH.sub.2.sup.- 363.3 47.1 0 Di-Citrate
(R-PAIH.sup.+).sub.2CitH.sup.-2 534.5 64.0 0 Tri-Citrate
(R-PAIH.sup.+).sub.3Cit.sup.-3 705.7 72.8 0 Mono-Citrate
(R-PAIH.sup.+)CitH.sub.2.sup.-.cndot.H.sub.2O 381.3 44.9 4.7
monohydrate Di-Citrate
(R-PAIH.sup.+).sub.2CitH.sup.-2.cndot.H.sub.2O 552.5 61.9 3.2
monohydrate Tri-Citrate
(R-PAIH.sup.+).sub.3Cit.sup.-3.cndot.H.sub.2O 723.7 70.9 2.5
monohydrate Di-Citrate
(R-PAIH.sup.+).sub.2CitH.sup.-2.cndot.2H.sub.2O 570.5 60.0 3.1
dihydrate R-PAIH.sup.+ - Rasagiline base (R-PAI) cation Cit.sup.-n
- Citrate anion
[0448] Rasagiline citrate salts prepared in Examples 18a-18d
demonstrate extremely high aqueous solubility. Solutions of mono-
di- and tricitrate salts prepared in the Examples 18b, 18c and 18d
had concentrations of dissolved solid of 59, 66 and 70 wt %,
respectively. These solutions did not show saturation and were
found stable at low temperatures. No precipitation was observed
during 15 hrs at +5.degree. C. This data shows extremely high
solubility of the citrate salts of rasagiline in water. Solutions
with more than 70% wt of rasagiline citrate could be prepared.
Rasagiline citrate salts having 3-10 wt % water content appear as
syrups or honey-like semi-solid.
[0449] The most soluble rasagiline salt described previously is
monobasic maleate salt of rasagiline, which has a solubility not
less than 1000 mg/ml water, as described in U.S. Pat. No.
6,630,514. But the phenomenon of extremely high solubility
exhibited by rasagiline citrate was not observed in any previously
identified salt of rasagiline.
[0450] Such extremely high solubility is a property of practical
value, and allows for preparation of highly concentrated liquid and
semi-solid formulations. Aqueous or alcoholic solution of
Rasagiline Citrate containing 60-80% of active pharmaceutical
ingredient (API) could be used in the production of transdermal
patches, sublingual strips, and other formulations benefiting from
such highly concentrated liquid or semi-solid. Such highly
concentrated solutions are also useful for optimizing the
efficiency of production processes, e.g. for tablets.
Example 19
Additional Preparation of Rasagiline Citrate
[0451] Solid crystalline rasagiline base used in this example was
prepared in a similar process as described below:
A) Preparation of Rasagiline Base Oil
[0452] 100.0 g of Rasagiline Tartrate was suspended in 458 ml
deionized water, 229 ml Toluene was added and 46 ml of 25% NaOH
solution was introduced at stirring. The mixture was heated to
45.degree. C., stirred at 45 C for 15 minutes and settled at this
temperature.
[0453] Two phases were separated. The lower aqueous phase
(pH=13-14) was discarded, the upper toluenic phase was washed with
140 ml deionized water. The resulting emulsion was settled, and two
phases were separated. The lower aqueous phase (pH=9-10) was
discarded. The toluenic solution was evaporated under vacuum in
evaporator.
[0454] After the solvent evaporation completion 60 ml isopropanol
was added to the residue and evaporation was continued. After
completion of the evaporation 50 ml of isopropanol was added and
distilled out under the same conditions. The residue, oil of R-PAI
base, was obtained.
B) Crystallization of Rasagiline Base
[0455] The rasagiline base oil obtained in step A) above was
dissolved in 56 ml isopropanol. The solution was cooled to
16.degree. C. and 147.5 ml of deionized water was added by portions
in 3 hr at cooling and stirring. During the addition of water
precipitation development was observed and the batch was
immediately seeded with crystalline R-PAI base.
[0456] The resulting suspension was cooled to 2.degree. C., stirred
at this temperature overnight and filtered. The solid was washed
with water and dried at room temperature under vacuum. Solid dry
R-PAI base were obtained, with a yield of 96% relative to oil
base.
[0457] This example describes the additional preparations and
characterization of rasagiline citrate salt.
Starting Materials
[0458] Citric acid--anhydrous acid of USP grade was used for
preparation of Citrate salts.
[0459] Rasagiline base--pure crystalline Rasagiline base (DS)
prepared as described in example 18 was used in this study.
Example 19.1
[0460] 3.84 g of citric acid was dissolved in 25 ml water and 3.42
g of rasagiline base was added to the solution, which was stirred
at room temperature and monitored by TLC. After 30 minutes no
traces of R-PAI was observed on TLC. The reaction mixture was
extracted with 2.times.30 ml toluene after one hour. The combined
toluenic extract was evaporated to dryness. Yield: 0.06 g (1.75%)
(R-PAI).
[0461] The aqueous phase was evaporated in vacuum to dryness.
Hony-like semi-solid product was obtained. Yield: 7.53 g
(103.7%).
Example 19.2
[0462] 1.92 g of citric acid was dissolved in 10 ml water and 1.71
g of rasagiline base added to the solution. The mixture was stirred
for 18 hours and then the solvent was removed by lyophilization
(1-0.3 mbar; -20-+20.degree. C.; 46 hours). Yield: 3.69 g
(101.65%).
[0463] The product was solid foam but after several hours became a
semi-solid honey-like material. According to NMR data the salt
formed with 0.73 equivalent of acid.
Example 19.3
[0464] 1.92 g of citric acid was dissolved in 15 ml water and 3.42
g of rasagiline base was added to the solution. The reaction
mixture was stirred at room temperature for 22 hours. The water was
removed by lyophilization (1-0.3 mbar, -20-+20.degree. C.; 46
hours).
[0465] Crystalline-like foam were obtained, which then became
semi-solid honey-like material in a few hours. According to the
data of NMR the salt formed with 0.48 equivalent of acid.
Example 19.4
[0466] 3.84 g of citric acid was dissolved in 30 ml water and 6.84
g of rasagiline base was added to the solution, which was stirred
for 2 hours and then the reaction mixture was extracted with
2.times.40 ml toluene. The combined toluenic extract was evaporated
to dryness. 20 ml IPA was added to the residue and the solvent was
evaporated in vacuum to dryness. Yield: 1.5 g (22%, R-PAI).
[0467] The aqueous phase was evaporated to dryness, resulting
honey-like semi-solid product. Yield: 9.47 g (103.3%).
[0468] .sup.1H-NMR--0.65 equivalent of acid formed the salt.
Example 19.5
[0469] 3.84 g of citric acid was dissolved in 50 ml water and 10.26
g of rasagiline base was added to the solution, which was stirred
at room temperature for 3 hours.
[0470] The reaction mixture was extracted with 2.times.50 ml
toluene. The combined toluenic extract was evaporated to dryness in
vacuum. IPA was added to the residue and then evaporated to
dryness. Yield: 3.92-4.13 g (R-PAI) (38.2-40.2%).
[0471] The aqueous phase was evaporated to dryness, resulting
honey-like semi-solid product. Yield: 10.54-9.73 g.
[0472] .sup.1H-NMR--0.58 equivalent of acid formed the salt.
Example 19.6
[0473] 3.84 g of citric acid was dissolved in 50 ml water and 10.26
g of rasagiline base was added to the solution, which was stirred
for 3 hours at 60.degree. C.
[0474] The reaction mixture was extracted with 2.times.50 ml
toluene. The combined toluenic extract was evaporated to dryness in
vacuum. IPA was added to the residue and then evaporated to
dryness. Yield: 3.92-4.13 g (R-PAI) (38.2-40.2%).
[0475] The aqueous phase was evaporated to dryness, resulting
honey-like semi-solid product. Yield: 10.54-9.73 g.
[0476] .sup.1H-NMR--0.58 equivalent of acid formed the salt.
Example 19.7
[0477] 3.84 g of citric acid was dissolved in 50 ml water and 10.26
g of rasagiline base was added to the solution, which was stirred
for 42 hours at 25.degree. C.
[0478] The reaction mixture was extracted with 2.times.50 ml
toluene. The combined toluenic extract was evaporated to dryness in
vacuum. IPA was added to the residue and then evaporated to
dryness. Yield: 3.92-4.13 g (R-PAI) (38.2-40.2%).
[0479] The aqueous phase was evaporated to dryness, resulting
honey-like semi-solid product. Yield: 10.54-9.73 g.
[0480] .sup.1H-NMR--0.58 equivalent of acid formed the salt.
Example 19.8
[0481] 1.92 g of citric acid was dissolved in 25 ml water and 5.13
g of rasagiline base was added to the solution, which was stirred
at room temperature for 16 hours. The reaction mixture was
extracted with 2.times.30 ml toluene and the toluenic extract was
evaporated to dryness. Yield: 2.19 g (R-PAI; 42.7%).
[0482] The aqueous phase was dried by lyophilization. The product
was crystalline-like foam which then became honey-like
semi-solid.
[0483] .sup.1H-NMR--0.55 equivalent of acid formed the salt.
Example 19.9
[0484] 1.92 g of citric acid was dissolved in 25 ml water and 5.13
g of rasagiline base was added to the solution, which was stirred
at room temperature for 9 days. The solid was filtered off, washed
with 5 ml water, and dried with air. Yield: 0.31 g (6%, R-PAI),
Mp.: 39.3-41.0.degree. C.
[0485] The aqueous phase was lyophilized. The crystalline-like foam
was formed which became honey-like semi-solid in a few hours.
[0486] .sup.1H-NMR--0.35 equivalent of acid formed the salt.
Example 19.10
[0487] 1.6 g of citric acid was dissolved in 10 ml water and 1.0 g
of rasagiline base was added to the solution, which was stirred at
room temperature. The solvent was removed by lyophilization. The
product was crystalline-like foam which became semi-solid after a
few hours.
[0488] .sup.1H-NMR--1.2 equivalent of acid formed the salt.
Example 19.11
[0489] 1.92 g of citric acid was dissolved in 15 ml IPA and 1.71 g
of rasagiline base was added to the solution, which was stirred at
room temperature for 2 hrs. No R-PAI was detected by TLC. The
solvent was removed in vacuum. Yield: 3.85 (106%)
[0490] The foam-like semi-solid product became honey-like upon
contacting with the humidity in the air.
Example 19.12
[0491] 1.92 g of citric acid was dissolved in 15 ml IPA and 3.42 g
of rasagiline base was added to the solution, which was stirred at
room temperature for 2 hours. The reaction mixture became clear,
which was monitored by TLC (hexane:EtOAc=1:1). The traces of R-PAI
was detected. The solvent was removed in vacuum. The residue was
slurred in 2.times.30 ml toluene. The combined toluenic phase was
evaporated to dryness. Yield: 0.65 g (19%; R-PAI).
[0492] The crude product was dissolved in IPA and the solution was
evaporated to dryness, resulting honey-like product.
Example 19.13
[0493] 1.92 g of citric acid was dissolved in 15 ml IPA and 5.13 g
of rasagiline base was added to the solution, which was stirred at
room temperature for 2 hours. The reaction was monitored by TLC.
Free R-PAI was present. The solvent was removed in vacuum. The
residue was slurred in 2.times.30 ml toluene. The combined toluenic
phase was evaporated to dryness. Yield: 2.47 g (48%; R-PAI).
[0494] The crude product was dissolved in IPA and the solution was
evaporated to dryness. A honey-like product was obtained.
Example 19.14
[0495] 1.92 g of citric acid was dissolved in 15 ml methanol and
1.71 g of rasagiline base was added to the solution, which was
stirred at room temperature for 22 hours and was then evaporated to
dryness. Yield: 3.77 g (103.86%).
[0496] .sup.1H-NMR--0.72 equivalent of acid formed the salt.
Example 19.15
[0497] 1.92 g of citric acid was dissolved in 20 ml methanol and
3.42 g of rasagiline base was added to the solution, which was
stirred at room temperature for 22 hours and was then evaporated to
dryness. Yield: 5.48 g-103.6%. By TLC, the free R-PAI in product
was detected.
[0498] .sup.1H-NMR--0.5 equivalent of acid formed the salt.
Example 19.16
[0499] 1.92 g of citric acid was dissolved in 25 ml methanol and
5.13 g of rasagiline base was added to the solution, which was
stirred at room temperature for 22 hours and was then evaporated to
dryness. Yield: 7.32 g-103.8%. By TLC, the free R-PAI in product
was detected.
[0500] .sup.1H-NMR--0.33 equivalent of acid formed the salt.
Example 19.17
[0501] 1.92 g of citric acid was stirred in 20 ml EtOAc and 1.71 g
of rasagiline base was added to the solution, which was stirred for
additional 72 hours. The reaction was monitored by TLC. The free
rasagiline base was detected.
[0502] The solution, was decantated from the reaction mixture. The
solvent was removed under vacuum. Yield: 1.32 g (77%) R-PAI.
[0503] The isolated R-PAI was re-dissolved in 20 ml ethylacetate
and 10 ml water was added to the mixture. The reaction mixture was
stirred for 22 hours. The unreacted R-PAI remained in the EtOAc
phase according to the data of TLC. The phases were separated. The
organic phase was evaporated to dryness. Yield: 0.13 g (7.6%)
R-PAI.
Example 19.18
[0504] 1.92 g of citric acid was stirred in 20 ml EtOAc and 3.42 g
of rasagiline base was added. The solution was stirred for
additional 72 hours. The reaction was monitored by TLC. The free
rasagiline base was detected.
[0505] The solution was decantated from the reaction mixture. The
solvent was removed under vacuum. Yield: 2.87 g (83.9%, R-PAI).
[0506] The isolated R-PAI was re-dissolved in 20 ml ethylacetate
and 10 ml water was added to the mixture. The reaction mixture was
stirred for 22 hours. The unreacted R-PAI remained in the EtOAc
phase according to the data of TLC. The phases were separated. The
organic phase was evaporated to dryness. Yield: 0.62 g
(18%-R-PAI).
Example 19.19
[0507] 1.92 g of citric acid was stirred in 25 ml EtOAc and 5.13 g
of rasagiline base was added. The reaction mixture was stirred for
additional 72 hours. The reaction was monitored by TLC. The free
rasagiline base was detected in all cases.
[0508] The solution was decantated from the reaction mixture. The
solvent was removed in vacuum. Yield: 4.49 g (87.5%, R-PAI).
[0509] The isolated R-PAI was re-dissolved in 20 ml ethylacetate
and 10 ml water was added to the mixture. The reaction mixture was
stirred for 22 hours. The unreacted R-PAI remained in the EtOAc
phase according to the data of TLC. The phases were separated. The
organic phase was evaporated to dryness. Yield: 1.76 g (34.3%
R-PAI).
Example 19.20
[0510] 1.92 g of citric acid was stirred in 25 ml toluene and 1.71
g rasagiline base was added to the mixture. The heterogenous
mixture was stirred at room temperature for 24 hours. The solution
was decantated from the reaction mixture. The toluenic phase was
evaporated to dryness. Yield: 1.58 g (92.4%); (R-PAI by TLC).
[0511] The isolated R-PAI was re-dissolved in 10 ml of toluene and
was returned to the solid phase. 20 ml water was added to the
heterogenous mixture and stirred for 3 hours. The reaction was
monitored by TLC. The phases were separated. The toluenic phase was
evaporated to dryness. Yield: 0.12 g (7%), R-PAI was detected
according to the data of TLC. The aqueous phase was evaporated to
dryness.
Example 19.21
[0512] 1.92 g of citric acid was dissolved in 20 ml acetone and
1.71 g of rasagiline base was added to the reaction mixture, which
was stirred at room temperature for 2 hours. The reaction was
monitored by TLC. No R-PAI was detected.
[0513] The solution was decantated from the honey-like
precipitation. Yield: 2.43 g (66.9%).
[0514] The acetonic solution was evaporated to dryness. Honey-like
product was obtained. Yield: 1.48 (40.7%).
[0515] The total yield was 107.6% (acetone remained in the
product).
Example 19.22
[0516] 1.92 g of citric acid was dissolved in 20 ml acetone and
3.42 g of rasagiline base was added to the mixture, which was
stirred at room temperature for 22 hours. R-PAI was detected by
TLC. The acetonic solution was decantated from the honey-like
precipitation. Yield: 4.41 g (82.6%) semi-solid product.
[0517] The acetonic phase evaporated to dryness. Yields: 1.34 g
(25.1%)
TABLE-US-00057 TABLE 19a Summary of Experimental Results
Proportions of Equivalent of reagents (mole) Extracted Citric acid
pH (after Citric Rasagiline R-PAI (%) in the salt R-PAI extraction
Example Solvent acid, mole base, mole (*Filtered) by NMR By TLC of
R-PAI) 19.11 IPA 1 1 - 19.1 Water 1 1 Extr. with Toluene - 0.06
g-1.75% 19.4 Water 1 2 1.51 g (22%) + 19.5 Water 1 3 4.13 g (40.2%)
+ 19.6 Water 1 3 4.44 g (43.3%) + 60.degree. C. 19.7 Water 2 1 3
3.92 g (38.2%) + days 19.9 Water 1 3 0.31 g (6%) 0.35 + 19.3 Water
1 2 0.48 + 19.13 IPA 1 3 2.47 g (48%) 1.55 + 19.12 IPA 1 2 0.65 g
(19%) 1.62 + 19.10 Water 1 0.7 lyophilized 1.2 - 19.8 Water 1 3
Extr. 2.19 g + (42.7%) 19.2 Water 1 1 lyophilized 0.73 - 19.14 MeOH
1 1 0.72 - 3.53 (3.49) 19.15 MEOH 1 2 0.5 + 4.88 (4.46) 19.16 MeOH
1 3 0.33 + 6.09 (4.66) 19.20 Toluene 1 1 + 19.17 EtOAc 1 1 7.6 +
(3.41) 22.18 EtOAc 1 2 18 + (4.43) 19.19 EtOAc 1 3 34.3 + (4.90)
19.21 Acetone 1 1 - 19.22 Acetone 1 2 +
Discussion of Example 19
[0518] Rasagiline base readily forms salts with citric acid in
almost all various types of solvents, but most readily in water and
in alcohols.
[0519] Mono-rasagiline citrate salt forms and is stable in most
solvents. A few percent of free rasagiline may be extracted from
the aqueous solution of this salt.
[0520] Di- and tri-citrates are not as stable in the aqueous and
other solutions (alcohol, MEK, acetone). Free rasagiline base may
be detected by TLC and extracted with toluene.
[0521] The separation of free rasagiline base from the aqueous
solution of di- and tri-rasagiline citrates resulted the change of
pH of the solution, as shown in Table 19a.
[0522] All of the rasagiline citrate salts are hygroscopic salts
and readily absorb the humidity from air. The rasagiline citrates
more readily form strong solvates with the solvents in which the
salt formation occurred (up to 10%).
[0523] The aqueous solution of rasagiline citrates may be dried by
lyophilization.
[0524] The NMR study of rasagiline citrate in the above examples
provides information about the composition (proportion) of the
samples and not the proportion of the free base and the charged
base (cationic form) with citric acid.
[0525] The results of this example also demonstrate that the ratio
of rasagiline base:citric acid used correlates with content of the
"extractable" rasagiline base and amount of unreacted Citric acid
found in the salt by NMR. The results are summarized in the Table
19b below.
TABLE-US-00058 TABLE 19b Effect of salt composition on content of
extractable rasagiline base Content of extractable Ratio Equivalent
of Citric base Base to acid by .sup.1HNMR for (toluene) acid salt
prepared in: % on total Salt mole:mole Methanol water base content
Mono 0.7:1.0 N.A. N.A. N.A. citrate Mono 1.0:1.0 0.72 0.73 1.75-3.6
citrate Di 2.0:1.0 0.50 0.48 22.0 citrate Tri 3.0:1.0 0.33 0.35
42.7 citrate
[0526] The data in Table 19b show that excess of citric acid
dramatically reduce the content of extractable rasagiline base.
[0527] It is concluded that lower content of extractable rasagiline
base (or higher content of citric acid) provides higher stability
of Rasagiline in the salt. Therefore, the most stable rasagiline
citrate salt is mono-citrate salt and the most stable compositions
of rasagiline citrate are compositions containing less than 1 mole
of Rasagiline base per 1 mole of Citric acid.
Example 20
Evaluation of Rasagiline Citrate Salts
[0528] Three samples of rasagiline citrates prepared in examples
18b, 18c and 18d were exposed to atmospheric air in open dishes at
ambient temperature. The changes were observed and recorded. The
results are presented in the Table 20a below:
TABLE-US-00059 TABLE 20a Changes in Citrate salts exposed to
atmosphere at ambient temperature Example 4b Example 4c Example 4d
Salt type Mono- Di- Tri- Time of exposure (hrs:min) 0:00 Powder
Powder Powder 0:30 Powder Powder 0:50-1:00 Sticky Powder Sticky
aggregates aggregates 1:50-2:00 Semi-solid Powder Sticky aggregates
5:00 Honey-like Lump powder Semi-solid semi-solid 6:00 Syrup Sticky
Semi-solid aggregates 7:00 Syrup Sticky Honey-like aggregates
semi-solid 25:00 N.A. Sticky N.A. aggregates + semi-solid
Discussion
[0529] The results in Table 20a show that all three salts disclosed
above are highly hygroscopic when exposed to atmosphere at ambient
temperature. The results also show that there is no significant
difference in hygroscopicity between the mono-, di- and
tri-rasagiline citrates. All three salts appear as hydrates.
[0530] Parkinsonian patients suffer from swallowing disorders which
prevent them from swallowing standard tablets or capsules.
(Potulska A., "Swallowing disorders in Parkinson's disease",
Parkinsonism Relat. Disord. (2003 August) Vol. 9(6), pages 349-53).
This difficulty hinders their treatment by reducing patient
compliance. Patients will be more likely to comply to dosage
regimens if swallowing tablets or capsules is not required.
[0531] A means to avoid the absorption of rasagiline in the
stomach, and to eliminate the need for swallowing tablets, is by
absorption of rasagiline into the body before reaching the stomach.
Such absorption of rasagiline, and hence resolution of both
problems, can be accomplished by contact with the buccal,
sublingual, pharyngeal and/or esophageal mucous membranes. To
accomplish this, oral compositions can be designed to rapidly
disperse within the mouth to allow maximum contact of rasagiline
with the buccal, sublingual, pharyngeal and/or esophageal mucous
membranes. The unexpectedly high hygroscopicity of the citrate
salts of rasagiline is particularly suitable for such oral
formulations.
[0532] Another three samples of rasagiline citrates prepared in
Examples 18b, 18c and 18d were stored in closed transparent glass
vials sealed with paraffin film in refrigerator at 7.+-.2.degree.
C. The changes were observed and recorded. The results are
presented in the Table 20b below:
TABLE-US-00060 TABLE 20b Appearance of Citrate salts stored in
refrigerator Example 4b Example 4c Example 4d Salt type Monobasic
Dibasic Tribasic Time of Storage, Appearance: month(s) 0 White
powder White powder White powder 3 White powder White powder White
powder 6 White powder White powder White powder
Discussion
[0533] The results in Table 20b show that all three salts could be
stored for a long time (more than 6 month) under sealed condition
at low temperature (.about.7.degree. C.) with no change of color
and appearance in spite of their high hygroscopicity at ambient
temperature. This finding was surprising and may be the result of
effect of temperature on hygroscopic point of Rasagiline
citrates.
[0534] The results in Table 20b also show that all three salts
could be handled and processed under controlled conditions such as
low temperature and low humidity without change of their physical
appearances, despite their high hygroscopicity.
Example 21
Characterization of Rasagiline Citrate--XRD Analysis
[0535] Samples were tested using Scintag X-Ray powder
diffractometer model X'TRA, Cu-tube, solid-state detector.
Scanning Parameters
[0536] Range: 2-40 degrees two-theta. Scan mode: Continuous scan
Step size: 0.05 deg.
Rate: 3 deg./min.
[0537] Sample Holder: a Round Standard Aluminum Sample Holder with
Round Zero Background Quartz Plate with Cavity of 25 (Diameter)*0.5
(Dept.) mm.
TABLE-US-00061 TABLE 21 CHARACTERISTIC XRD PEAK POSITIONS OF THE
DIFFERENT SAMPLES Amorphous Amorphous Amorphous Amorphous Form form
form form form Sample 1 2 3 4 Peak Not Not Not Not positions
applicable applicable applicable applicable (.+-.0.2 DEGREES
TWO-THETA)
Discussions
[0538] Results in Table 21 show that samples of rasagiline citrate
do not show any characteristic peaks in XRD analysis, which
indicates that rasagiline citrates prepared are of the form of
amorphous.
Example 23
Comparison of Properties of Rasagiline Citrate to Other Salts
[0539] Rasagiline citrate exhibits properties which are different
from the properties of other citrate salts as shown in Table 22a,
and also different from the properties of other rasagiline salts as
shown in Table 22c.
TABLE-US-00062 TABLE 22a Summary of Citrate of various drug
substances Citrate Salt of Drug Substance Polynorpb References
5,8,14-Triazatetracyclo- Crystalline WO 02/092597
hexdecqa-2(11),3,5,7,9- pentaene 2-hydroxy-3-[5-(morpholin-4-
Crystalline WO 07/089191 ylmethol)pyridine-2-yl]1H-
indole-5-carbonitrile 2-(6-{2-[(2(2R)-2-Methyl-1- Crystalline US
2005/0256127 pyrrolidin-1-yl]-ethyl}-2-
naphthalen-2-yl)-2H-pyridazin- 3-one 4-(3,4-dichlorophenyl)-2-(2-
Crystalline US 2003/0181444 94-Methlpiperazin-1-yl)-
Bennylidene]-thiomorpholin-3- one 4-[(4-Methyl-1- Crystalline US
2008/0249104 piperazinyl)methyl]-N-[4-
methyl-3-[[(4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]- benzamide
5-(5-Fluoro-2-oxo-1,2-dihydro- Crystalline US 2008/0275101
indol-3-ylidenemethyl)-2,4- dimethyl-1H-pyrrole-3- carboxylic acid
(2-pyrrolidin- 1-yl-ethyl)-amide 3-{(3R,4R)-4-methyl-3-[methyl-
Crystalline US 2005/0159434 (7H-pyrrole]2,3-d]pyrimidin-4-
yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile Decitabine
Crystalline US 2006/0069060
[0540] As shown in Table 22a, unlike citrate salts of other drug
substance, the rasagiline citrate salts are amorphous. No
crystalline forms of rasagiline citrate have been detected.
TABLE-US-00063 TABLE 22b Summary of Properties of Rasagiline Base
and Citric Acid Water Hygroscopicity solubility by KF (mg/ml)
References Solid R-PAI Not hygroscopic low US 2008/0161408 (Free
Base) Citric Acid low 1330 "Pharmaceutical Excipients" database
TABLE-US-00064 TABLE 22c Summary of Properties of Rasagiline Salts
Water R-PAI base/ Hygroscopicity solubility R-PAI salts by KF
(mg/ml) References Chloride Not hygroscopic 238 U.S. Pat. No.
5,457,133 Mesylate Not hygroscopic 635 U.S. Pat. No. 5,532,415
Tartrate Not hygroscopic 33 U.S. Pat. No. 5,532,415 Maleate N.A.
>=1000 U.S. Pat. No. 5,532,415 Sulphate N.A. 485 U.S. Pat. No.
5,532,415 Tosylate N.A. 60-70 U.S. Pat. No. 5,532,415 Fumarate N.A.
95 U.S. Pat. No. 5,532,415 Phosphate N.A. >=720 U.S. Pat. No.
5,532,415 Esylate N.A. >=300 U.S. Pat. No. 5,532,415 Acetate
N.A. >=720 U.S. Pat. No. 5,532,415 Tannate <10% (R-PAI low
U.S. Pat. No. 7,547,806 content related) Citrate Highly Extremely
hygroscopic High (Higher than rasagiline maleate) Edisilate Not
hygroscopic 342.5 WO 2008/019871 Oxalate Not hygroscopic 19.7 WO
2008/019871
[0541] The results in Table 22b and 22c show that compared to
rasagiline base and other rasagiline salts, rasagiline citrate salt
exhibits the highest water solubility and highest
hygroscopicity.
* * * * *