U.S. patent application number 12/456029 was filed with the patent office on 2010-07-29 for delayed release rasagiline formulation.
This patent application is currently assigned to Teva Pharmaceutical Industries, Ltd.. Invention is credited to Rachel Cohen, Anton Frenkel, Daniella Licht, Muhammad Safadi, Marina Zholkovsky.
Application Number | 20100189790 12/456029 |
Document ID | / |
Family ID | 42354337 |
Filed Date | 2010-07-29 |
United States Patent
Application |
20100189790 |
Kind Code |
A1 |
Safadi; Muhammad ; et
al. |
July 29, 2010 |
Delayed release rasagiline formulation
Abstract
Disclosed are formulations which are designed to delay release
of rasagiline while maintaining specific pharmacokinetic
properties.
Inventors: |
Safadi; Muhammad; (Nazareth,
IL) ; Licht; Daniella; (Givat Shmuel, IL) ;
Cohen; Rachel; (Hadera, IL) ; Frenkel; Anton;
(Netanya, IL) ; Zholkovsky; Marina; (Bat-Yam,
IL) |
Correspondence
Address: |
COOPER & DUNHAM, LLP
30 Rockefeller Plaza, 20th Floor
NEW YORK
NY
10112
US
|
Assignee: |
Teva Pharmaceutical Industries,
Ltd.
|
Family ID: |
42354337 |
Appl. No.: |
12/456029 |
Filed: |
June 9, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61205833 |
Jan 23, 2009 |
|
|
|
Current U.S.
Class: |
424/475 |
Current CPC
Class: |
A61K 9/2059 20130101;
A61P 25/24 20180101; A61P 9/10 20180101; A61K 9/2054 20130101; C07C
2602/08 20170501; A61P 25/18 20180101; A61K 9/2886 20130101; A61K
9/2846 20130101; C07C 211/42 20130101; A61P 25/28 20180101; A61P
25/00 20180101; C07C 59/265 20130101; A61K 9/2013 20130101; A61K
31/135 20130101; A61K 9/2018 20130101; A61P 25/16 20180101; A61K
9/2893 20130101 |
Class at
Publication: |
424/475 |
International
Class: |
A61K 9/30 20060101
A61K009/30; A61P 25/16 20060101 A61P025/16 |
Claims
1. 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 a) preparing the core by admixing rasagiline base,
citric acid and/or malic acid, and a pharmaceutically acceptable
excipient; and b) coating the core with the acid resistant
pharmaceutically acceptable coating.
2. The dosage form of claim 1, wherein the rasagiline base is
crystalline rasagiline base.
3. The dosage form of claim 1, wherein the content of rasagiline is
0.5 mg.
4. The dosage form of claim 1, wherein the content of rasagiline is
1.0 mg.
5. The dosage form of claim 1, wherein step a) comprises preparing
a wet granulate of the rasagiline base, citric acid and/or malic
acid, and a pharmaceutically acceptable excipient.
6. The dosage form of claim 5, wherein step a) further comprises:
i) drying the wet granulate to form a dry granulate, ii) milling
the dry granulate to form particles, and iii) admixing the
particles with at least one lubricant.
7. The dosage form of claim 6, wherein in step iii) the lubricant
is talc or stearic acid, or a combination thereof.
8. The dosage form of claim 6, wherein in step i) 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.
9. The dosage form of claim 8, wherein in step i) the inlet air
temperature is 45.degree. C.
10. The dosage form of claim 6, wherein in step ii) the dry
granulate is milled through an oscillating granulator.
11. The dosage form of claim 1, wherein step a) further comprises a
step of forming the core by compression.
12. The dosage form of claim 11, wherein the core is a tablet.
13. The dosage form of claim 1, wherein in step a) the core is
prepared by admixing rasagiline base, citric acid, and a
pharmaceutically acceptable excipient.
14. The dosage form of claim 1, wherein in step a) the core is
prepared by admixing rasagiline base, malic acid, and a
pharmaceutically acceptable excipient.
15. The dosage form of claim 1, wherein in step a) the core is
prepared by admixing rasagiline base, citric acid and malic acid,
and a pharmaceutically acceptable excipient.
16. The dosage form of claim 1, wherein in step b) the core is
coated with methacrylic acid-ethyl acrylate copolymer (1:1) and a
plasticizer.
17. The dosage form of claim 16, wherein in step b) the ratio of
methacrylic acid-ethyl acrylate copolymer (1:1) to the plasticizer
in the outer one of the two coating layers is between 10 to 1 and 2
to 1.
18. The dosage form of claim 17, wherein in step b) the ratio of
methacrylic acid-ethyl acrylate copolymer (1:1) to the plasticizer
in the outer one of the two coating layers is 5 to 1.
19. The dosage form of claim 16, wherein in step b) the plasticizer
is triethyl citrate.
20. The dosage form of claim 1, wherein in step b) the acid
resistant coating comprises two coating layers.
21. The dosage form of claim 20, wherein in step b) the inner one
of the two coating layers comprises hypromellose.
22. The dosage form of claim 20, wherein in step b) the outer one
of the two coating layers further comprises talc.
Description
[0001] The application claims benefit of U.S. Provisional
Application No. 61/205,833, filed Jan. 23, 2009, the contents of
which are hereby incorporated by reference.
[0002] Throughout this application various publications, published
patent applications, and patents are referenced. The disclosures of
these documents in their entireties are hereby incorporated by
reference into this application in order to more fully describe the
state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. Nos. 5,532,415, 5,387,612, 5,453,446, 5,457,133,
5,599,991, 5,744,500, 5,891,923, 5,668,181, 5,576,353, 5,519,061,
5,786,390, 6,316,504, 6,630,514 disclose
R(+)-N-propargyl-1-aminoindan ("R-PAI"), also known as rasagiline.
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 and PCT International Application
Publication No. WO 95/11016 disclose pharmaceutical formulations
comprising rasagiline. PCT International Application Publication
No. WO 2006/014973 also discloses pharmaceutical formulations
comprising rasagiline.
[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).
SUMMARY OF THE INVENTION
[0006] 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 [0007] a) preparing the core by
admixing rasagiline base, citric acid and/or malic acid, and a
pharmaceutically acceptable excipient; and [0008] b) coating the
core with the acid resistant pharmaceutically acceptable
coating.
DETAILED DESCRIPTION OF THE INVENTION
[0009] 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 [0010] a) preparing the core by
admixing rasagiline base, citric acid and/or malic acid, and a
pharmaceutically acceptable excipient; and [0011] b) coating the
core with the acid resistant pharmaceutically acceptable
coating.
[0012] In an embodiment of the dosage form, the rasagiline base is
crystalline rasagiline base.
[0013] In another embodiment of the dosage form, the content of
rasagiline in the dosage form is 0.5 mg.
[0014] In yet another embodiment of the dosage form, the content of
rasagiline in the dosage form is 1.0 mg.
[0015] 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.
[0016] In yet another embodiment of the dosage form, step a) of the
process further comprises: [0017] i) drying the wet granulate to
form a dry granulate, [0018] ii) milling the dry granulate to form
particles, and [0019] iii) admixing the particles with at least one
lubricant.
[0020] 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.
[0021] 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.
[0022] In yet another embodiment of the dosage form, in step i) of
the process the inlet air temperature is 45.degree. C.
[0023] In yet another embodiment of the dosage form, in step ii) of
the process the dry granulate is milled through an oscillating
granulator.
[0024] In yet another embodiment of the dosage form, step a) of the
process further comprises a step of forming the core by
compression.
[0025] In yet another embodiment of the dosage form, the core is a
tablet.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] In yet another embodiment of the dosage form, in step b) of
the process the core is coated with methacrylic acid-ethyl acrylate
copolymer (1:1) and a plasticizer.
[0030] In yet another embodiment of the dosage form, in step b) of
the process the ratio of methacrylic acid-ethyl acrylate copolymer
(1:1) to the plasticizer in the outer one of the two coating layers
is between 10 to 1 and 2 to 1.
[0031] In yet another embodiment of the dosage form, in step b) of
the process the ratio of methacrylic acid-ethyl acrylate copolymer
(1:1) to the plasticizer in the outer one of the two coating layers
is 5 to 1.
[0032] In yet another embodiment of the dosage form, in step b) of
the process the plasticizer is triethyl citrate.
[0033] In yet another embodiment of the dosage form, in step b) of
the process the acid resistant coating comprises two coating
layers.
[0034] In yet another embodiment of the dosage form, in step b) of
the process the inner one of the two coating layers comprises
hypromellose.
[0035] In yet another embodiment of the dosage form, in step b) of
the process the outer one of the two coating layers further
comprises talc.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.)
[0042] 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.
[0043] 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.
[0044] 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##
The ratio of the free carboxyl groups to the ester groups is
approximately 1:1. The average molecular weight is approximately
250,000.
[0045] 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. It may also start
releasing after the stomach. 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.
[0046] In general, the release process encompasses three major
steps:
[0047] 1. Transport to the site where the pH is high enough to
initiate release from the dosage form;
[0048] 2. Dissolution of the coating; and
[0049] 3. Disintegration and release of the drug from the core.
[0050] 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.
[0051] 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.
[0052] 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.)
[0053] 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.
[0054] 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.
[0055] In all of its aspects, the present invention provides an
oral pharmaceutical dosage form useful for treating: Parkinson's
disease, brain ischemia, 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, schizophrenia, and/or
affective illness, but with a reduced risk of peripheral MAO
inhibition that is typically associated with administration of
rasagiline with known oral dosage forms.
[0056] 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.).
[0057] 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.
[0058] The basket-type apparatus used in this invention is the
apparatus 1 described in the United States Pharmacopeia, 29.sup.th
Edition (2006), chapter 711. The apparatus is constructed as
follows:
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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.
EXAMPLE 1
Rasagiline Immediate Release Tablets
[0063] Rasagiline immediate release tablets were prepared using the
ingredients listed in Table 1.
TABLE-US-00001 TABLE 1 Per Tablet(mg) Per Tablet(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, Disintegrant 10.0 20.0
Pregelatinized (Starch STA-RX 1500) Talc Lubricant 2.0 4.0 Stearic
Acid Lubricant 2.0 4.0 Total core Tablet 105 210 Weight
[0064] 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
[0065] 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.
[0066] A process for preparing crystalline rasagiline base is
disclosed in U.S. Patent Application Publication No. 2008/0161408
(and which corresponds substantially 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.
[0067] 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 base Rasagiline base Rasagiline base
Rasagiline base Rasagiline base Citric Acid Maleic Acid Succinic
Acid Malic Acid BHT Mannitol USP/EP Mannitol USP/EP Mannitol USP/EP
Mannitol USP/EP Mannitol USP/EP Colloidal Silicon Colloidal Silicon
Colloidal Colloidal Colloidal Dioxide Dioxide Silicon Dioxide
Silicon Dioxide Silicon 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
[0068] The batches were produced in lab scale of .about.500 tablets
using laboratory equipment with non-GMP lot of API.
[0069] 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.
[0070] Composition 1
TABLE-US-00003 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0
25.degree. C. 40.degree. C. 40.degree. C. 0.82 Citric Acid Assay
stability results (%) Water 101.6% 94.2% 94.8% 98.0% 1.00
Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch
Stability Results - NF/EP Level of Impurity (%) 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
[0071] Composition 2
TABLE-US-00004 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0
25.degree. C. 40.degree. C. 40.degree. C. 0.7 Maleic Assay
stability results (%) Acid 82.3 84.6 79.8 80.8 Water 1.00
Rasagiline base 80.0 Manitol USP/EP 0.3 Aerosil Stability Results -
200 Level of Impurity (%) 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
[0072] Composition 3
TABLE-US-00005 Mg/ Raw 2 wks 2 wks 1 mo tab Materials Time 0
25.degree. C. 40.degree. C. 40.degree. C. 0.7 Succinic Assay
stability results (%) Acid 102.9 99.4 100.6 101.9 Water 1.00
Rasagiline base 80.0 Manitol Stability Results - USP/EP Level of
Impurity (%) 0.3 Aerosil 200 Total 0.4 0.4 0.6 1.2 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
[0073] Composition 4
TABLE-US-00006 Raw 2 wks 2 wks 1 mo Mg/tab Materials Time 0
25.degree. C. 40.degree. C. 40.degree. C. 0.8 Malic Acid Assay
stability results (%) Water 103.4 101.5 101.5 102.2 1.00 Rasagiline
base 80.0 Manitol USP/EP 0.3 Aerosil 200 10.0 Starch Stability
Results - NF/EP Level of Impurity (%) 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
[0074] Composition 5
TABLE-US-00007 Mg/ Raw 2 wks 2 wks 1 mo tab Materials Time 0
25.degree. C. 40.degree. C. 40.degree. C. Ethanol Assay stability
results (%) 95% 67.8 65.7 48.5 31.9 0.02 BHT 1.00 Rasagiline base
80.0 Manitol Stability Results - USP/EP Level of Impurity (%) 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
[0075] Dissolution Results (% in 0.1N HCl)
TABLE-US-00008 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
[0076] Dissolution Results (% in Phosphate buffer pH 6.8)
TABLE-US-00009 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
[0077] Discussion:
[0078] 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 3a
Preparation of Rasagiline Base Delayed Release Enteric Coated
Tablet--Formulation I:
[0079] In this example, a 1 mg rasagiline base delayed release
enteric coated tablet containing citric acid (117 mg core tablet
weight) was prepared.
TABLE-US-00010 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/Stabilizer 1.6 Mannitol Filler 79.84 Colloidal Silicon
Flowing Agent 0.6 Dioxide Starch NF Binder 10.0 Starch,
Disintegrant 20.0 Pregelatinized (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.
[0080] I. Dry Mixing:
[0081] 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.
[0082] II. Wet Granulation:
[0083] 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.
[0084] 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.
[0085] The wet granulate was discharged into a fluid bed dryer
trolley at mixer speed I.
[0086] III. Fluid Bed Drying:
[0087] 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.
[0088] IV. Milling:
[0089] The dry granulate and the residual amount of Aerosil were
milled through an oscillating granulator with screen 0.6 mm into a
storage container.
[0090] The milled granulate was further weighted.
[0091] V. Final Blending:
[0092] Stearic Acid and Talc were sieved through a 50 mesh screen
and were transferred to the Y-cone/Bin. [0093] 1. The mixture was
mixed for 5 minutes. [0094] 2. The Final Blend and the percentage
yield were determined. [0095] 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. [0096] 4. Samples were taken for a Blend
Uniformity test.
[0097] VI. Tablet Compression:
[0098] A tablet compression machine (FETTE 1200) was set up with
the designated punches 6.0 mm.
[0099] The in-process control testing for tablets included average
weight, individual weight, thickness, hardness, friability and
disintegration.
[0100] 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 -- -- 5 (minutes)
[0101] The tablets were weighted and the percentage yield was
calculated.
[0102] VII. Sub-Coating:
[0103] Tablet cores were first coated with hypromellose (Pharmacoat
606.RTM.) as a pre-coating, followed by coating with Methacrylic
Acid-Methyl Methacrylate Copolymer [1:1] (30% dispersion of
Eudragit.RTM. L100-55) to prevent any possible interaction between
the Rasagiline base in the core and the Eudragit L polymer. [0104]
1. Preparation of Pharmacoat 606.RTM. solution: [0105] Hypromellose
USP solution was prepared using hypromellose, in purified water in
a weight ratio of approximately 1:10. [0106] 2. Pre heating: [0107]
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. [0108] 3. Spraying process: [0109] 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.).
[0110] VIII. Enteric Coating: [0111] 1. Preparation of Enteric
Coating dispersion of Eudragit.RTM. L100-55: [0112] 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.
[0113] 2. Pre heating: [0114] 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.). [0115] 3. Spraying process: [0116] 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.
[0117] 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
Preparation of 1 mg Rasagiline Base Delayed Release Enteric Coated
Tablet--Formulation III
[0118] In this example, a 1 mg rasagiline base delayed release
enteric coated tablet containing citric acid (76 mg core tablet
weight) 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
86.2 *Dry substance remaining on the core.
EXAMPLE 3c
Preparation of 0.5 mg Rasagiline Base Delayed Release Enteric
Coated Tablet
[0119] In this example, a 0.5 mg rasagiline base delayed release
enteric coated tablet containing citric acid (117 mg core tablet
weight) 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
Preparation of 0.5 mg Rasagiline Base Delayed Release Enteric
Coated Tablet
[0120] In this example, a 0.5 mg rasagiline base delayed release
enteric coated tablet containing citric acid (76 mg core tablet
weight) 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 Weight 76.0 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
[0121] 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.
[0122] The % rasagiline released in the following tables is
relative to a standard which is 1 mg rasagiline.
[0123] Tablet Cores:
[0124] 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
[0125] 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
[0126] Sub-Coated Tablets:
[0127] Dissolution Profile (% rasagiline released)--0.1N HCl, 75
rpm, 37.degree. C.
TABLE-US-00017 10 min 20 min 30 min 45 min 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
[0128] Coated Tablets:
[0129] 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.
[0130] Dissolution Profile (% rasagiline released)--Phosphate
buffer pH 5.8
TABLE-US-00018 10 min 20 min 30 min 40 min 60 min 90 min % Mean 0 0
0 0 0
[0131] Dissolution Profile (% rasagiline released)--Phosphate
buffer pH 6.4
TABLE-US-00019 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
[0132] Dissolution Profile (% rasagiline released)--Phosphate
buffer pH 6.8
TABLE-US-00020 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
[0133] Discussion: 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.
[0134] 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.
[0135] 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.)
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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
[0140] Stability of enteric coated tablets produced using
formulations containing citric acid was tested under different
storage conditions. The results are summarized below.
[0141] Stability Results (Accelerated Conditions):
[0142] 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.
[0143] The following table shows that dissolution profile for
enteric coated tablets after different period of storage.
[0144] Dissolution Profile of Coated Tablets--Phosphate buffer pH
6.8, 37.degree. C.
TABLE-US-00021 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
[0145] The % rasagiline released in the above table is relative to
a standard which is 1 mg rasagiline.
[0146] The following tables show that analytical results for
different batches of the enteric coated tablets under various
storage conditions.
[0147] Coated Tablets--Batch 1
TABLE-US-00022 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
[0148] Coated Tablets--Batch 2
TABLE-US-00023 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
[0149] Coated Tablets--Batch 3
TABLE-US-00024 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
[0150] N-(2-Chloroallyl)-1(R)-aminoindan (2-Cl-AAI) Impurities
TABLE-US-00025 Batch No. 2-Cl-AAI Content, % 1 LT 0.00004 2 LT
0.00004
Example 6a
Preparation of Rasagiline Base Delayed Release Enteric Coated
Tablets
[0151] In this example, a 1 mg rasagiline base delayed release
enteric coated tablet containing malic acid (117 mg core tablet
weight) was prepared.
TABLE-US-00026 TABLE 4a 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.
[0152] I. Dry Mixing:
[0153] 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.
[0154] II. Wet Granulation:
[0155] Malic acid solution was prepared using malic acid in
purified water in the ratio of approximately 1:10.6 to 1:6.
[0156] Rasagiline Base was added with stirring for approximately 15
minutes. The stirring was continued until a clear solution was
observed.
[0157] 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.
[0158] The wet granulate was discharged to a fluid bed dryer
trolley at mixer speed I.
[0159] III. Fluid Bed Drying:
[0160] 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.
[0161] IV. Milling:
[0162] The dry granulate was milled with the residual amount of
Aerosil through an oscillating granulator with screen 0.6 mm into
storage container.
[0163] The milled granulate is weighed.
[0164] V. Final Blending:
[0165] 1. Stearic Acid and Talc were sieved through a 50 mesh
screen and transferred to the Y-cone or Bin.
[0166] 2. The mixture was mixed for 5 minutes.
[0167] 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.
[0168] 4. Samples were taken for a Blend Uniformity test.
[0169] VI. Tablet Compression:
[0170] The compressing tablet machine was set up with the
designated punches 6.0 mm. The diameter of the punch may change
.+-.10%.
[0171] The in-process control testing for tablets includes average
weight, individual weight, thickness, hardness, friability and
disintegration.
[0172] 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)
[0173] The tablet cores are weighed and the percentage yield is
calculated.
[0174] VII. Sub-Coating:
[0175] Tablet cores were first coated with hypromellose (Pharmacoat
606) as a pre-coating, followed by Methacrylic Acid--Methyl
Methacrylate Copolymer [1:1] (30% dispersion of Eudragit.RTM.
L100-55) to prevent any possible interaction between the Rasagiline
base in the core and the Eudragit L polymer. [0176] 1. Preparation
of Pharmacoat 606 solution Pharmacoat 606 (hypromellose USP)
solution was prepared using Pharmacoat 606 in purified water in a
weight ratio of 1:10. [0177] 2. Pre heating: [0178] 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. [0179] 3. Spraying process: [0180] 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.).
[0181] VIII. Enteric Coating:
[0182] The Rasagiline subcoated drug product tablet formulation
described in previous section was used for the enteric coated.
[0183] 1. Preparation of Eudragit.RTM. L100-55 dispersion: [0184]
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. [0185] Eudragit.RTM. L100-55
was added to Triethyl citrate/talc dispersion, filtered and stirred
to the continuation of the process. [0186] 2. Pre heating: [0187]
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.). [0188] 2. Spraying
process: [0189] 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
Preparation of 1 mg Rasagiline Base Delayed Release Enteric Coated
Tablet
[0190] In this example, a 1 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-00028 TABLE 4b 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
Preparation of 0.5 mg Rasagiline Base Delayed Release Enteric
Coated Tablet
[0191] In this example, a 0.5 mg rasagiline base delayed release
enteric coated tablet containing malic acid (117 mg core tablet
weight) was prepared using similar steps as described in example
6a.
TABLE-US-00029 TABLE 4c 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
[0192] 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 4d 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
Dissolution Results of Tablets According to Example 6a
[0193] The tablets prepared according to example 6a were tested for
dissolution profile in various media according to USP procedures.
The data below represents the average for 4 tablets.
[0194] 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.
Example 8
Stability Results of Tablets Prepared According to Example 6a
[0195] Stability of enteric coated tablets produced using
formulations containing citric acid was tested under different
storage conditions. The results are summarized below.
[0196] Stability Results (Accelerated Conditions):
[0197] 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.
[0198] The following table shows that dissolution profile for
enteric coated tablets after different period of storage.
[0199] Dissolution Profile of Coated Tablets--Phosphate buffer pH
6.8, 37.degree. C.
TABLE-US-00031 Storage Dissolution Profile after Different Period
Period of Storage (% rasagiline released) (months) 10 min 20 min 30
min 40 min 60 min 90 min 1 0 89 93 94 94 94 2 0 92 93 93 94 94
[0200] The % rasagiline released in the above table is relative to
a standard which is 1 mg rasagiline.
[0201] The following tables show that analytical results for
tablets under various storage conditions.
[0202] Tablet Cores:
TABLE-US-00032 Conditions Assay (%) Total Impurities T = 0 101.2
<DL 40.degree. C., 75RH 1 Mo 101.1 0.1 2 Mo 98.3 0.3 3 Mo 93.3
0.5 4 Mo 93.1 0.4 30.degree. C., 65RH 1 Mo 101.4 <DL 2 Mo 101.9
<QL 3 Mo 98.3 <QL 25.degree. C., 60RH 1 Mo 101.5 <DL 2 Mo
102.0 <QL 3 Mo 100.3 <QL
[0203] Enteric Coated Tablets:
TABLE-US-00033 Conditions Assay % Total Impurities T = 0 98.2
<QL 40.degree. C., 75RH 1 Mo 100.5 0.2 2 Mo 96.4 0.3 3 Mo 96.6
0.5 30.degree. C., 65RH 1 Mo 98.2 <QL 2 Mo 100.2 <QL 3 Mo
101.0 0.1 25.degree. C., 60RH 1 Mo 101.5 <QL 2 Mo 96.7 <QL 3
Mo 99.5 <QL
[0204] N-(2-Chloroallyl)-1(R)-aminoindan (2-Cl-AAI) Impurities
TABLE-US-00034 Batch No 2-Cl-AAI Content, % 1 <0.00004
Example 9
Preparation of Rasagiline Base Tablet Cores (With Citric Acid):
TABLE-US-00035 [0205] mg/ Raw material 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 20.0 25.0
NF/Ph. Eur 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
[0206] 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.
[0207] Calculated amounts of external excipients in accordance with
actual amount of granulate:
TABLE-US-00036 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
[0208] I. Granulation Solution Preparation: [0209] 1. Weigh 80% of
needed amount of Purified water into glass. [0210] 2. Weigh into
the same glass Citric acid. [0211] 3. Insert stirrer into the glass
and start to stir up to complete solubility about 5-10 minutes.
[0212] 4. Weigh Rasagiline base and add it into the obtained Citric
acid solution. [0213] 5. Continue stirring about 30 minutes to
complete solubility of API.
[0214] II. Granulation Preparation: [0215] 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). [0216] 2. Mix the excipient for 1 addition minute with
Mixer I (270 rpm) and Chopper I (1500 rpm) [0217] 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). [0218]
4. Clean glass after granulation solution with 46.563 g of Purified
water and add it into the Diosna P-6 (Diosna). [0219] 5. Mix for 2
minutes with Mixer II (540rpm) and Chopper II (2200 rpm). [0220] 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%.
[0221] Conditions of drying:
[0222] Inlet: Min.--35.degree. C.; Target--50.degree. C.;
Max.--55.degree. C.
[0223] Outet: Product temperature--37.degree. C.
[0224] Flow: Min.--25; Target--60; Max.--1000
[0225] III. Milling:
[0226] Mill granulate through 0.6 mm sieve using Frewitt.
[0227] IV. Final Blend: [0228] 1. Weigh obtained amount of
granulate. [0229] 2. Calculate amounts of Aerosil 200, Stearic acid
and Talc in accordance with actual granulation weight. [0230] 3.
Screen Aerosil 200 through 50 mesh sieve. [0231] 4. Weigh needed
amount of Aerosil 200 after sieving. [0232] 5. Transfer milled
granulate and Aerosil 200 after sieving into the Y-cone. [0233] 6.
Mix for 2 minutes. [0234] 7. Weigh Stearic acid and Talc. [0235] 8.
Screen these excipients through 50 mesh sieve. [0236] 9. Transfer
them into the Y-cone. [0237] 10. Mix for 5 minutes.
[0238] V. Tablet Compression:
[0239] Machine: Sviac
[0240] Diameter of punch: 5.0 mm (it may be changed .+-.10%)
[0241] Tablet weight--80 mg.+-.5%
[0242] Hardness: 3-7 kP
[0243] Friability: Not More Than 1%
[0244] Disintegration: Not More Than 5 minutes
Example 10
Preparation of Rasagiline Base Tablet Cores (With Malic Acid):
TABLE-US-00037 [0245] mg/ Raw material 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
[0246] 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.
[0247] I. Granulation Solution Preparation. [0248] 1. Weigh 80% of
needed amount of Purified water into glass. [0249] 2. Weigh Malic
acid and add it into the same glass. [0250] 3. Insert stirrer into
the glass and start to stir up to complete solubility about 5-10
minutes. [0251] 4. Weigh Rasagiline base and add it into the
obtained Malic acid solution. [0252] 5. Continue stirring about 30
minutes to complete solubility of API.
[0253] II. Granulation Preparation. [0254] 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. [0255] 2. Mix the excipient for 1 addition minute with Mixer I
and Chopper I rpm. [0256] 3. Add granulation solution into the
Diosna P-10 (Diosna) and mix for 2 minutes with Mixer II and
Chopper II. [0257] 4. Add additional Purified Water into the Diosna
P-10 (Diosna) and mix for 2 minutes with Mixer II, and Chopper II.
[0258] 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%.
[0259] Conditions of drying:
[0260] Inlet: Min.--35.degree. C.; Target--50.degree. C.;
Max.--55.degree. C.
[0261] Outet: Product temperature--37.degree. C.
[0262] III. Milling.
[0263] Weigh and add Aerosil 200 to granulate and milled granulate
through 0.6 mm sieve using Frewitt.
[0264] IV. Final Blend. [0265] 1. Weigh Stearic acid and Talc.
[0266] 2. Screen the excipients through 50 mesh sieve. [0267] 3.
Transfer milled granulate and sieved Stearic acid and Talc into the
Y-cone. [0268] 4. Mix for 5 minutes.
[0269] V. Tablet Compression:
[0270] Machine: Sviac
[0271] Diameter of punch: 4.0 mm (it may be changed .+-.10%)
[0272] Tablet weight--43 mg.+-.5%
[0273] Hardness: 3-5 kP
[0274] Friability: Not More Than 1%
[0275] Disintegration: Not More Than 5 minutes
Example 11
Preparation of Rasagiline Base Tablet Cores (Citric and Malic Acids
Together)
TABLE-US-00038 [0276] Mg/ Raw material 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 20.0 17.09 NF/Ph.
Eur Part III Aerosil 200 0.3 0.26 Part IV Stearic acid 2.0 1.71
Talc 2.0 1.71 Total: 117.0 100
[0277] Calculated Amounts of External Excipients in Accordance with
Actual Amount of Granulate
TABLE-US-00039 mg/ Raw material tablet Percentage Part III
Granulate Aerosil 200 0.3 0.26 Part IV Stearic acid 2.0 1.71 Talc
2.0 1.71
[0278] I. Granulation Solution 1 Preparation. [0279] 1. Weigh 80%
of needed amount of Purified water into glass. [0280] 2. Weigh into
the same glass Citric acid. [0281] 3. Insert stirrer into the glass
and start to stir up to complete solubility about 5-10 minutes.
[0282] 4. Weigh Rasagiline base and add it into the obtained Citric
acid solution. [0283] 5. Continue stirring about 30 minutes to
complete solubility of API.
[0284] II. Granulation Solution 2 Preparation. [0285] 1. Weigh 20%
of needed amount of Purified water into the glass. [0286] 2. Add
into this glass weighed amount of Malic acid. [0287] 3. Insert
stirrer into the glass and start to stir up to complete solubility
about 5-10 minutes.
[0288] III. Granulation Preparation. [0289] 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). [0290] 2. Mix the excipient for 1 addition minute with
Mixer I (270 rpm) and Chopper I (1500 rpm) [0291] 3. Add
Granulation solution 1 into the Diosna P-6 (Diosna) and mix for 2
minutes with Mixer II (540rpm) and Chopper II (2200 rpm). [0292] 4.
Clean glass after granulation solution 1 with Granulation solution
2 and add it into the Diosna P-6(Diosna). [0293] 5. Mix for 2
minutes with Mixer II (540rpm) and Chopper II (2200 rpm). [0294] 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%.
[0295] Conditions of drying:
[0296] Inlet: Min.--35.degree. C.; Target--50.degree. C.;
Max--55.degree. C.
[0297] Outet: Product temperature--37.degree. C.
[0298] Flow: Min.--25; Target--60; Max--1000
[0299] IV. Milling:
[0300] Mill obtained granulate through 0.6 mm sieve using
Frewitt.
[0301] V. Final Blend: [0302] 1. Weigh obtained amount of
granulate. [0303] 2. Calculate amounts of Aerosil 200, Stearic acid
and Talc in accordance with actual granulation weight. [0304] 3.
Screen Aerosil 200 through 50 mesh sieve. [0305] 4. Weigh needed
amount of Aerosil 200 after sieving. [0306] 5. Transfer milled
granulate and Aerosil 200 after sieving into the Y-cone. [0307] 6.
Mix for 2 minutes. [0308] 7. Weigh Stearic acid and Talc. [0309] 8.
Screen these excipients through 50 mesh sieve. [0310] 9. Transfer
them into the Y-cone. [0311] 10. Mix for 5 minutes.
[0312] VI. Tablet Compression
[0313] Machine: Sviac
[0314] Diameter of punch: 6.0 mm (it may be changed .+-.10%)
[0315] Tablet weight--117 mg.+-.5%
[0316] Hardness: 6-8 kP
[0317] Friability: Not More Than 1%
[0318] Disintegration: Not More Than 5 minutes
[0319] VII. Subcoating:
TABLE-US-00040 Mg/tablet Raw material 4.8 Pharmacoat 606
(Hypromellose USP)
[0320] Equipment: O'HARA, Peristaltic pump [0321] 1. Preparation of
Sub-coating solution: [0322] Pharmacoat 606 (hypromellose USP) was
added into the vessel with 1510g of Purified water and mixed for 30
minutes using stirrer. [0323] 2. Preheating: [0324] The core
tablets were placed into the Pan 2.5 kg of O'HARA Coater and
preheated: [0325] Inlet air temperature--50.degree. C. (45.degree.
to 55.degree. C.) [0326] Outlet air temperature--45.degree. C.
(40.degree. to 50.degree. C.). [0327] Difference pressure---50 Pa
[0328] 3. Spraying process (the process was continued till desired
tablet weight was achieved): [0329] Sub-coating solution was
sprayed on the preheated core tablets at the following conditions:
[0330] Number of spray guns--1 [0331] Nozzle bore--1 mm [0332]
Distance tablet bed/spray gun--15 cm [0333] Pan speed 10 rpm (8-12
rpm) [0334] Inlet air temperature--50.degree. C. (45.degree. to
55.degree. C.) [0335] Outlet air temperature--35.degree. C.
(30.degree. to 40.degree. C.) [0336] Spraying rate--10-20 g/min
[0337] Difference pressure---50 Pa [0338] Atomizing air
pressure--30 Psi [0339] Pattern air pressure--30 Psi [0340] 4.
Drying process: [0341] Inlet air temperature--45.degree. C.
(40.degree. to 50.degree. C.) [0342] Outlet air
temperature--40.degree. C.-50.degree. C. [0343] Pan speed--5 rpm
Jogging [0344] Drying time--60 min
Example 12a
Rasagiline Base 0.5 mg Enteric Coated Optional Formulations--with
Citric Acid
[0345] 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-00041 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, Disintegrant 20.0 20.0 15.0 20.0 Pregelatinized
(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
Rasagiline Base 1 mg Enteric Coated Optional Formulations--with
Citric Acid
[0346] 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-00042 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, Disintegrant 20.0 20.0 15.0 20.0
Pregelatinized (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 76.0 (+/-10%)
105.0 (+/-10%) 76.0 (+/-10%) 117.0 (+/-10%) Tablet 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- Coating
Agent 4.0 (+/-10%) 4.0 (+/-10%) 4.0 (+/-10%) 6.25 (+/-10%) 55 Talc
USP Extra Lubricant 1.9 (+/-10%) 1.9 (+/-10%) 1.9 (+/-10%) 3.1
(+/-10%) Fine Triethyl citrate Plasticizer 0.8 (+/-10%) 0.8
(+/-10%) 0.8 (+/-10%) 1.25 (+/-10%) NF Purified Water Processing
Agent
Example 13a
Rasagiline Base 0.5 mg Enteric Coated Optional Formulations--with
Malic Acid
[0347] 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-00043 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, Disintegrant 20.0 20.0 15.0 20.0 Pregelatinized
(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 13b
Rasagiline Base 1 mg Enteric Coated Optional Formulations--with
Malic Acid
[0348] 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-00044 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, Disintegrant 20.0 20.0 15.0 20.0
Pregelatinized (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 Lubricant 1.9 (+/-10%) 1.9 (+/-10%) 1.9 (+/-10%) 3.1 (+/-10%)
Fine Triethyl citrate NF Plasticizer 0.8 (+/-10%) 0.8 (+/-10%) 0.8
(+/-10%) 1.25 (+/-10%) Purified Water Processing Agent
Example 14a
Rasagiline Base 0.5 mg Enteric Coated Optional Formulations--with
Both Citric and Malic Acid
[0349] 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-00045 Per Tablet Per Tablet Per Tablet Per Tablet
Component Function (mg) (mg) (mg) (mg) Core tablets Rasagiline base
Drug 0.5 0.5 0.5 0.5 Substance 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, Disintegrant 20.0 20.0 15.0 20.0
Pregelatinized (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 14b
Rasagiline Base 1 mg Enteric Coated Optional Formulations--with
Both Citric and Malic Acid
[0350] 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-00046 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, Disintegrant 20.0 20.0 15.0 20.0
Pregelatinized (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 15a
Rasagiline Base 0.5 mg Enteric Coated Optional Formulation--with
Citric Acid, Color Coated
[0351] This example describes a 0.5 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 0.5 Substance Citric acid Antioxidant 1.6
Mannitol Filler 80.3 Aerosil Flowing 0.6 Agent 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 Weight 117.0 Subcoating Pharmacoat 606 (Hypromellose
Coating 4.8 USP) Granules Agent Purified Water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat OPADRY II OY-GM-28900
WHITE Coating 1-5 (catnum. 415850005) Agent 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
Rasagiline Base 1 mg Enteric Coated Optional Formulation--with
Citric Acid, Color Coated
[0352] This example describes a 1 mg rasagiline base formulation
containing citric acid with an extra color coating.
TABLE-US-00048 Per Tablet Component Function (mg) Core tablets
Rasagiline base Drug 1.0 Substance Citric acid Antioxidant 1.6
Mannitol Filler 79.8 Aerosil Flowing 0.6 Agent 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 Weight 117.0 Subcoating Pharmacoat 606 Coating 4.8
(Hypromellose USP) Granules Agent Purified Water Processing Agent
Coating Suspension Eudragit L-30D-55 Coating 6.25* Agent Talc USP
Extra Fine Lubricant 3.1 Triethyl citrate NF Plasticizer 1.25
Purified Water Processing Agent Top coat Opadry .RTM. II 31F20721
Blue Coating 1-5 OR Agent Opadry .RTM. II 34G24627 Pink OR/AND
Opadry fx 63f97546 silver Purified Water Processing Agent *Dry
substance remaining on the core.
Example 16a
Rasagiline Base 0.5 mg Enteric Coated Optional Formulation--with
Malic Acid, Color Coated
[0353] 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 Weight 117.0 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 16b
Rasagiline Base 1 mg Enteric Coated Optional Formulation--with
Malic Acid, Color Coated
[0354] 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 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 Weight 117.0 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
Blue Coating Agent 1-5 OR Opadry .RTM. II 34G24627 Pink OR/AND
Opadry fx 63f97546 silver Purified Water Processing Agent *Dry
substance remaining on the core.
Example 17
Extraction of Rasagiline Base from Tablets
[0355] The aim of the study was to evaluate the amount of free
Rasagiline base in 1 mg tablets of "Citric" formulation.
[0356] Rasagiline is assumed to present in the formulation in salt
form or as free base.
[0357] 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.
[0358] Rasagiline salts are not soluble in non-polar solvents and
probability of the extraction of rasagiline citrate with hexane,
toluene, 1-octanol or ethylacetate is very low.
[0359] 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.
[0360] 17 core tablets, 1 mg of Rasagiline base each were crushed
and ground in mortar to homogeneous fine powder.
[0361] 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.
[0362] 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.
[0363] Maximal possible calculated concentration of Rasagiline base
in the extracts is 0.85 mg/ml (17 mg in 20 ml solvent).
[0364] The results are summarized in Table 5 below.
TABLE-US-00051 TABLE 5 Extractions of Rasagiline base from core
tablets with organic solvents Achieved Weight concentration of
Experiment No. of of Rasagiline in No. tablets 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
[0365] The experimental results in Table 5 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.
[0366] Amount of the extractable base does not depend on the
solvent type for non polar solvent as n-hexane, toluene, 1-octanol
and dichloromethane.
[0367] At the same time more polar solvent as ethylacetate
extracted more Rasagiline from the core tablets.
Example 18
Clinical Study Based on Tablets According to Examples 3a and 3b
[0368] This study evaluates 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 1 mg) following a single dose administration, and to
assess the effect of food on each one of the test formulations.
[0369] This study also evaluates the safety and tolerability of
each treatment.
[0370] 1. Study Design
[0371] This study is 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).
[0372] Each part is an open-label, three-period, three-sequence,
comparative crossover study in 15 healthy males and females (5 per
sequence).
[0373] Treatment A: One Rasagiline Base 1 mg Enteric Coated Tablets
(test Formulation I or test Formulation III) in the fasted
state.
[0374] Treatment B: One Azilect.RTM. tablet (reference 1 mg
rasagiline as rasagiline mesylate) in the fasted state.
[0375] 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.
[0376] The 3 treatments are administered across 3 study periods
each of which is separated by a 14-day washout interval. They are
administered according to one of three sequences to which subjects
are randomly assigned: A-B-C, B-C-A, or C-A-B.
[0377] In each period, subjects are confined for two overnight
stays [at least 10.5 hours prior to and until at dose
administration]. Subjects return for an ambulatory blood sample
collection (36 hours) on Day 2.
[0378] In Part 1, Subjects 1-15 receive test Formulation I or
reference, while in Part 2, Subjects 16-30 receive test Formulation
III or reference. The decision to proceed with each study part is
based on the availability of the test Formulation.
[0379] AEs, vital signs, physical examination, and clinical
laboratory tests are assessed for safety and blood samples are
taken at regular pre-defined time points throughout the study for
the measurement of rasagiline and aminoindan concentrations in
plasma.
[0380] 2. Subject Selection
[0381] Thirty (30) healthy adult (.about.50%/50% male and female)
subjects are selected from non-institutionalized subjects
consisting of members of the community at large.
[0382] 3. Pharmacokinetic (PK) Sampling and Analysis
[0383] A total of 80 samples (about 400 mL) are drawn from each
subject for PK purposes. Pharmacokinetic sampling occurs at the
following timepoints:
[0384] a) Treatment A (test, fasted): [0385] 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).
[0386] b) Treatment B (reference, fasted): [0387] 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).
[0388] c) Treatment C (test, fed): [0389] 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).
[0390] Blood are drawn either by direct venipuncture or through an
indwelling intravenous cannula. Whenever the latter is performed,
the cannula is flushed with 1.5 mL normal saline after each
sampling. In addition, to avoid sample dilution, 1 mL blood is
discarded before the next sample (as long as the cannula is in
place). Therefore, up to 5 mL blood is collected at each time
point. The total blood volume taken per subject for pharmacokinetic
sampling is approximately 400 ml over a 4-week period.
[0391] Samples are collected into appropriate volume K2-EDTA
vacutainers. The labels for all biological sample collection and
storage containers contain, at a minimum, Protocol Number,
Sub-study number, Subject Number; Dosing Period; Dosing Day; PK
time point. Immediately following sample collection, samples are
mixed by inverting the collection tube at least 2-3 times. Samples
are cooled by an ice bath or cooling device until processed. Blood
processing occur within 2 hours of collection: the sample is
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 bioanalytieal
laboratory. At least 0.7 mL of plasma is transferred into the first
polypropylene tube and the remaining plasma is transferred to the
second polypropylene tube. The time at which samples are placed at
-20.degree. C. are recorded in the study documentation.
[0392] Actual sampling time is recorded directly in the source data
or CRF. Sample processing procedures are documented in the PK
logbook.
[0393] The rasagiline and aminoindan plasma concentrations are
measured using a validated LC/MS/MS bioanalytical method and
according to the Bioanalytical Laboratory's Standard Operating
Procedures and FDA Guidelines.
[0394] Analysis of the PK data of each sub-study is performed
separately, according to audited bioanalytical data availability.
The individual plasma concentrations of rasagiline and aminoindan
are listed, displayed graphically as appropriate and summarized
using descriptive statistics for each of the treatments.
[0395] Pharmacokinetic analysis are performed with rasagiline and
aminoindan concentration profiles using appropriate
non-compartmental methods.
[0396] The following parameters are 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 will be calculated if deemed necessary.
All the PK parameters are listed and summarized using descriptive
statistics.
[0397] Statistical analysis is 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 are
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 are calculated using ANCOVA
on the log-transformed data (MIXED procedure, SAS). The conclusion
regarding bioequivalence are based on the back-transformed point
estimate and CI. T.sub.max are analyzed using nonparametric
analysis (Wilcoxon Signed Rank Test).
[0398] 4. Results
[0399] Bioequivalence Tests
[0400] The testing results show that the delayed release
formulations tested (Formulation I and Formulation III) meets the
criteria for bioequivalence to the known immediate release
formulation. Each of the C.sub.max and AUC.sub.t achieve a range of
80-140% within a 90% confidence interval between the formulation
tested and the reference immediate release formulation.
[0401] MAO Assay:
[0402] The testing results show MAO-B activity for formulation
prepared according to each of the Examples 3a and 3b are comparable
to the reference immediate release formulation.
[0403] The standard method is used for the enzymatic determination
of MAO: "Determination of monoamine oxidase (MAO) by an extraction
method using radiolabelled substrate in various tissues".
[0404] Briefly, fifty (50) .mu.l of homogenate are 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) are added and
incubation continued for next 20 minutes. The reaction is then
stopped by addition of citric acid 2 M.
[0405] Radioactive metabolites are extracted into toluene/ethyl
acetate (1:1 v/v.), a solution of 2,5-diphenyloxazole is added to a
final concentration of 0.4% and the metabolite content is estimated
by liquid scintillation counting.
[0406] Activity of rat brain homogenate serves as standard
(positive control) to the assay.
[0407] Protein determination is performed by the Lowrey method.
[0408] Safety and Tolerability
[0409] The testing results show that safety and tolerability for
each treatment are acceptable.
Example 19
Additional Studies Based on Tablets According to Examples 3c, 3d,
6a-6d and 9-16
[0410] Additional studies are conducted evaluating the
bioavailability of two different rasagiline base 1 mg enteric
coated tablet formulations prepared according to each of Examples
3c, 3d, 6a-6d and 9-16 verses the marketed rasagiline drug product
(Azilect 1 mg) following a single dose administration, and the
effect of food on each one of the test formulations.
[0411] The results show that all of these formulations tested have
acceptable bioavailability characteristics and MAO-B activity.
* * * * *