FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
PATENTS RULES, 2006

COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
"STABLE ORAL PHARMACEUTICAL COMPOSITIONS OF RASAGILENE AND PROCESS FOR PREPARING THEREOF"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBA1 - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
FIELD OF THE INVENTION
The present invention relates to stable oral pharmaceutical compositions comprising rasagiline or a pharmaceutically acceptable salt thereof and process for the preparing thereof.
BACKGROUND OF THE INVENTION
Rasagiline is a propargylamine-based drug which is a selective irreversible inhibitor of the enzyme monoamine oxidase (hereinafter MAO) and provides the R(+) enantiomer of N-propargyl-l-aminoindan which is a selective irreversible inhibitor of the B-form of monoamine oxidase enzyme (hereinafter MAO-B). Rasagiline is used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. Human cells contain two forms of monoamine oxidase, MAO-A and MAO-B. Both are found in the brain, but MAO-B is far more prevalent and is responsible for the breakdown of dopamine after its release into the synapse. Parkinson's disease is characterized by the death of cells that use dopamine to transmit their signals, this result in a decrease in synaptic signal strength and concomitant symptomology. By inhibiting the breakdown of dopamine in the synapse, rasagiline permits the signaling neurons to reabsorb more of it for reuse later, somewhat compensating for the diminished quantities manufactured.
The subject invention is in the field of selective irreversible inhibitors of the enzyme MAO and provides the R(+) enantiomer of N-propargyl-l-aminoindan which is a selective irreversible inhibitor of the B-form of monoamine oxidase enzyme. The subject invention also provides pharmaceutical compositions containing rasagiline which are particularly useful for the treatment of Parkinson's disease.
Rasagiline is currently administered orally in the form of a conventional tablet designed to be swallowed whole and is presently marketed in US as Azilect® by Teva Pharma. AZILECT® (rasagiline tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.
US6126968 discloses a pharmaceutical composition in tablet form comprising rasagiline or its acceptable salt as an active ingredient and atleast one alcohol selected from group of pentahydric or hexahydric alcohols like mannitol, xylitol and sorbitol.
EP0814789 discloses formulations of MAO-B inhibitors which attempt to address some of the known problems. However, it carries out lyophilization of the MAO-B inhibitor formulations which is an expensive process and results in high friability of the product, further increasing cost.
US20060188581A1 discloses a mixture of particles of a pharmaceutically acceptable salt of R(+)-N-propargyM -aminoindan, wherein more than 90% of the total amount by volume of R(+)-N-propargyl-l-aminoindan salt particles have a size of less than 250 microns along with a solid composition comprising thereof and a carrier.
US20080107729 & US20090111892 disclose solid pharmaceutical composition comprising rasagiline or its acceptable salt of rasagiline, and particles having a non- filamentous microstructure of at least two sugar alcohols. This is a tedious and expensive process which uses at least two sugar alcohols in its preparation.
W02009122301A2 discloses rasagiline mesylate having a 90 volume-percent of the particles (D90) with a size of about 600 microns to about 1500 microns. It also relates to a substantially pure rasagiline mesylate and a process for controlling the particle size of rasagiline mesylate to obtain rasagiline mesylate having a D90 particle size of about 255 microns to about 1400 microns and a pharmaceutical composition comprising rasagiline mesylate having a 90 volume- percent of the particles (D90) with a size of about 255 microns to about 1500 microns and one or more pharmaceutical!y acceptable excipients.
The present invention meets the unfulfilled needs of the pharmaceutical industry by providing a stable oral pharmaceutical composition that overcomes the problems of the prior art.
We have surprisingly found that oral pharmaceutical compositions which are stable and bioequivalent to the commercially available formulation in US i.e. Azilect® tablets can be prepared without using the pentahydric or hexahydric alcohols as used by the prior arts.
Moreover, above cited prior arts relate to rasagiline of particular particle size to provide an acceptable formulation. For example, US20060188581A1 relates to rasagiline particles with d(90) of less than 250 microns to provide content uniformity and W02009122301A2 discloses rasagiline mesylate having d(90) with a size of about 600 microns to about 1500 microns to achieve homogeneous distribution of the drug substance in a tablet blend, good flow properties, better dissolution and solubility properties with greater bioavailability. We have surprisingly developed a process in which rasagiline is solubilised and then used to prepare pharmaceutical dosage forms, which avoids the necessity of using a particular particle size of rasagiline as used by the prior arts mentioned before. Thus by using the present process, stable oral pharmaceutical compositions of rasagiline or its pharmaceutically acceptable salt thereof can be prepared irrespective of particle size used to achieve considerable physicochemical properties with desired drug content uniformity for pharmaceutical dosage units.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutical! y acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the said composition is free of pentahydric or hexahydric alcohols which affords an excellent composition while avoiding afore mentioned disadvantages.
It is also an object of the present invention to provide a process for the preparation of a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically
acceptable salt thereof, wherein the said composition is free of pentahydric or hexahydric alcohols.
Accordingly, it is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
SUMMARY OF THE INVENTION
The present invention relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) 01 mixtures thereof; and wherein the said composition is free of pentahydric or hexahydric alcohols.
The present invention relates to a process for the preparation of a stable oral pharmaceutical composition of rasagiline or a pharmaceutically acceptable salt thereof comprising:
(i) Solubilizing rasagiline in a solvent,
(ii) Using a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof,
(iii) Manufacturing a pharmaceutical dosage form of rasagiline by using (i) and (ii), wherein the said composition is free of pentahydric or hexahydric alcohols.
The invention may be summarized as given below:
A. A stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof; and wherein the said composition is free of pentahydric or hexahydric alcohols.
B. A stable oral pharmaceutical composition as in A above, wherein the said composition is bioequivalent to the commercially available formulation in US i.e. Azilect® tablets,
C. A stable oral pharmaceutical composition as in A above, wherein the said composition relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable polysaccharide(s) wherein the composition is free of pentahydric or hexahydric alcohols.
D. A stable oral pharmaceutical composition as in A above, wherein a polyhydric alcohol is selected from maltitol or lactitol.
E. A stable oral pharmaceutical composition as in A above, wherein disaccharide(s) are selected from sucrose or maltose or mixtures thereof.
F. A stable oral pharmaceutical composition as in A above, wherein polysaccharide(s) are selected from starch or crystalline cellulose like microcrystalline cellulose or mixtures thereof.
G. A process for the preparation of a stable oral pharmaceutical composition of rasagiline or a pharmaceutically acceptable salt thereof comprising:
(i) Solubilizing rasagiline in a solvent,
(ii) Using a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof,
(iii) Manufacturing a pharmaceutical dosage form of rasagiline by using (i) and (ii), wherein the said composition is free of pentahydric or hexahydric alcohols.
H. A process as in G above, wherein the said process comprises:
(i) Solubilizing rasagiline in a solvent,
(ii) Granulating a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof with the solution of (i) and optionally pharmaceutically acceptable excipients,
(iii) Drying the granulate of (ii) and blending with extra granulate material,
(iv) Compressing or encapsulating the blend of (iii) to convert into a pharmaceutical dosage form, wherein the said composition is free of pentahydric or hexahydric alcohols.
I. A process as in G above, wherein the said process comprises:
(i) Solubilizing rasagiline in a solvent,
(ii) Coating a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof with the solution of (i), wherein the said composition is free of pentahydric or hexahydric alcohols.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
The term 'rasagiline' or 'rasagiline or a pharmaceutically acceptable salt thereof as used herein refers to rasagiline free base or any pharmaceutically acceptable salt of rasagiline. A particularly preferred pharmaceutically acceptable salt of rasagiline is rasagiline mesylate.
The term 'stable' as used herein refers to chemical stability of rasagiline in solid dosage forms wherein there is no change in impurities percentages and dissolution profile when kept at 40°C / 75% RH for 3 months
We have surprisingly found that oral pharmaceutical compositions which are stable and bioequivalent to the commercially available formulation in US i.e. Azilect® tablets can be prepared without using the pentahydric or hexahydric alcohols as used by the prior arts.
Moreover, prior arts relate to rasagiline of particular particle size to provide an acceptable formulation. For example, US20060188581AI relates to rasagiline particles with d(90) of less than 250 microns to provide content uniformity and W02009122301A2 discloses rasagiline mesylate having d(90) with a size of about 600 microns to about 1500 microns to achieve homogeneous distribution of the drug substance in a tablet blend, good flow properties, better dissolution and solubility properties with greater bioavailability. We have surprisingly developed a process in which rasagiline is solubilised and used to prepare pharmaceutical dosage forms, which avoids the necessity of using a particular particle size of rasagiline as used by the prior arts mentioned before. Thus by using the present process, stable oral pharmaceutical compositions of rasagiline or its pharmaceutically acceptable salt thereof can be prepared irrespective of particle size used to achieve considerable physicochemical properties with desired drug content uniformity for pharmaceutical dosage units.
The present invention relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof; and wherein the said composition is free of pentahydric or hexahydric alcohols.
The present invention relates to a process for the preparation of a stable oral pharmaceutical composition of rasagiline or a pharmaceutically acceptable salt thereof comprising:
(i) Solubilizing rasagiline in a solvent,
(ii) Using a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide^) or mixtures thereof,
(iii) Manufacturing a pharmaceutical dosage form of rasagiline by using (i) and (ii), wherein the said composition is free of pentahydric or hexahydric alcohols.
The present invention also provides a stable oral pharmaceutical composition comprising rasagiline or a pharmaceutically acceptable salt which is particularly useful for the treatment of Parkinson's disease.
This invention provides a stable oral pharmaceutical composition comprising rasagiline or a pharmaceutically acceptable salt thereof which is bioequivalent to the commercially available formulation in US i.e. Azilect® tablets.
The carriers used in the present invention are selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof. The carriers used in the present invention are free of pentahydric or hexahydric alcohols. The polyhydric alcohol may be selected from maltitol or lactitol. More preferably the polyhydric alcohol is maltitol, consisting of one glucose unit linked with one sorbitol unit via an alpha (1,4) bond. Disaccharides may be selected from sucrose or maltose. Polysaccharides may be selected from polydextrose composed of randomly cross linked glucose with all types of glucosidic bonds (1,6 predominate) like starches; or crystalline cellulose like microcrystalline cellulose which is purified, partially depolymerized cellulose. The carriers may be present in the composition in an amount of from about 20 % w/w to about 70 % w/w of the composition.
The composition of the present invention may optionally also include conventional additives such as disintegrants, binders, lubricants, glidants, and the like, all as known per se. Examples of disintegrants which may be used in accordance with the present invention are pre gelatinized starch, sodium starch glycolate, croscarmellose sodium and the like thereof. Examples of binders which may be used in accordance with the present invention are starch, polyvinyl pyrrolidine (PVP), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC) and the like thereof. Examples of lubricants and glidants which may be used in accordance with the present invention are talc, stearic acid, colloidal silicon dioxide and the like thereof.
The present invention relates to the use of solvents that may be used in the present process for the preparation of a stable oral pharmaceutical composition of rasagiline or a pharmaceutically acceptable salt thereof. Any solvent can be used which can dissolve rasagiline mesylate with more than 10mg/mL solubility. Examples of solvents that may be used include but not limited to isopropyl alcohol, water, ethanol or mixtures thereof.
The present invention relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof, wherein the pharmaceutical dosage forms may include solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules.
The present invention relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof, and wherein the said composition is free of pentahydric or hexahydric alcohols. The said pharmaceutical compositions may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression. In wet granulation, rasagiline or its pharmaceutically acceptable salt thereof is mixed with a carrier material which is free of pentahydric and hexahydric alcohols along with the excipients. Granulation may occur in the presence of purified water or other alcoholic solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator and blended with the extra granular material. The lubricant was added, mixed and compressed into tablets. Dry granulation can be done by two processes: (1) slugging, which involves mixing the rasagiline or its pharmaceutically acceptable salt thereof with a carrier which is free of pentahydric and hexahydric alcohols and further mixing with the excipients, slugging, dry screening, lubrication and compression, or (2) roller compaction process. Direct compression involves compressing tablets directly from the physical mixture of rasagiline or its pharmaceutically acceptable salt thereof with a carrier which is free of pentahydric and hexahydric alcohols, with the excipients. Alternatively the pharmaceutical compositions of the present invention may be obtained by preparing
placebo granules comprising the suitable carrier material and pharmaceutically acceptable excipients, and mixing these with rasagiline to obtain a blend, which may be encapsulated or compressed into tablets. These methods afford excellent compositions of rasagiline or its pharmaceutically acceptable salt thereof. It is preferred that the pharmaceutical compositions of the present invention be prepared by solubilizing rasagiline in a suitable solvent and using the rasagiline solution to prepare a suitable pharmaceutical dosage form by the conventional processes such as wet granulation or solvent coating.
In a preferred embodiment, pharmaceutical compositions of the present invention were prepared by a solubilization process wherein rasagiline was solubilised in a suitable solvent. Drug content uniformity is a unique requirement for all dosage forms. When following the solubilization process of the present invention, consequently favorable content uniformity of the blend as well as of dosage units was obtained. Thus, pharmaceutical compositions of the present invention were prepared by solubilizing rasagiline in a suitable solvent and using the rasagiline solution to prepare a suitable pharmaceutical dosage form by wet granulation. In wet granulation, rasagiline or its pharmaceutically acceptable salt thereof was dissolved in a solvent; further this solution was added to the binder solution and stirred. The carrier material which is free of pentahydric and hexahydric alcohols was mixed with the disintegrant. Granulation may occur in the presence of purified water or other alcoholic solvents. The above dry mix was granulated with the rasagiline solution using Fluid bed processor or Rapid mixer granulator and blended with the extra granular material. The lubricant was added, mixed and compressed into tablets.
In another preferred embodiment, pharmaceutical compositions of the present invention were prepared by solubilizing rasagiline in a suitable solvent and using the rasagiline solution to prepare a suitable pharmaceutical dosage form by solvent coating methods. In solvent coating methods, pharmaceutical compositions of the present invention were prepared by coating the rasagiline solution over the carrier which is free of pentahydric and hexahydric alcohols and converting into a suitable pharmaceutical dosage form or by
compressing the placebo tablets comprising the carrier which is free of pentahydric and hexahydric alcohols and coating the rasagiline solution over the placebo tablets or by coating the placebo pellets comprising the carrier which is free of pentahydric and hexahydric alcohols with the rasagiline solution which may be encapsulated or compressed into tablets.
In another embodiment, present invention involves wet granulation process of preparation wherein rasagiline or its pharmaceutically acceptable salt thereof and all other ingredients were screened; dry mixed the intra granular material with a carrier which is free of pentahydric and hexahydric alcohols in a rapid mixer granulator. Further the prepared binder solution was added to the intragranular material and granulated. And the above dried granules were blended with extragranular material and then lubricant was added, mixed and compressed into tablets.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Examples
Example 1: Composition and preparation of 0.5 mg tablet of Rasagiline Table 1
Name of Ingredients (Mg/Tab) O.Smg
Intra granular
Maltitol 75.0
Pre Gelatinized Starch 5.0
Binder preparation
Rasagiline Mesylate eq. to rasagiline 0.5
Starch 10
Extra granular
Pre Gelatinized Starch 5.0
Colloidal Silicon Dioxide 0.5
Talc 2.0
Stearic Acid 2.0
Total 100

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as a polyhydric alcohol which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 2: Composition and preparation of 1 mg tablet of Rasagiline Table 2
Name of Ingredients (Mg/Tab) lmg
Intra granular
Maltitol 74.5
Sodium starch glycolate 5.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 1.0
PVP 10
Extra granular
Sodium starch glycolate 5.0
Colloidal Silicon Dioxide 0.5
Talc 2.0
Stearic Acid 2.0
Total 100

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as a polyhydric alcohol which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared or binder was dissolved in solvent, addition of the binder solution or starch paste solution to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other alcoholic solvents. The above dry mix was granulated with the granulating solution using "Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 3: Composition and preparation of 0.5 mg tablet of Rasagiline Table 3
Name of Ingredients (Mg/Tab) 0.5/ng
Intra granular
Maltitol 37.11
Microcrystalline Cellulose-102 37.11
Colloidal Silicon Dioxide 2.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 0.78
Corn Starch 2.0
Extra granular
Croscarmellose Sodium 10.0
Pregelatinized starch 10.0
Colloidal Silicon Dioxide 2.0
Talc 2.0
Stearic Acid 2.0
Total 105

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as polyhydric alcohol or crystalline cellulose or mixtures thereof, which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other alcoholic solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 4: Composition and preparation of 1 mg tablet of Rasagiline Table 4
Name of Ingredients (Mg/Tab) lmg
Intra granular
Maltitol 74.22
Microcrystalline Cellulose-102 74.22
Colloidal Silicon Dioxide 4.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 1.56
Corn Starch 4.0
Extra granular
Croscarmellose Sodium 20.0
Pregelatinized starch 20.0
Colloidal Silicon Dioxide 4.0
Talc 4.0
Stearic Acid 4.0
Total 210

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as polyhydric alcohol or crystalline cellulose or mixtures thereof, which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other alcoholic solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 5: Composition and preparation of 1 mg tablet of Rasagiline Table 5
Name of Ingredients (Mg/Tab) 0.5 mg
Intra granular
Microcrystalline Cellulose 170.44
Colloidal Silicon Dioxide 2.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 1.56
Corn Starch 4.0
Extra granular
Croscarmellose Sodium 20.0
Colloidal Silicon Dioxide 4.0
Talc 4.0
Stearic Acid 4.0
Total 210

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as crystalline cellulose, which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 6: Composition and preparation of 1 mg tablet of Rasagiline Table 6
Name of Ingredients (Mg/Tab) 0.5mg
Intra granular
Microcrystalline Cellulose 120.0
Corn starch 50.44
Colloidal Silicon Dioxide 2.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 1.56-
Corn Starch 4.0
Extra granular
Croscarmellose Sodium 20.0
Colloidal Silicon Dioxide 4.0
Talc 4.0
Stearic Acid 4.0
Total 210

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as crystalline cellulose, which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 7: Composition and preparation of 1 mg tablet of Rasagiline Table 7
Name of Ingredients (Mg/Tab) 0.5mg
Intra granular
Microcrystalline Cellulose 120.0
Corn starch 50.44
Colloidal Silicon Dioxide 2.0
Binder preparation
Rasagiline Mesylate eq to rasagiline 1.56
Corn Starch 4.0
Extra granular
Pregelatinized starch 20.0
Colloidal Silicon Dioxide 4.0
Talc 4.0
Stearic Acid 4.0
Total 210

Process of preparation involves, all the materials were sifted the intra granular material was dry mixed with a carrier such as crystalline cellulose, which is free of pentahydric and hexahydric alcohols in Fluid bed processor or Rapid mixer granulator, then drug was dissolved in the solvent. Starch paste solution was prepared, added to the drug solution and was stirred for few minutes. Granulation may occur in the presence of purified water or other solvents. The above dry mix was granulated with the granulating solution using Fluid bed processor or Rapid mixer granulator; blend the above blend with the extra granular material for 25min. The lubricant was added and mixed for another 5 min and compressed into tablets.
Example 8: Composition and preparation of 0.5 mg tablet of Rasagiline Table 8
Name of Ingredients (Mg/Tab) 0.5 mg
Intra granular
Rasagiline Mesylate eq to rasagiline 0.5
Maltitol 75.0
Starch 10.0
Extra granular
Pre Gelatinized Starch 10.0
Colloidal Silicon Dioxide 0.5
Talc 2.0
Stearic Acid / magnesium stearate 2.0
Total 100

Process of preparation involves rasagiline or its pharmaceutically acceptable salt thereof and all other ingredients are screened; dry mix the intra granular material with a carrier such as a polyhydric alcohol which is free of pentahydric and hexahydric alcohols in a Rapid mixer granulator. Further the prepared binder solution was added to the intragranular material and granulated. Blend above dried granules with extragranular material and then lubricant was added and mixed for 5 min and compressed into tablets.
Example 9: Composition and preparation of 1 mg tablet of Rasagiline
Table 9
Name of Ingredients (Mg/Tab) lmg
Intra granular
Rasagiline Mesylate eq to rasagiline 1.0

Maltitol 74.5
Starch 10.0
Extra granular
Pre Gelatinized Starch 10.0
Colloidal Silicon Dioxide 0.5
Talc 2.0
Stearic Acid / magnesium stearate 2.0
Total 100

Process of preparation involves rasagiline or its pharmaceutically acceptable salt thereof and all other ingredients are screened; dry mix the intra granular material with a carrier such as a polyhydric alcohol which is free of pentahydric and hexahydric alcohols in a Rapid mixer granulator. Further the prepared binder solution was added to the intragranular material and granulated. Blend above dried granules with extragranular material and then lubricant was added and mixed for 5 min and compressed into tablets.
Example 10: Composition and preparation of 0.5 mg and 1 mg tablets of Rasagiline
Table 10
Sr. No. Ingredient Specification 0.5 mg 1 mg % w/w
Intra granular
1. Macrocrystalline Cellulose (Grade-112) USP/NF 43.22 86.44 43.22
2. Corn starch 400 L USP/NF 20.00 40.00 20.00
3. Colloidal silicon dioxide (Aerosil 200) USP/NF 3.00 6.00 3.00
Binder solution
4. Rasagiline mesylate 1H 0.78 1.56 0.78
5. Corn starch 400 L USP/NF 3.00 6.00 3.00
6. Citric acid monohydrate USP/NF 3.00 6.00 3.00

7- Purified Water® USP/NF q.s. q.s.
Extra granular
8. Partially pregelatinised maize starch (Lycatab- C) USP/NF 20.00 40.00 20.00
9. Colloidal silicon dioxide (Aerosil 200) USP/NF 2.00 4.00 2.00
10. Talc USP/NF 3.00 6.00 3.00
11. Strearic acid (DUB Microlub 50) USP/NF 2.00 4.00 2.00
Tablet core weight 100,00 200.00 100.00

Manufacturing process: Dry Mixing:
The following intra granular materials were sifted
Sr. No. Ingredients
1. Microcrystalline Cellulose + Colloidal silicon dioxide
2. Corn starch

The materials of the above step were charged in Rapid Mixer Granulator and mix ed. Granulation & Drying: Preparation of binder:
The required quantity of starch was dispersed in required quantity of purified water and heated to get a translucent paste. Citric acid was mixed with the required quantity of water add stirred till a clear solution is obtained, then rasagiline mesylate was added and stirred till a clear solution is obtained. This solution was mixed with previously prepared starch paste. The dry mix was granulated with the binder solution prepared in Rapid Mixer Granulator. The wet mass was dried and blended with extra granulate material and lubricatee (for content uniformity results refer below table no. 11). This blend was compressed using suitable punches and below set parameters (refer table no. 12). (stratified sampling was done and tested for the uniformity of the dosage units, for details refer table no. 13)
Example 11: Content uniformity of the tablets as prepared in example 10 Table 11
Sample % Assay no.
1 99.53
2 101.7
3 100.58
4 100.12
5 99.8
6 103.66
7 99.67
8 99.85
9 99.75
10 101.65
11 Mean 100.63
12 Min 99.53
13 Max 103.66 % RSD 1.32
Example 12: Tablets parameters as prepared in example 10 Table 12
Sr. Parameter limits
No.
1 Average weight 100 to 200 mg
2 Weight variation Avg wt ± 5%
3 Hardness 40 to 150 N
4 Disintegration Less than 5 min
5 Friability NMT1%
Example 13: Uniformity of dosage units as prepared in example 10 Table 13
Samples at
Sr. No. different % Assay
time intervals
Tablet 1 98.9
Tablet 2 98.63
Tablet 3 101.38
Tablet 1 101.89
2 Sample 2 Tablet 2 100.62
Tablet 3 101.1
Tablet 1 99.64
3 Sample 3 Tablet 2 99.29
Tablet 3 99.39
Tablet 1 100.94
4 Sample 4 Tablet 2 100.68
Tablet 3 101.08
Tablet 1 101.74
5 Sample 5 Tablet 2 101.26
Tablet 3 101.97
Tablet 1 101.47
6 Sample 6 Tablet 2 100,69
Tablet 3 100.64
Tablet 1 100.68
7 Sample 7 Tablet 2 100.06
Tablet 3 101.18
Tablet 1 101.14
8 Sample 8 Tabtel2 101.85
Tablet 3 101.45
9 Mean 10.74
10 Min 98.63
11 Max 101.97
12 % RSD 0.95
Example 14: Stability data of the tablets as prepared in example 10 Table 14
Rasagiline tablets 1 mg Accelerated (40°C / 75% RH)
Parameters Initial 1M 2M 3M
Assay 97.04% 96.25 % 96.33% 97.1%
Dissolution (30 min) 98.8 94.8% 96.0 % 97.2%
Related substances
Highest unknown (NMT 0.5%) 0.089% 0.09% 0.093% 0.092%
Total impurities (NMT 1.5%) 0.556% 0.435% 0.46% 0.438%
Example 15: Bio equivalence Study - Summary of the pharmacokinetic parameters for rasagiline tablets 1 mg as prepared in example 10 (Fasting condition)
The composition prepared in example 10 was subjected to bioequivalence studies. An open label, randomized two-treatment, two period, two sequence, two way cross over, single dose, comparative oral bio-availability study i.e. composition of example 10 (1 mg) with Azilect® (Rasagiline tablets-1 mg) of Teva, United States of America under fasting conditions was carried out.
Study design: A balanced, open label, randomized, two-treatment, two-period, two sequence, single dose, crossover comparative bioavailability study under fasting conditions.
Study duration: 10 days including the wash out period for at least 7 days between two periods.
Investigational products:
Test product: Rasagiline tablets 1 mg (Example 10) Reference product. Azilect tablets 1 mg (Mfg by.Teva)
No. of subjects: Sufficient no. of subjects were enrolled to dose 12+2(stand by) in each group.
Drug administration: After an overnight fast of at least 10 hrs, dosing was done with 240 ml of water at ambient temperature. In each study period a single dose of Rasagiline tablet (1 mg) was administered to the subjects. Subjects receiving the test product in one study period received the reference product (Azilect® 1 mg) in the other period. Subjects were instructed not to chew or crush the tablets.
Blood Sample collection: A total of 17 samples were taken per period at 0.16, 0.33, 0.50, 0.67,0.87, 1.0, 1.25, 1.5,2.0,3.0,4.0,5.0, 6.0, 8.0, 10.0 and 12.0 hrs post dose.
Pharmacokinetic parameters: Employing the estimated plasma concentration time profile of rasagiline, pharmacokinetic parameters like C max, AUC 0->.Auc o-inf, were calculated.
The results of the above bioequivalence studies at fasting condition are given in Table 15.
Table 15
Parameter Ratio 90 % CI
Lower Upper
Cmas 99.17 80.88 121.60
AUCo-4 107.06 95.88 119.54
AUC o-inf 107.14 96.06 119.49
So it can be seen that the composition of the present invention is bioequivalent to the commercially available Rasagiline tablet in the United States of America i.e. Azilect®.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above- described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
We claim:
1. A stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, wherein the carrier is selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof; and wherein the said composition is free of pentahydric or hexahydric alcohols.
2. A stable oral pharmaceutical composition according to claim 1, wherein the said composition is bioequivalent to the commercially available formulation in US i.e. Azilect® tablets.
3. A stable oral pharmaceutical composition according to claim 1, wherein the said composition relates to a stable oral pharmaceutical composition comprising rasagiline or its pharmaceutically acceptable salt thereof with a pharmaceutically acceptable polysaccharide(s) wherein the composition is free of pentahydric or hexahydric alcohols.
4. A stable oral pharmaceutical composition according to claim 1, wherein a polyhydric alcohol is selected from maltitol or lactitol.
5. A stable oral pharmaceutical composition according to claim 1, wherein disaccharide(s) are selected from sucrose or maltose or mixtures thereof.
6. A stable oral pharmaceutical composition according to claim 1, wherein polysaccharide(s) are selected from starch or crystalline cellulose like microcrystalline cellulose or mixtures thereof.
7. A process for the preparation of a stable oral pharmaceutical composition of rasagiline or a pharmaceutically acceptable salt thereof comprising:
(i) Solubilizing rasagiline in a solvent,
(ii) Using a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof,
(iii) Manufacturing a pharmaceutical dosage form of rasagiline by using (i) and (ii), wherein the said composition is free of pentahydric or hexahydric alcohols.
8. A process according to claim 7, wherein the said process comprises:
(i) Solubilizing rasagiline in a solvent,
(ii) Granulating a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof with the solution of (i), and optionally pharmaceutically acceptable excipients,
(iii) Drying the granulate of (ii) and blending with extra granulate material,
(iv) Compressing or encapsulating the blend of (iii) to convert into a pharmaceutical dosage form, wherein the said composition is free of pentahydric or hexahydric alcohols.
9. A process according to claim 7, wherein the said process comprises:
(i) Solubilizing rasagiline in a solvent,
(ii) Coating a suitable pharmaceutically acceptable carrier selected from a polyhydric alcohol, disaccharide(s) and polysaccharide(s) or mixtures thereof with the solution of (i), wherein the said composition is free of pentahydric or hexahydric alcohols.