Field of the invention
The present invention relates to stable composition of ginkgo biloba extract and methylcobalamine combination and process of preparation thereof.
Background of the Invention
Extracts of Ginkgo biloba leaves have been used therapeutically for about 30 years. Phytopharmaceutical extracts from the leaves of Ginkgo biloba have been used to treat cerebrovascular and peripheral vascular diseases in many countries. The extract contains approximately 24% flavone glycosides (primarily composed of quercetin, kaempferol, and isorhamnetin) and 6% terpene lactones (2.8-3.4% ginkgolides A, B, and C, and 2.6-3.2% bilobalide). Ginkgolide B accounts for about 0.8% of the total extract, and bilobalide accounts for about 3% of the extract. Vitamin B12 is used to describe compounds of the cobalt corrinoid family. Methylcobalamine is an active form of Vitamin B12. It is used alone to treat pernicious anemia, and peripheral neuritis, and is used as a dietary supplement. The combination of methylcobalamine with ginkgo biloba extract provides a synergistic effect, as compared to the monotherapy, for proper brain function and optimum health. Compositions containing Ginkgo biloba extract and methyl cobalamine provide mental health, mental energy, mental strength, stress reduction and improved mood.
PCT applications WO05105122, WO2005025587 and Chinese patent application CN1476832A disclose various formulations of ginkgo biloba extract.
PCT application WO9806868 discloses a process for the preparation of a composition comprising natural vitamin B12.
Methylcobalamine is known to be unstable and loses its activity when exposed to light, oxygen and acid or alkali containing environments. In order to overcome the above problems attempts have been made to stabilize methylcobalamine using various formulation techniques, such as, use of ion exchange resins.
It was observed that the tablets comprising the combination of ginkgo biloba extract and methylcobalamine were highly unstable due to incompatibility between ginkgo biloba extract and methytcobalamine. In order to overcome this incompatibility it is advantageous to physically separate the active agents in the composition. Thus the objective of the present invention is to prepare a stable composition comprising the combination of ginkgo biloba extract and methylcobalamine. The present composition avoids direct contact between the two actives,
thereby preventing the incompatibility between ginkgo biioba extract and methylcobalamine. The composition is stable and has desirable release profile.
Summary Of The Invention
According to one embodiment of the specification there is provided a stable composition comprising ginkgo biioba extract, methylcobalamine and one or more pharmaceutically acceptable excipients.
According to another embodiment of the specification there is provided a stable composition consisting of two subunits, wherein a) one subunit comprises ginkgo biioba extract and one or more pharmaceutically acceptable excipients, and b) the second subunit comprises methylcobalamine and one or more pharmaceutically acceptable excipients.
According to further embodiment of the specification there is provided a stable composition consisting of a) granules comprising ginkgo bifoba extract and one or more pharmaceutically acceptable excipients, and b) tablet comprising methylcobalamine and one or more pharmaceutically acceptable excipients.
According to still another embodiment of the specification there is provided a process for the preparation of a stable composition of ginkgo biioba extract and methycobafamine, the process comprising the steps of:
a) preparing one subunit by granulating methylcobalamine and one or more pharmaceutically
acceptable excipients, followed by compression into tablets, and,
b) preparing a second subunit by blending ginkgo biioba extract with pharmaceutically
acceptable excipients followed by granulation to obtain granules, and,
c) filing the tablet of step (a) and the granules of step (b) into capsules to obtain the stable
composition.
Detailed Description of the Invention
The term "ginkgo biioba extract" as used herein and in the appended claims refers to extract from the leaves of Ginkgo biioba. The extract contains approximately 24% flavone glycosides (primarily composed of quercetin, kaempferol, and isorhamnetin) and 6% terpene lactones (2.8-3.4% ginkgolides A, B, and C, and 2.6-3.2% bilobalide).
The term "methylcobalamine" as used herein and in the appended claims refers to an active form of vitamin B12.
The term "stable composition" as used herein and in the appended claims refers to composition of ginkgo biloba extract and methylcobalamine combination wherein the initial assay values of both ginkgo biloba extract and methylcobalamine in the composition is not less than 90% of the label claim.
The composition can be in the form of tablet or capsule. Preferably the composition is a capsule dosage form. The capsule is filled with subunits comprising ginkgo biloba extract and methylcobalamine.
The "subunit" may be in the form of tablet, capsule, granules or blend comprising either ginkgo biloba extract or methylcobalamine and one or more pharmaceutically acceptable excipients.
The "pharmaceutically acceptable excipients" may be selected from one or more of binders, diluents, disintegrants, lubricants/glidants, and solubilizers/wetting agents and such like.
Suitable binders may be selected from one or more of starches such as corn starch, pregelatinized starch and maize starch; cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; sugars such as sorbitol and mannitol.
Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such as powdered cellulose and microcrystalline cellulose; starches such as corn starch, pregelatinized starch and maize starch.
Suitable disintegrants may be selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and such like.
The composition may be prepared by conventional processes known to a person skilled in the art. The subunits in the form of blend, capsule, granules or tablets are prepared first followed by filling of the subunits into capsules. All the ingredients may be blended together to obtain a >lend or the blend may be granulated further (by dry granulation or wet granulation) to obtain he granules. The blend/granules may be either directly filled into capsule or may be compressed into tablets using suitable toolings. Alternatively, the granules can be compressed
to form an inner core containing one active ingredient and subsequently an outer coat of granules containing the other active ingredient can be compressed around the inner core.
The tablet may be optionally coated with a coating composition comprising water soluble polymers and optionally one or more inert pharmaceutically acceptable additives.
The water soluble polymers may be selected from one or more of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellullose and the like. A particularly good film-coating material is hydroxypropyl methylcellulose (HPMC). HPMC may be obtained commercially, for example, from Colorcon Corp., in coating formulations containing additives which serve as coating aids, as Opadry. Opadry formulations may contain lactose, polydextrose, triacetin, polyethylene glycol, polysorbate 80, titanium dioxide, and one or more dyes or lakes.
The inert pharmaceutically acceptable additives include one or more of plasiticizers, viscosity modifiers, flow aids and colorants.
According to one embodiment, the process for the preparation of a stable composition of ginkgo biloba extract and methycobalamine comprises the steps of:
a) preparing one subunit by granulating methylcobalamine and one or more pharmaceutically
acceptable excipients, followed by compression into tablets, and,
b) preparing a second subunit by blending ginkgo biloba extract with pharmaceutically
acceptable excipients followed by granulation to obtain granules, and,
c) filling the tablet of step (a) and the granules of step (b) into capsules to obtain the stable
composition.
According to another embodiment, the process for the preparation of a stable composition of ginkgo biloba extract and methycobalamine comprises the steps of:
a) preparing one subunit by granulating ginkgo biloba extract and one or more pharmaceutically
acceptable excipients, followed by compression into tablets, and,
b) preparing a second subunit by blending methylcobalamine with pharmaceutically acceptable
excipients followed by granulation to obtain granules, and,
c) filling the tablet of step (a) and the granules of step (b) into capsules to obtain the stable
composition.
According to still another embodiment, the process for the preparation of a stable composition of ginkgo biloba extract and methycobalamine comprises the steps of: preparing one subunit by blending ginkgo biloba with pharmaceutically acceptable excipients
followed by granulation to obtain granules, and,
a) preparing a second subunit by blending methylcobalamine with pharmaceutically acceptable
excipients followed by granulation to obtain granules, and,
b) filling the granules of step (a) and the granules of step (b) into capsules to obtain the stable
composition.
According to still another embodiment, the process for the preparation of a stable composition of ginkgo biloba extract and methycobalamine comprises the steps of:
a) preparing one subunit by granulating methylcobalamine and one or more pharmaceutically
acceptable excipients, followed by compression into tablets and coating to obtain coated
tablets, and,
b) preparing a second subunit by blending ginkgo biloba extract with pharmaceutically
acceptable excipients followed by granulation to obtain granules, and,
c) filling the coated tablet of step (a) and the granules of step (b) into capsules to obtain the
stable composition.
The composition after preparation retained the potency or percentage purity of both ginkgo biloba extract and methylcobalamine. The composition may be stable even after storage at room temperature and humidity conditions for at least about two months.
The following non-limiting examples illustrate the composition comprising ginkgo biloba extract and methylcobalamine disclosed in various embodiments of the specification.
Comparative Example 1: Ginkgo biloba extract and methylcobalamine tablets

(Table Removed)
* Quantity of methylcobalamine contains 100 % Overages
** The given quantities include 10 % extra to compensate Processing losses.
Manufacturing Process
1. Ginkgo biloba extract, microcrystalline cellulose and lactose monohydrate were sifted
together through 18 mesh BSS and premixed to obtain a blend.
2. Methylcobalamine and maize starch were sifted and mixed geometrically to obtain a
blend.
3. The blend of step 1 was granulated with starch paste to obtain granules.
4. The granules of step 3 were dried at 40-50°C and sifted through #22BSS mesh
5. Extragranular microcrystalline cellulose, maize starch, croscarmellose sodium and
colloidal silicon dioxide were sifted through # 44 BSS mesh to obtain a blend.
6. Granules of step 4 and blend of step 2 & 5 were mixed together for 10 min
7. Magnesium stearate was sifted through #44 BSS mesh and mixed with blend of step 6
for 3 min to obtain a mixture.
8. The mixture of step 7 was compressed using approved punches to obtain tablets.
9. Hydroxy propyl methylcellulose, titanium dioxide, talc, polyethylene glycol and lake of
sunset yellow IH were added with stirring in purified water to obtain a coating solution.
10. The tablets of step 8 were coated using coating solution obtained in step 9.
Stability Data For Comparative Example 1 The assay values are:
(Table Removed)
The initial stability data was not satisfactory due to incompatibility between ginkgo biloba extract and methylcobalamine in the composition. Further stability studies were not performed.
Example 1: Ginkgo Biloba Extract And Methylcobalamine Capsules I. Methylcobalamine Tablet:

(Table Removed)
* Quantity of methylcobalamine contains 100 % Overages II. Ginkgo Biloba Granules:

(Table Removed)
Brief Manufacturing Process
I. METHYLCOBALAMINE TABLET:
1. Microcrystalline Cellulose and Pregelatinized Starch were sifted through #44 BSS Mesh
to obtain a blend.
2. Methylcobalamine was Geometrically mixed with the blend of Step 1.
3. Colloidal Silicon Dioxide and Magnesium Stearate were sifted through # 44 BSS Mesh
4. The Step 2 material was mixed with Step 3 material for 5 min to obtain a blend.
5. The blend of step 4 was compressed using the approved punch tooling to obtain tablets.
6. Hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol were added with
stirring in purified water to obtain a coating solution.
7. The tablet of step 5 was coated using the coating solution obtained in step 6.
II. GINKGO BILOBA EXTRACT GRANULES:
1. Ginkgo Biloba extract, Microcrystalline Cellulose and Pregelatinized starch were sifted
through # 44 BSS Mesh and mixed for 10 minutes to obtain a blend.
2. The blend of step 1 was granulated using water to obtain granules.
3. The granules of step 2 were dried at temperature of 50°C - 60°C.
4. The dried granules of step 3 were sifted through # 30 BSS Mesh.
5. Talc and Magnesium Stearate were sifted through # 44 mesh.
6. The Step 4 material was lubricated using Step 5 material for 5 minutes.
III. GINKGO BILOBA EXTRACT + METHYLCOBALAMINE CAPSULE:
1. One methylcobalamine tablet was placed in each capsule.
2. The capsule was filled to the desired weight using the Ginkgo Biloba extract granules.
Stability Data For Example 1 The assay values noted are:
(Table Removed)
The above data shows that ginkgo biloba extract and methylcobalamine are stable in the composition, soon after preparation. Further, the composition showed acceptable potency even after storage for about two months.

WE CLAIM:
1. A stable composition comprising ginkgo biloba extract, methylcobalamine and one or
more pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein the composition consists of two subunits,
wherein

a) one subunit comprises ginkgo biloba extract and one or more pharmaceutically
acceptable excipients, and,
b) the second subunit comprises methylcobalamine and one or more pharmaceutically
acceptable excipients.

3. The composition according to claim 2, wherein the pharmaceutically acceptable
excipients are selected from one or more of binders, diluents, disintegrants, surfactants
and lubricants.
4. The composition according to claim 3, wherein binder is selected from one or more of
starches selected from corn starch, pregelatinized starch or maize starch; cellulose
derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose or
methylcellulose; gums selected from xanthan gum, gum acacia or tragacanth; water-
soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone or copolymer of
vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol or mannitol.
5. The composition according to claim 3, wherein the diluent is selected from one or more
of sugars selected from dextrose, glucose or lactose; sugar alcohols selected from
sorbitol, xylitol or mannitol; cellulose derivatives selected from powdered cellulose or
microcrystalline cellulose; and starches selected from corn starch, pregelatinized starch
or maize starch.
6. The composition according to claim 3, wherein the disintegrant is selected from one or
more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
7. The composition according to claim 2, wherein the subunit is selected from one or more
of tablets, capsule, granules or blend.
8. The composition according to claim 2, wherein the composition consists of a) granules
comprising ginkgo biloba extract and one or more pharmaceutically acceptable
excipients, and b) tablet comprising methylcobalamine and one or more
pharmaceutically acceptable excipients.
9. A process for the preparation of a stable composition of ginkgo biloba extract and
methycobalamine, the process comprising the steps of:
a) preparing one subunit by granulating methylcobalamine and one or more
pharmaceutically acceptable excipients, followed by compression into tablets,
and,
b) preparing a second subunit by blending ginkgo biloba extract with
pharmaceutically acceptable excipients followed by granulation to obtain
granules, and,
c) filling the tablet of step (a) and the granules of step (b) into capsules to obtain the stable composition.
10. A stable composition comprising ginkgo biloba extract and methylcobalamine
substantially described and exemplified herein.