The present invention relates to a pharmaceutical composition comprising L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract. The present invention relates to a pharmaceutical composition comprising L-Camosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract, wherein at least one active ingredient is in controlled release form. The present invention relates to a controlled release pharmaceutical composition comprising L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract.

BACKGROUND OF INVENTION

Oxidative stress, ion balance and pH balance are some the most critical factors involved in the major acute and chronic physiological imbalance. The depletion of powerful antioxidant renders cells particularly vulnerable to oxidative stress. The resulting damage is the key step in the onset and progression of many disease states.

Degenerative nerve diseases relates to progressive damage to the neurons in the nervous system. Several nervous disorder includes Alzheimer's disease (AD), Parkinson's disease (PD), Dementia and so on. Several endogenous and exogenous compound are known to protect against oxidative stress and apoptosis. These endogenous and exogenous compound are helpful in management and prevention of degenerative nerve diseases.

L-Carnosine is used as protective agent for many therapies. Ginkgo Biloba extract reduces oxidative damage and stimulates cell survival. While both these compounds are known to be administrated individually for their respective mechanism of action, administration with immediate release has a limitation of multiple daily administration leading to fluctuating plasma concentrations.

Therefore, there is an urgent need for the improved controlled delivery therapy with pharmaceutical composition comprising L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract which can delivery either or both active ingredients in controlled manner.

Till date, pharmaceutical composition comprising L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract, wherein at least one or both active ingredient are in controlled release form, are not known.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical composition comprising L- Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract. The present invention relates to pharmaceutical composition comprising L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract, wherein at least one active ingredient is in controlled release form. The present invention relates to a controlled release pharmaceutical composition comprising L-Camosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract. The active ingredient as per present invention are used in therapeutically effective amount.

“Therapeutically effective amount” or “effective amount” refers to the amount of a pharmaceutically active agent when administered, is sufficient to affect such prevention or treatment. The therapeutically effective amount will vary depending on the disease and its severity, and the age, weight, and other conditions of the patient to be treated. The term “pharmaceutical compositions” herein refers to any composition for administration to human or animal by any route and includes but are not limited to delayed release, extended release and pulsed-release.

The term “immediate release” herein refers to any composition for administration to human or animal which releases active ingredient upon administration immediately.

The term “controlled release” herein refers to any composition for administration to human or animal which is not immediate release and includes extended release, delayed release and pulsatile release.

In an embodiment, the present invention relates to a pharmaceutical composition comprising a. therapeutically effective amount of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and b. Ginkgo Biloba extract, wherein at least one active ingredient is in controlled release form.

In an embodiment, the present invention relates to a pharmaceutical composition comprising a. therapeutically effective amount of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and b. Ginkgo Biloba extract, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in controlled release form.

In an embodiment, the present invention relates to a pharmaceutical composition consisting of a. therapeutically effective amount of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and b. Ginkgo Biloba extract, wherein at least one active ingredient is in controlled release form.

In an embodiment, the present invention relates to a controlled release pharmaceutical composition comprising c. therapeutically effective amount of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and d. Ginkgo Biloba extract.

In an embodiment, the present invention relates to a controlled release pharmaceutical composition consisting of c. therapeutically effective amount of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof, and d. Ginkgo Biloba extract.

In a preferred embodiment, the present invention relates to a pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein at least one active ingredient is in controlled release form.

In a preferred embodiment, the present invention relates to a pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in controlled release form. In a preferred embodiment, the present invention relates to an oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein at least one active ingredient is in controlled release form.

In a preferred embodiment, the present invention relates to an oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in controlled release form and wherein said composition is a bilayer tablet.

In a preferred embodiment, the present invention relates to an oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in controlled release form and wherein said composition comprises comprises Hydroxy Propyl Methyl cellulose as extended release polymer. In a preferred embodiment, the present invention relates to an oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in controlled release form and wherein said composition releases less than 90% L-Carnosine or pharmaceutically acceptable salts or derivatives thereof after 8 hours in 6.8 pH phosphate buffer.

In a preferred embodiment, the present invention relates to an oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg, wherein L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in extended release form and wherein said composition is a bilayer tablet.

In a preferred embodiment, the present invention relates to a controlled release pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg.

In a preferred embodiment, the present invention relates to a controlled release oral pharmaceutical comprising a. L-Carnosine or pharmaceutically acceptable salts or derivatives thereof in an amount equivalent to 50 mg to 400 mg of L-Carnosine, and b. Ginkgo Biloba extract in an amount of 20 mg to 200 mg.

In one or more embodiments, a pharmaceutical composition as per present invention includes delayed release, extended release, pulsatile release or combination thereof.

In one or more embodiments, a pharmaceutical composition as per present invention comprises active ingredients in homogenous mixture or physically separated compartments.

In one or more embodiments, a pharmaceutical composition as per present invention comprises L-Carnosine or pharmaceutically acceptable salts or derivatives thereof are in extended release form.

In one or more embodiments, a pharmaceutical composition as per present invention includes for oral, intravenous or other routes of administration.

In one or more embodiments, a pharmaceutical composition as per present invention includes solid, liquid, semisolid or other dosage forms.

In one or more embodiments, the present invention also relates to a process for preparation of a pharmaceutical composition wherein said process comprises step of a. Preparing granules of L-Carnosine or pharmaceutically acceptable salts or derivatives thereof with at least one controlled release excipient, b. Preparing granules of Ginkgo Biloba extract, c. Processing granules of step (a) and step (b) into bilayer tablet. In a preferred embodiments, a process as per present invention involves non aqueous solvent granulation.

L- Carnosine

Carnosine is an endogenous dipeptide, composed of b-alanine and L- histidine. Carnosine has pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. Carnosine is found naturally mainly in the skeletal muscles, central nervous system, olfactory neurons and in the lens of the eye in some vertebrates, including humans.

It has been suggested that carnosine may be involved in the prevention and therapy of oxidative driven disorders, including neurodegenerative diseases and hypoxic-ischemic damage of CNS. Carnosine treatment has been reported to improve glucose metabolism as well as spatial recognition memory, retention and recall. It has also been reported to have pronounced neuroprotective action on Parkinson’s disease increasing efficiency of basic therapy and suppressing beta amyloid peptide toxicity in Alzheimer’s disease.

In one or more embodiments, L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in the equivalent therapeutically effective amount of L-Carnosine. In a preferred embodiment, L-Carnosine or pharmaceutically acceptable salts or derivatives thereof is in an amount equivalent to 50mg to 400mg of L-Camosine.

Ginkgo Biloba Extract

Ginkgo Biloba is the leaf extract primarily for China. It has antioxidant, anti-apoptotic, anti-ageing properties. In ancient and modem Chinese herbal pharmacopoeia, it is indicated for treatment for heart and lung complications. In US and Europe, it is used for its protective effect on neuron in de-generative dementias of the Alzheimer type. Dementia is a chronic or progressive condition characterized by impaired cognitive capacity.

Ginkgo Biloba Extract mainly contains 22.0 - 27.0% flavonoids, calculated as flavonoid glycosides and terpenoids, terpenoids consisting of bilobalide and the ginkgolides (2.6 - 3.2% bilobalide and 2.8 - 3.4% ginkgolides A, B and C). Usually administered doses of Ginkgo Biloba extract is 120-240 mg/day divided into 2 or 3 doses with meals. It has time to peak plasma concentration (Tmax) of 1 to 2 hours and shorter plasma half-life of ginkgolide A (3 to 4 hours) and B (4 to 6 hours) and bilobalide (2 to 3 hours) with primary excreted in the urine unchanged. Multiple daily doses lead to non-uniform plasma levels of its content in the body.

In one or more embodiments, Ginkgo Biloba Extract is in an amount of 20 mg to 200 mg.

Pharmaceutical Composition

L-Carnosine is the antioxidant with neuroprotective effect through involvement in endogenous pathway. Gingko biloba extract is a herbal exogenous antiapoptotic agent with directly neuroprotective effect. The present invention relates to a pharmaceutical composition comprising L-Camosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract, wherein at least one active ingredient is in controlled release form. The present invention relates to a controlled release pharmaceutical composition comprising L- Carnosine or pharmaceutically acceptable salts or derivatives thereof, and Ginkgo Biloba extract.

The pharmaceutical composition as per present invention contains Ginkgo Biloba extract and L-Carnosine in the ratio between 1:1 and 1:6. In one embodiment, the pharmaceutical composition as per present invention contains Ginkgo Biloba extract and L-Camosine in an amount of 60mg;200mg, 90mg;300mg and 120mg; 400mg.

The pharmaceutical compositions are the different type of medicinal preparation designed for the administration of targeted one or more drugs. The pharmaceutical compositions as per present invention includes immediate release, delayed release, extended release and pulsed-release. The pharmaceutical compositions can be prepared using uniform mixture of two or more drugs. In one or more embodiments, pharmaceutical composition can be prepared with one or more drugs in separate compartment within a single dosage form. The pharmaceutical compositions as per present invention can be administered by oral, intravenous or other routes of drug administration. The pharmaceutical compositions as per present invention can be solid, liquid, semisolid or any other dosage form. The pharmaceutical compositions as per present invention can be prepared as one or more drug in modified release and other drugs as immediate release in single dosage form.

The oral pharmaceutical dosage form are tablets, capsules, suspensions, powders and granules, multi-particulate dosage forms and the likes. The multicompartment dosage form are bilayer tablets, capsule-in-capsule, tablet-in capsule and any other dosage form. The pharmaceutical compositions can be formulated by any techniques known to or appreciated by a person skilled in the art

The controlled release excipients as per present invention includes enteric polymer, sustained release polymers, natural polysaccharides, wax. The representative controlled release agents are hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, polyethylene glycol, sodium alginate and so on. In an embodiment, the oral pharmaceutical composition further includes optionally any one or a combination of one or more pharmaceutically acceptable excipients, such as but not limited to carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants and solubility enhancers.

Having described the invention with reference to the different embodiments of the invention, other embodiments will become apparent to one skilled in the art from consideration of the specifications.

The innovation is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to the composition and treatment, may be practiced without departing from the scope of this invention.

EXAMPLE - 1

Representative tablet composition of L- Camosine and Ginkgo Biloba extract

EXAMPLE - 2

Representative capsule composition of L- Carnosine and Ginkgo Biloba extract

EXAMPLE - 3

Representative capsule composition of L- Carnosine and Ginkgo Biloba extract

EXAMPLE - 4

Each film coated bilayer tablet Contains: Ginkgo biloba 60 mg (as immediate release form) and L-Camosine 200 mg (as sustained release form)

L- Carnosine (SR) Layer:

Mix L-Carnosine, Hydroxy Propyl Methyl cellulose (K4-M), Microcrystalline Cellulose (PH-101) and Dicalcium Phosphate dihydrate into the RMG.

Add the Povidone IPA binder solution slowly in to RMG to get uniform granulated mass. Sift the semi dried granules and dried granules through 20# mesh sieve and collect into a poly bag.

Sift Hydroxy Propyl Methyl cellulose (K-100), Colloidal Silicon di oxide, Croscarmellose sodium and Sodium stearyl fumarate through 40# mesh sieve and collect into a poly bag Transfer the 20# mesh sifted dried granules into the blender and add the total sifted (40 # mesh) quantity of Hydroxy Propyl Methyl cellulose (K-100), Colloidal Silicon di oxide, Croscarmellose sodium and Sodium stearyl fumarate into the blender and mix for 15min at 10 RPM.

Sift total dispensed quantity of Magnesium stearate through 40# mesh sieve and transfer into the above blender and mix for 5min at 10 RPM.

Collect the sifted dried granules in poly bags.

Ginkgo Biloba Layer:

Sift Ginkgo Biloba Extract, Microcrystalline cellulose (PH -102), Crospovidone (XL- 10) through 40# mesh sieve and collect into a poly bag and transfer the sifted dry mix part into the RMG and mix for 15min with impeller at slow speed and Chopper off.

Add the Povidone IPA binder solution slowly in to RMG to get uniform granulated mass.

Dry the above wet mass. Sift the semi dried granules and dried granules through 20# mesh sieve and collect into a poly bag.

Sift Crospovidone (XL- 10, Colloidal Silicon di oxide, Polacrilin Potassium and Sodium stearyl fumarate through 40# mesh sieve and collect into a poly bag Transfer the 20# mesh dried sifted granules into the blender and add the total sifted (40 # mesh) quantity of Crospovidone (XL- 10), Colloidal Silicon di oxide, Polacrilin Potassium and Sodium stearyl fumarate into the blender and mix for 15min at 10 RPM.

Sift total dispensed quantity of Magnesium stearate through 40# mesh sieve and transfer into the above blender and mix for 5min at 10 RPM.

Collect the sifted dried granules in a poly bags and labeled with product identity.

Compression and Coating

The above lubricated blend (L- Carnosine (SR) Layer and Ginkgo Biloba Layer) compressed using caplet shaped, slightly biconvex with break line on one side and plain on another side punch. The compressed tablets are coated with Insta sol. Dissolution for L-Carnosine using 6.8 pH phosphate buffer. (USP 2; Volume 900ml, 50RPM)