Claims:CLAIMS

We claim

1. A nutraceutical vegetarian capsule formulation comprising Phosphatidylserine, one or more nutraceutical ingredient selected from selected from the group consisting of Acetylcarnitine, N-Acetyl Cysteine, Alpha Lipoic Acid, Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine and one or more inactive ingredient.

2. The nutraceutical vegetarian capsule formulation as claimed in claim 1, wherein Phosphatidylserine is present in the range from 25 mg to 150 mg, more preferably is in the range from 35 mg to 125 mg.

3. The nutraceutical vegetarian capsule formulation as claimed in claim 1, comprising 125 to 325 mg of Acetylcarnitine, 50 to 250 mg of N-Acetyl Cysteine, 50 to 200 mg of Alpha Lipoic Acid, 10 to 100 mg of Ginkgo Biloba Extract, 1 to 15 mg of Vinpocetin, 550 to 950 mcg of Cyanocobalamin and 10 to 150 mcg of Huperzine.

4. The nutraceutical vegetarian capsule formulation as claimed in claim 1, wherein inactive ingredient is selected from diluent, binder, disintegrant, lubricant, anti adherent and glidant.

5. The nutraceutical vegetarian capsule formulation as claimed in claim 1, wherein capsule shell is of HPMC or carrageenan.

6. The nutraceutical vegetarian capsule formulation as claimed in claim 1, wherein the formulation is prepared by dry granulation, direct compression, or wet granulation.

7. A nutraceutical vegetarian capsule formulation comprising 25 to 150 mg of Phosphatidylserine, 125 to 325 mg of Acetylcarnitine, 50 to 250 mg of N-Acetyl Cysteine, 50 to 200 mg of Alpha Lipoic Acid, 10 to 100 mg of Ginkgo Biloba Extract, 1 to 15 mg of Vinpocetin, 550 to 950 mcg of Cyanocobalamin and 10 to 150 mcg of Huperzine and one or more inactive ingredients.

8. A nutraceutical vegetarian capsule comprising 50 to 100 mg of Phosphatidylserine, 150 to 300 mg of Acetylcarnitine, 75 to 200 mg of N-Acetyl Cysteine, 75 to 150 mg of Alpha Lipoic Acid, 20 to 60 mg of Ginkgo Biloba Extract, 2 to 10 mg of Vinpocetin, 650 to 850 mcg of Cyanocobalamin and 20 to 100 mcg of Huperzine and one or more inactive ingredients.

9. The nutraceutical vegetarian capsule formulation as claimed in any preceding claims, prepared by process comprising the steps of
a. Mixing Acetylcarnitine, N-Acetyl Cysteine, and diluent
b. Granulating mixture of step a) with binding solution followed by drying and sifting the granules,
c. Mixing Alpha Lipoic Acid with another diluent,
d. Granulating mixture of step c) with binding solution followed by drying and sifting the granules,
e. Mixing the granules of step b) and d) with Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine,
f. Mixing the lubricant, glidant and anti-adherent to mixture of step e) and
g. filling the mixture of step f) in vegetarian capsule shell.

10. The nutraceutical vegetarian capsule formulation as claimed in any preceding claims, wherein the formulation is used for the prophylactic and treatment of cognitive impairment, including Alzheimer's disease, age-associated memory impairment and some non-Alzheimer's dementias.

Dated this 07th October 2020
, Description:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – A NUTRACEUTICAL VEGETARIAN CAPSULE FORMULATION
2. Applicant(s)
NAME: TRION PHARMA INDIA LLP
NATIONALITY: INDIAN
ADDRESS: B/19 FIRST FLOOR, BARCELLONA MULTIPLE BUSINESS, SP RING ROAD CIRCLE, ODHAV, AHMEDABAD 382415 GUJARAT

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed.

A NUTRACEUTICAL VEGETARIAN CAPSULE FORMULATION

FIELD OF THE INVENTION

The present invention provides a nutraceutical vegetarian capsule formulation. The present invention in particular provides a nutraceutical vegetarian capsule formulation comprising Phosphatidylserine, one or more nutraceutical ingredient filled in vegetarian capsule. The present invention also provides the process for preparing a nutraceutical vegetarian capsule formulation.

BACKGROUND OF THE INVENTION

Glycerophospholipid, also called phospholipid, is widely present in nature, is a key component of the cell lipid bilayer, and is involved in cell metabolism and signal transduction. The hydroxyl group of the glycerol backbone of the phospholipid is replaced by a hydrophilic phosphate head and a hydrophobic tail that constitutes a nonpolar fatty acid. Glycerophospholipids can be subdivided into different classes based on the nature of the polar head such as, for example, phosphatidylcholine (also referred to as PC or lecithin), phosphatidylethanolamine (PE) and phosphatidylserine (PS). In addition to serving as a major component of the cell membrane and binding to sites for intracellular and intercellular proteins, some glycerophospholipids, such as phosphatidylinositol and phosphatidic acid, are membrane-induced secondary signaling agents or are themselves precursors. Animal studies have shown that PS enhances neuronal membrane function and therefore slows cognitive decline, especially in the elderly [McDaniel MA et al. Nutrition 19: 957-75 (2003) and Jorissen BL et al. Nutr Neurosci. 4 (2): 121-34 (2001)].

Phospholipids (PL) are very common substances in the biological world. They make up the membrane in most cells in both plants and animals. These lipids are organized in double layer structures serving as barriers between the various compartments and providing the proper environment for receptors, enzymes and transport proteins. They also serve as transmitters for communication between cells. A great part of the brain is made up by phospholipids. 15 % of the human brain phospholipids pool consists of phosphatidylserine (PS). As brain ages, material is lost and replaced by inactive substances like cholesterol.

PS has lately been shown great interest as an active component in nutraceutical foods for improved cognitive performance, counteraction of memory loss and as a stress release agent. The literature is exemplified by article of Benton et al. Nutritional Neuroscience, Vol. 4 pp 169-178 with title "The influence of Phosphatidylserine Supplementation on Mood and Heart Rate when Faced with an Acute Stressor ".

JP2007506733 discloses a blend of lecithin and phospholipid as an additional component with respect to phosphatidylserine. JP-A-7-238086 discloses a composition for deodorizing phosphatidylserine. JP-A-5-139957 discloses a degreased emulsion containing phosphatidylserine using lecithin.

US8324187B2 describes a stable PS preparations, in powder, liquid and dispersion forms, as well as methods of producing thereof. Most importantly, the stable PS preparations are particularly devoid of residual phospholipase D activity, and the methods of eliminating such activity are also described herein. Lastly, uses of these PS preparations in nutraceuticals or as active agents of pharmaceutical compositions are also provided herein.

Japanese Patent Application 2001-48743 and Japanese Patent 2005-263668 disclose a technique related to an aqueous solution in which lysolecithin and sucrose ester are dissolved in water. Japanese Patent Application 2004-154060 discloses a technique related to a solubilizing solution containing polyglycerin fatty acid ester, sucrose fatty acid ester, and organic acid monoglyceride. Since these solutions are aqueous solutions, when filled as a soft capsule, the film is dissolved due to moisture transfer to the capsule film, and thus cannot be applied to the soft capsule.

JP2003095953A phosphatidylserine-containing composition comprises a phosphatidylserine-containing substance, the medium-chain fatty acid triglyceride and the ethanol. The phosphatidylserine-containing composition described in claim 1 comprises 5-70 wt.% of the phosphatidylserine-containing substance, 4-60 wt.% of the medium-chain fatty acid triglyceride and 0.5-60 wt.% of the ethanol.

However there is still a need for the development to have a stable and effective formulation of nutraceutical ingredients mainly of phosphatidylserine with other nutraceutical ingredient in vegetarian capsule form to provide synergistic effect.

Inventors of present invention have surprisingly developed and found that nutraceutical formulation of phosphatidylserine with other nutraceutical ingredient can be formulated with specific formulation, concertation and process as described herein.

OBJECTIVE OF THE INVENTION

The main objective of the invention is to provide a stable nutraceutical vegetarian capsule formulation.

The other objective of the invention is to provide a nutraceutical vegetarian capsule formulation which is having good bioavailability.

Yet another objective of the invention is to provide a nutraceutical vegetarian capsule formulation which is easy to manufacture.

Yet another objective of the invention is to provide a nutraceutical vegetarian capsule formulation which is showing synergistic effect.

SUMMARY OF THE INVENTION

The present invention is related to a nutraceutical vegetarian capsule formulation.

The main aspect of the invention is to provide Phosphatidylserine, one or more nutraceutical ingredient selected from selected from the group consisting of Acetylcarnitine, N-Acetyl Cysteine, Alpha Lipoic Acid, Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine and one or more inactive ingredient.

Another aspect of the invention is to provide the process for preparing nutraceutical vegetarian capsule formulation.

DESCRIPTION OF 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 the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As used herein, the term "formulation" or “composition” unless otherwise defined refers to capsule formulation.

As used herein, whether in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components.

The term “synergistic effect on the prevention, reduction or / and treatment of epileptic seizures” refers to the prevention of epileptic seizures that are beyond additive compared to the effect of compound (a) or (b) provided alone.

As used herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

The term “about” is used herein to means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” or “approximately” is used herein to modify a numerical value above and below the stated value by a variance of 20%.

As used herein the term “Nutraceutical” is defined as any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease (DeFelice, 1994).

As used herein the term “vegetarian capsule” means the capsule shell made up of non-animal origin.

The present invention is described about the nutraceutical vegetarian capsule formulation.

As per one main embodiment of the present invention, it provides a nutraceutical vegetarian capsule formulation comprising Phosphatidylserine, one or more nutraceutical ingredient selected from selected from the group consisting of Acetylcarnitine, N-Acetyl Cysteine, Alpha Lipoic Acid, Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine and one or more inactive ingredient
Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. Phosphatidylserine is a fatty substance produced in the body that covers and protects every cell in the body, and is involved in the clotting function of the body. It's particularly vital for the proper functioning of nerve cells within the brain, helping to transmit messages between them. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine in reactions are catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function.

Phospholipids, which surround all of our cells, are essential molecules that provide cellular structure and protection. A phospholipid molecule is constructed from four components: fatty acids, a platform to which the fatty acids are attached, a phosphate and an alcohol attached to the phosphate. Phospholipids line up and arrange themselves into two parallel layers known as a phospholipid bilayer. This is the layer that makes up your cell membranes and is critical to each of your cell’s ability to function

Acetylcarnitine is a small molecule of growing interest for its biological and pharmacological properties. Originally, Acetylcarnitine primary function was attributed to its role in the transport of short- and medium-chain acyl groups outside mitochondria, a step required for utilization of fatty acids and glucose

Acetylcysteine (also known as N-acetylcysteine or N-acetyl-L-cysteine or NAC) is primarily used as a mucolytic agent and in the management of acetaminophen poisoning. It is a derivative of cysteine with an acetyl group attached to the amino group of cysteine. NAC is essentially a prodrug that is converted to cysteine (in the intestine by the enzyme aminoacylase 1) and absorbed in the intestine into the blood stream. Cysteine is a key constituent to glutathione and hence administration of acetylcysteine replenishes glutathione stores.

Alpha Lipoic Acid Alpha-lipoic acid or ALA is a naturally occurring compound that's made in the body. It serves vital functions at the cellular level, such as energy production. As long as you're healthy, the body can produce all the ALA it needs for these purposes. Despite that fact, there has been a lot of recent interest in using ALA supplements.

Ginkgo Biloba Extract, Ginkgo biloba has many health benefits. It’s often used to treat mental health conditions, Alzheimer’s disease, and fatigue. It’s been used in traditional Chinese medicine for about 1,000 years. Extracts of ginkgo leaves contain phenolic acids, proanthocyanidins, flavonoid glycosides, such as myricetin, kaempferol, isorhamnetin and quercetin, and the terpene trilactones, ginkgolides and bilobalides. The leaves also contain unique ginkgo biflavones, as well as alkylphenols and polyprenols.

Vinpocetin, Vinpocetine (ethyl apovincaminate) is a synthetic derivative of the vinca alkaloid vincamine. Vincamine is extracted from either the seeds of Voacanga africana or the leaves of Vinca minor (lesser periwinkle).
Cyanocobalamin and

Huperzine (HOOP-ur-zeen) A, a dietary supplement derived from the Chinese club moss Huperzia serrata, is sparking some interest as a potential treatment for Alzheimer's disease. Huperzine A acts as a cholinesterase inhibitor — a type of medication that works by improving the levels of neurotransmitters in the brain.

As per one embodiment, the present formulation also require one or more inactive ingredients which can be selected from diluent, binder, disintegrant, lubricant, anti-adherent and glidant.

Binders impart cohesive properties to the powdered material. Examples of binders suitable for use in the present invention include: starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), polymethacrylates, natural and synthetic gums (e.g., acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein), cellulose derivatives [such as carboxymethyl cellulose and salts thereof, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, and bentonites.

Diluents provide bulk, for example, in order to make the tablet a practical size for processing. Diluents may also aid processing, for example, by providing improved physical properties such as flow, compressibility, and tablet hardness. Because of the relatively high percentage of diluent and the amount of direct contact between the diluent and the active compound in the typical pharmaceutical formulation, the interaction of the diluent with the active compound is of particular concern to the formulator. Examples of diluents suitable for general use include: water-soluble fillers and water-insoluble fillers, such as calcium phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, spray dried or anhydrous lactose, cellulose (e.g., micro crystalline cellulose, powdered cellulose), pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin, powdered sugar, compressible sugar, sucrose, dextrose, and inositol. Suitable diluents for use in this invention include microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol, lactose and maltodextrin or combinations thereof.

Lubricants are generally used to enhance processing, for example, to prevent adhesion of the formulation material to manufacturing equipment, reduce interparticle friction, improve rate of flow of the formulation, and/or assist ejection of the formulations from the manufacturing equipment. Examples of lubricants suitable for use in the present invention include: talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oils, glyceryl behanate, polyethylene glycol, ethylene oxide polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal silica, pyrogenic silica, and hydrated sodium silicoaluminate). In one embodiment of the present invention, the lubricant comprises magnesium stearate.

Anti-adherents function to prevent tablet granulations from sticking to the faces of the punches and the die walls, but most importantly, prevent adherence of tablet granules from adhering to one another, a phenomenon known a-s blocking. Anti-adherents may be added to the tablet composition while the composition is in the hopper, or subsequent to grinding. The anti-adherent is selected from the group consisting of silicates, silicon dioxide, talc, alkali metal phosphates and mixtures thereof. The preferred anti-adherents are fumed silica and talc.

The disintegrant plays an important role in the formulation of solid oral dosage forms of poorly soluble compounds by promoting breakup of the solid oral dosage forms into smaller fragments in an aqueous environment thereby increasing the available surface area and in turn promoting a rapid release of the drug substance

Various disintegrant include, but are not limited, to croscarmellose sodium, carboxymethyl cellulose sodium, crospovidone, polacriiin potassium, sodium starch glycolate and/or combinations thereof.

Glidants for the present invention include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose

There are three commercially important processes for making capsule formulation: wet granulation, direct compression and dry granulation (slugging or roller compaction).

The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for filling in to capsules. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.

In general, powders do not have sufficient adhesive or cohesive properties to form hard, strong granules. A binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation. The large number of processing steps and processing time are problems due to high level manufacturing costs. Wet granulation has also been known to reduce the compressibility of some pharmaceutical excipients, such as microcrystalline cellulose.

Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing was believed to be essential in order to prepare “pharmaceutically acceptable” dosage forms. Some pharmaceutical scientists believe that the manner in which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Excessive blending of lubricants with the granulate ingredients can cause water proofing of the granule and reduces tablet hardness or strength of the compressed tablet. For these reasons, high-shear mixing conditions have not been used to prepare direct compression dosage forms.

As per one preferred embodiment, the nutraceutical formulation of present invention is prepared by wet granulation process.

According to preferred embodiment the solvent selected for the process of doing wet granulation is selected from water, alcohol, hydro alcohol, acetone, dichloromethane, and mixtures thereof.

As per one embodiment, the present invention provides the process for preparing the nutraceutical vegetarian capsule comprising the steps of
a. Mixing Acetylcarnitine, N-Acetyl Cysteine, and diluent
b. Granulating mixture of step a) with binding solution followed by drying and sifting the granules,
c. Mixing Alpha Lipoic Acid with another diluent,
d. Granulating mixture of step c) with binding solution followed by drying and sifting the granules,
e. Mixing the granules of step b) and d) with Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine,
f. Mixing the lubricant, glidant and anti-adherent to mixture of step e) and
g. filling the mixture of step f) in vegetarian capsule shell.

As per one embodiment, the process comprising is wet granulation process and more preferably the wet granulation of two different portion followed by mixing it with other ingredients.

As per one embodiment, the nutraceutical vegetarian capsule of present invention is used for the prophylactic and treatment of cognitive impairment, including Alzheimer's disease, age-associated memory impairment and some non-Alzheimer's dementias.

As per one embodiment, the present invention is to provide a nutraceutical vegetarian capsule formulation comprising 25 to 150 mg of Phosphatidylserine, 125 to 325 mg of Acetylcarnitine, 50 to 250 mg of N-Acetyl Cysteine, 50 to 200 mg of Alpha Lipoic Acid, 10 to 100 mg of Ginkgo Biloba Extract, 1 to 15 mg of Vinpocetin, 550 to 950 mcg of Cyanocobalamin and 10 to 150 mcg of Huperzine and one or more inactive ingredients.

As per another embodiment, the present invention is to provide a nutraceutical vegetarian capsule comprising 50 to 100 mg of Phosphatidylserine, 150 to 300 mg of Acetylcarnitine, 75 to 200 mg of N-Acetyl Cysteine, 75 to 150 mg of Alpha Lipoic Acid, 20 to 60 mg of Ginkgo Biloba Extract, 2 to 10 mg of Vinpocetin, 650 to 850 mcg of Cyanocobalamin and 20 to 100 mcg of Huperzine and one or more inactive ingredients.

The examples are presented to illustrate the invention, parts and percentages being used by weight, unless and otherwise indicated.

EXAMPLES

Example 1: Nutraceutical Formulation

Ingredient Quantity (mg/Capsule)
Acetylcarnitine 225
N-Acetyl Cysteine 125
Calcium Carbonate 10
Ethyl Cellulose 50
Methylene Di Chloride q.s
Alpha Lipoic Acid 100
Light Magnesium Oxide 50
Polyvinylpyrrolidone K –30 1
Acetone q.s
Phosphatidylserine 75
Ginkgo Biloba Extract 30
Vinpocetin 5
Cyanocobalamin 0.75
Huperzine A 0.05
Talc 6
Magnesium stearate 6
Colloidal silicon dioxide (Aerosil) 6
Vegetarian Capsule Shell 1 pc

Procedure:
a. Acetylcarnitine, N-Acetyl Cysteine, and diluent were mixed,
b. Mixture of step a) was granulated with binding solution followed by drying and sifting the granules,
c. Alpha Lipoic Acid was mixed another diluent,
d. Mixture of step c) was granulated with binding solution followed by drying and sifting the granules,
e. the granules of step b) and d) were mixed with Ginkgo Biloba Extract, Vinpocetin, Cyanocobalamin and Huperzine,
f. mixture of step e) were mixed with the lubricant, glidant and anti-adherent followed by filling the mixture in vegetarian capsule shell.