GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF GREEN TEA

FIELD OF THE INVENTION

The present invention relates to gastro retentive dosage form of green tea. The present invention also relates to process for preparing gastro retentive dosage form of green tea.

BACKGROUND OF THE INVENTION

Tea is generally in the form of black, oolong, and green tea, all originating from the tea plant, Camellia sinensis. Tea is cultivated in approximately thirty countries worldwide, and is consumed globally. Although the level of tea consumption varies around the world, it is believed-that tea consumption is second only to water (Ahmad et al., 1998, Nutrition and Chemical Toxicity, John Wiley and Sons, Sussex, England, pp. 301-343). Black tea is consumed predominantly in Western and some Asian countries and green tea is consumed predominantly in China, Japan, India, and a few countries in North Africa and the Middle East (Ahmad et al., 1998, Nutrition and Chemical Toxicity, John Wiley and Sons, Sussex, England, pp. 301-343).

Green tea has been prized as a traditional tonic and has been widely consumed in East Asia. Recent studies have attempted to link green tea to antioxidant benefits including protection against the damage caused by cigarette smoke, pollution, stress, and other toxins (for an overview, see e.g., Mitscher, 1998, The Green Tea Book, Avery Publishing Group, Garden City Park, N.Y. and Weisburger, 1997, Can. Lett. 114:315-317).

An empirical link between green tea and its cancer prevention properties was made in the late 1980s (Khan et al, 1988, Can. Lett. 42:7-12 and Wang et al., 1989, Carcinogenesis 10:411-415). Epidemiological studies show that cancer onset of patients in Japan who had consumed ten cups of green tea per day was 8.7 years later among females and 3 years later among males, compared with patients who had consumed under three cups per day (Fujiki et al., 1998, Mutation Res. 402:307-310). As such, a possible relationship between high consumption of green tea and low incidence of prostate and breast cancer in Asian countries where green tea consumption is high has been postulated (Liao et at, 1995, Can. Lett. 96:239-243 and Stoner and Mukhtar, 1995, J. Cell. Biochem, 22:169-180). However, because of the many variables in lifestyle inherent to such a study, a definitive link between green tea and its cancer prevention effects could not be concluded.

Scientists have now identified many of the natural substances in green tea that may provide the majority of its health benefits. One class of chemicals that has attracted much study is the polyphenols, also known as catechins.

The polyphenols describe a class of substituted phenolic compounds that are known as flavanols or catechins. The polyphenols in green tea that have been identified are catechin (C), epicatechin (EC), gallocatechin (GC), gallocatechin gallate (GCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCg). In addition, caffeine, theobromine, theophylline, and phenolic acids, such as gallic acid, are also present as constituents of green tea in smaller quantities than the polyphenols (Ahmad et al, 1998, Nutrition and Chemical Toxicity, John Wiley and Sons, Sussex, England, pp. 301-343).

Epigallocatechin gallate (EGCg), the major catechin in green tea, has been the focus of many studies to determine if it is responsible for the antioxidant and anticarcinogenic effects of green tea, as reviewed by Ahmad and Mukhtar, 1999, Nutr. Rev. 57:78-83. The administration of a pharmacologically effective amount of EGCg has been alleged to reduce the incidence of lung cancer in a mammal (U.S. Pat. No. 5,391,568). A bioavailability study showed that frequent green tea consumption results in high levels of EGCg in various body organs, suggesting that green tea consumption may protect against cancers localized to different sites of the body (Sugunama et al., 1998, Carcinogenesis 19:1771-1776).

EGCg has been implicated in blocking DNA transcription of a number of genes in cancer cell lines. For example, in the human epidermal carcinoma cell line A431, EGCg inhibits the DNA and protein synthesis of the growth factor receptors epidermal growth factor receptor

(EGF-R), platelet-derived growth factor receptor (PDGF-R), and fibroblast growth factor receptor (FGF-R) (Liang et al., 1997, J. Cell. Biochem. 67:55-65). EGCg has also been implicated in blocking transcription of nitric oxide (NO) synthase by inhibiting the binding of transcription factor NF.kappa.B to the NO synthase promotor (Lin and Lin, 1997, Mol. Pharmacol. 52:465-472 and Chan et al„ 1997, Biochem. Pharmacol. 54:1281-1286). In the tumor cell line JB6, EGCg inhibits AP-1 transcriptional activity (Dong et al., 1997, Can. Res. 57:4414-4419). These results suggest that EGCg may prevent cancer at the level of gene transcription, i.e., by blocking the DNA synthesis of genes involved in signal transduction pathways.

Further, the focus of many other studies has been the effect of EGCg on apoptosis, or programmed cell death. Apoptosis differs from necrosis, and is regarded as an ideal mechanism for the elimination of cells. Studies have shown that several anti-cancer preventative agents may induce apoptosis, and conversely, several tumor-promoting agents inhibit apoptosis (Wright et al., 1994, FASEB J 8:654-660 and Ahmad and Mukhtar, 1999, Nutr, Rev. 57:78-83).

Although the focus of much of the prior research has been on EGCg, the putative biological functions of some of the other catechins has been examined. For example, both epicatechin gallate (ECG) and epigallocatechin (EGC) have been reported to be as effective as EGCg in inducing apoptosis of human epidermal carcinoma cells A431 at similar concentrations, whereas epicatechin (EC) did not show a similar effect (Ahmad et al., 1997, J. of the Nat. Can. Inst. 89:1881-1886). Growth inhibition in lung tumor ceil lines H661 and H1299 was also observed with EGCg and EGC, whereas ECG and EC were less effective (Yang et al., 1998, Carcinogenesis 19:611-616).

Catechins have been implicated in growth inhibition of the human lung cancer cell line PC-9, with the order of catechin potency being reported as EGCg=ECG>EGC>EC (Okabe et al., 1993, Jpn. J. Clin. Oncol. 23:186-190). It has also been demonstrated that catechin combinations of EGCg and EC, ECG and EC, and EGC and EC induce apoptosis of the human lung cancer cell line PC-9 in vitro (Suganuma et al., 1999, Can. Res. 59:44-47). EC is thought to enhance incorporation of EGCg into the cells, which is thought to inhibit TNF a release resulting in the induction of apoptosis (Suganuma et ah, 1999, Can. Res. 59:44-47).

The polyphenols in green tea are catechins, with multiple linked ring-like structures. Polyphenols are a form of bioflavonoids with several phenol groups. They control both taste and biological action. The dominant and most important catechin in green tea is (-) Epigallocatechin Gallate (EGCG), a potent antioxidant which is used for food production, as well as in animal research studies. The phenol groups capture pro-oxidants and free radicals. EGCG is over 200 times more powerful than vitamin E in neutralizing the pro-oxidants and free radicals that attack lipids in the brain, in vivo. It is 20 times more potent than vitamin E in reducing formation of peroxides in lard by the Active Oxygen Method, in vitro.

Epigallocatechin gallate (EGCG) chemically known as (2R,3R)-2-(3,4,5- Trihydroxy-phaiyl)-3,4-dmydro-l(2H)-betizopyran-3,5,7-triol-3-(3,4)5-trihydroxy-benzonate)).

Williamson MP et al and Hamza A, Zhan et al discloses benefit of EGCG in the treatment of HIV infection. One study examined the molecular binding of EGCG to the CD4 receptor molecule on human lymphocytes. The CD4 receptor is the site where the HIV virus attaches to a cell before infecting it. To bind to CD4, HIV uses its own receptor gpl20. The study found "clear evidence of high-affinity binding of EGCG to the CD4 molecule" and "inhibition of gpl20 binding to human CD4+ T cells". The mechanism is very similar to a new class of anti-HIV medications, the entry inhibitors.

US 7115283 patent discloses solid matrix composition comprising polyphenol derived from green tea extract and a therapeutically effective amount of the nutraceutical, the solid matrix coated with methyl cellulose.

US 6410052 patent discloses a sustained release composition of tea catechins comprising tea catechins and at least one component which controls the release of said catechins, comprising EGCg and EC catechins wherein, EGCg comprises at least 0.01% of said catechins, and the EC content is at least 10 fold greater than the EGCg content.

US 64150061 patent discloses method for treating cancer in a mammal which comprises administering to a mammal in need of cancer treatment, wherein the cancer is a type having cancer cells which express tNOX, a therapeutically effective amount of a composition comprising tea catechins, wherein said composition comprises more than one tea catechin, and wherein EGCg comprises about 40% of the catechins and ECG comprises about 15% of the catechins.

US 20050181044 patent application discloses a composition comprising one or more pellets for a timed or retarded release of a water-soluble nutritional supplement mix and immediate release powder composition comprising green tea extract.

US 20070077279 patent application discloses polyphenol composition comprising polyphenol and polyethylenglycol to mask the bitter taste of polyphenols.

WO 0117494 patent application discloses tooth paste or dentifrice composition, comprising tea polyphenol, buffering agent and one or more aqueous carriers.

WO 2008/25468 (DSM) patent application discloses the effervescent formulation of epigallocatechin gallate, comprising ascorbic acid, epigallocatechin gallate and gas generating compound.

Advantages of sustained release formulations may include: (1) extended activity of the composition; (2) reduced dosage frequency; and (3) increased patient compliance. In addition, sustained release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the composition, and thus can affect the occurrence of side effects.

Currently green tea is available as immediate release tablets, capsules and ointments by various suppliers. The above prior-art applications have not disclosed gastro retentive dosage form of green tea. Hence, there is need to develop gastro retentive dosage forms of green tea.

SUMMARY OF THE INVENTION

The present invention provides gastro retentive dosage form of green tea.

The present invention also provides process for preparing gastro retentive dosage form of green tea.

The present invention also provides use of gastro retentive dosage form of green tea for head aches, body aches, pains, digestion, energy, antacid, general well-being, cancer, HIV infection.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is gastro retentive dosage form of Green tea.

In another embodiment of the present invention is process for preparing gastro retentive dosage form of Green tea.

In an another embodiment of the present invention, gastro retentive dosage form of Green tea comprising green tea and one or more pharmaceutically acceptable excipients.

One or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, floating agents, polymers, glidants, lubricants, anti adherents, preservatives and combinations there of.

Suitable diluents used according to the present invention may be selected from microcrystalline cellulose, lactose, starch, sorbitol, sucrose, dicalcium phosphate or combinations thereof.

Suitable binders used according to the present invention may be selected from povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose or combinations thereof.

Suitable disintegrants used according to the present invention may be selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, and combinations thereof.

Suitable floating agents used according to the present invention may be selected from sodium bicarbonate, potassium bicarbonate, citric acid and combinations thereof.
Suitable polymers used according to the present invention may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polymethacrylates, acrylic polymers, methacrylic acid, methacylic acid copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof.

Suitable lubricants used according to the present invention may be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like.

Suitable glidants used according to the present invention may be selected from calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof.

Suitable preservatives used according to the present invention may be selected from methyl paraben, propyl paraben, benzalkonium chloride, butylated hydroxy anisole and combinations thereof.

In another embodiment of the present invention, the gastro retentive dosage from of green tea may be prepared by direct compression, wet granulation or dry granulation.

In another embodiment of the present invention, the gastro retentive dosage from of green tea tablets may be coated tablets or uncoated tablets.

Suitable solvents used for wet granulation according to the present invention may be selected from water, isopropyl alcohol, ethanol and combinations thereof.

Green tea used according to the present invention contains varying amounts of catechin (C), epicatechin (EC), gallocatechin (GC), gallocatechin gallate (GCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCg). In addition, caffeine, theobromine, theophylline, and phenolic acids, such as gallic acid, are also present as constituents of green tea in smaller quantities than the polyphenols. Among all Epigallocatechin gallate is main active ingredient in green tea.

In another embodiment of the present invention, the gastro retentive dosage from comprising green tea may be used as a dietary or nutritional supplement for the use of head aches, body aches, pains, digestion, energy, antacid, general well-being, cancer, HIV infection.

In another embodiment of the present invention, the total daily dose may be from about 10 mg to about 800 mg of Epigallocatechin gallate administered in divided doses or single dose. A preferred total daily dose is from about 50 mg to about 500 mg of Epigallocatechin gallate.

In a another embodiment, a total daily dose of a gastro retentive dosage form may be from about 10 mg to about 800 mg of Epigallocatechin gallate administered once daily or twice daily.

The invention is illustrated by the following non limiting examples: Example 1:

Manufacturing process:

1. Sift & mix green tea extract, Methyl paraben sodium, Propyl paraben sodium) Sodium bi carbonate, Microcrystalline Cellulose, Hydroxypropyl Methylcellulose, Colloidal anhydrous silica and magnesium stearate.

2. Compress the mixture obtained in step 1 into tablets.

We Claim:

1. Gastro retentive dosage form of Green tea.

2. Gastro retentive dosage form as claimed in claim 1, wherein the dosage form comprises diluents, binders, disintegrants, floating agents, polymers, lubricants, anti adherents, preservatives and combinations thereof,

3. Gastro retentive dosage form as claimed in claim 1, may be prepared by wet granulation, direct compression or dry granulation.

4. Gastro retentive dosage form as claimed in claim 1, may be used as a dietary or nutritional supplement for the use of head aches, body aches, pains digestion, energy, antacid, general well-being, cancer, HIV infection.

4. Diluents as claimed in claim 2, wherein diluents are selected from microcrystalline cellulose, lactose, starch, sorbitol, sucrose, dicalcium phosphate or combinations thereof.

5. Binders as claimed in claim 2, wherein binders are selected from povidone, potato starch, wheat starch, com starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose or combinations thereof.

6. Disintegrants as claimed in claim 2, wherein disintegrates are selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, and combinations thereof

7. Floating agents as claimed in claim 2, wherein floating agents are selected from sodium bicarbonate, potassium bicarbonate, citric acid and combinations thereof.

8. Polymers as claimed in claim 2, wherein polymers are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polymethacrylates, acrylic polymers, methacrylic acid, methacylic acid copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof.

9. Lubricants as claimed in claim 2, wherein lubricants are selected from sodium stearyl fumarate, magnesium steafale, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and combinations thereof.

10. Preservatives as claimed in claim 2, wherein preservatives are selected from methyl paraben, propyl paraben, benzalkonium chloride, butylated hydroxy anisole and
combinations thereof.