INTRODUCTION:

Since ancient times the therapeutic uses of traditional medicines and phytomedicines have proved very popular for health maintenance by various means. During the last century chemical and pharmacological studies have been performed on many plant extracts in order to investigate their chemical composition and confirm their therapeutic usefulness ^[1]. Over the past several years, great advances have been made on development of novel drug delivery systems (NDDS) for plant actives and extracts. Variety of novel formulations like polymeric nanoparticles, nanocapsules, liposomes, herbosomes, nanoemulsions, microsphere, transferosomes, and ethosomes have been reported using bioactive and plant extracts. Every nation is seeking health care beyond the traditional boundaries of modern medicine; turning to self-medication in the form of herbal remedies ^[2,
3].

Most of the bioactive constituents of phytomedicines are water-soluble molecules (e.g. phenolics, glycosides, flavonoids, xanthan, etc.).However, water soluble phytoconstituents are limited in their effectiveness because they are poorly absorbed when taken orally or when applied topically ^[4]. Flavonoids are first recognized for their anti-oxidant properties and are widely distributed in plants. To date more than 4000 naturally occurring flavonoids have been identified from plant source having diverse biological activities. Flavonoids are chemically polyphenolic and are less absorbed from GIT. The less absorption of flavonoids is due to multiple ring arrangement of the molecules and high water solubility which is a hindrance in passage through biomembrane. Some of the polyphenolics are highly lipophilic and possess inadequate dissolution in aqueous GI fluids ^[5]. Phytosome approach has shown to overcome such problems and become more bioavailable as compared to conventional herbal extract owing to their enhanced capacity to cross the lipoidal biomembrane and finally reaching the systemic circulation. Hence phytosome is fastly growing attractive way of delivering botanicals based drugs and neutraceuticals ^[6]. Herbosome is a synonym of Phytosome. ‘Herbo’ or ‘Phyto’ stands for herbal or plant based and ‘some’ means cell like ^[7]. It is a patented technology in which molar equivalent amount of phosphatidylcholine and polyphenolic compound are reacted in an aprotic solvent.

The lipid‐phase substances employed to make flavonoids lipid‐compatible are phospholipids from soy, mainly phosphatidylcholine. These are amphiphillic substance. Phosphatidylcholine is the essential molecular building block of cell membranes [Fig: 1], miscible both in water and in oil environments, and is well absorbed when taken by mouth. Chemical analysis indicates that in herbosomes a flavonoid molecule linked with at least one phosphatidylcholine molecule. A bond is formed between these two molecules, creating a hybrid molecule. This highly lipid‐miscible hybrid bond is better suited to merge into the lipid phase of the enterocyte's outer cell membrane ^[8]. The problem of aqueous solubility can also be removed by such a hybrid molecule, for example Rutin-Phosphatidylcholine complex ^[9]. Phosphatidylcholine not merely helps in passively carrying the bioactive flavonoids of the phytosomes, but is itself a bioactive nutrient with documented clinical efficacy for liver disease, including alcoholic hepatic steatosis, drug‐induced liver damage, and hepatitis ^[10].

Figure 1: A three dimensional view of the biological membrane ^[8]

Phytosome preparation:

Phytosomes are prepared by reacting one to three moles of a natural or synthetic phospholipid such as phosphatidylcholine with one mole of polyphenolic constituent, either alone or in the natural mixture in aprotic solvent such as dioxin or acetone from which complex can be isolated by precipitation with non-solvent such as aliphatic hydrocarbon or lyophilization or by spray drying [Fig: 2]. In the complex formation of phytosomes the ratio between these two moieties is in the range from 0.5-2 moles. The most preferable ratio of phospholipid to flavonoids is 1:1 ^[11]. Quercetin-phytosome ^[12] developed by refluxing 1 mole of Quercetin with 1 mole of hydrogenated soy phosphatidylcholine (HSPC) in 20ml of dichloromethane till all the quercetin dissolved. Resulting solution was reduced to 2-3 ml and 10 ml of n-hexane was added to above solution to get the complex as precipitate. The complex was then filtered, dried under vacuum and stored in air tight container. Similarly poor aqueous soluble curcumin was also transformed to phospholipid complex ^[13].

Figure 2: Steps involved in preparation of Herbosome ^[14]

Yanyu X and co-workers prepared a silybin- phospholipid complex using ethanol as a reaction medium. Silybin and phospholipid were dissolved into the medium, after that the organic solvent was removed under vacuum condition, and a silybin-phospholipid complex was formed ^[15].

Mechanism:

Phytoconstituents (mainly polyphenolics, saponin and triterpenes) that provide site for direct bonding (polyphenol) with the phosphatidylcholine can be converted into phytosomes. Phytosomes generally more bioavailable than a simple herbal extract due to its enhanced capacity to cross the lipid-rich biomembranes and reach circulation ^{[16, 17]}. Phospholipids are small lipid molecules where glycerol is bonded to two fatty acids, while the third, hydroxyl, normally one of the two primary methylenes bears a phosphate group bound to a biogenic amino or to an amino acid. By embedding the active compounds into the environment of phospholipids, these are shielded from water-triggered degradation while, at the same time, the rapid exchange of phospholipids between biological membranes and the extracellular fluids can shuttle them into biological membranes, boosting its cellular capitation ^[18].

Patents in the field:

Bioavailability of olive polyphenols in human volunteers was 3-5 times more when administered in complexed form with phospholipids (Oleaselected TM Phytosome®) ^[19]. Phospholipids to olive fruits and leave extract ratio in the prepared complexes was in the range of 10 to 1% (w/w). Phospholipid complexes of curcumin provided five times higher peak plasma levels and AUC in male Wister rats when compared to peak plasma levels and AUC value obtained after treatement with extract of uncomplexed curcumin^[20]. Phospholipid complexes of proanthoycynidins extracted from Vitis vinifera were prepared for use in suitable oral formulations, e.g. tablets or capsules, for treatment of atherosclerotic pathological conditions like myocardial and cerebaral infarctions ^[21]. The phospholipid complexes of proanthocyanidin A2 (2:1 to 1:2 ratio) were significantly more useful for the prevention and the treatment of atherosclerosis lesions in rabbit ^[22]. Phospholipid complexes of extracts of Vitis vinifera, and phospholipid complexes of standardized extract from Centella asiatica were incorporated in pharmaceutical and cosmetic compositions for prevention of skin aging ^[23]. Flavanolignane-phospholipid complexes with a molar ratio of 1:1 of silybin, silidianin and silicristin were prepared for oral administration for treatment of acute or chronic liver disease of toxic, metabolic and/or infective origin or of degenerative nature, and for prevention of liver damages resulting from the use of drugs and/or luxury substances injurious to the liver ^[24]. Poor absorption by oral route, poor tolerability by cutaneous/topical administration and remarkable toxicity by parenteral route limits the therapeutic utility of saponins. Complexes of saponins with phospholipids allowed overcoming these drawbacks, particularly allowing an effective absorption by oral and topical route and a high stability, due to the lipophilic characteristic attained ^[25]. Complex of flavonoids with phospholipids, characterized by high lipophilicity and improved bio-availability and therapeutic properties as compared with free, not complexed flavonoids were prepared for use as the active principle in pharmaceutical and cosmetic compositions like tablets, capsules, creams, gels etc. ^[26]. Complexes of extracts from Krameria triandra and other plants of the Eupomatia genus, as well as some phenol constituents thereof of neo-lignane or nor-neolignane nature, with phospholipids were prepared ^[27] for incorporation in the traditional pharmaceutical forms for the treatment of superficial infected inflammatory processes, in torpid sores and in all the phlogistic conditions of the oral cavity. Complexes between natural or synthetic phospholipids and bilobalide, a sesquiterpene extracted from the leaves of Gingko biloba, were prepared for their application as anti-inflammatory agents and as agents for the treatment of disorders associated with inflammatory or traumatic neuritic processes ^[28]. These complexes exhibited higher bioavailability compared with free bilobalide, and were suitable for incorporation into pharmaceutical formulations for systemic and topical administration.

Clinical Trial with Rational Dose of Phytosome:

Mascarella and co-workers ^[29] in one study of 232 patients with chronic hepatitis treated with the Silybin phytosome at a dose of 120 mg either twice daily or thrice daily for up to 120 days, investigated and found that the liver function returned to normal faster in patients taking the Silybin phytosome compared with a group of controls (49 treated with commercially available Silymarin, 117 untreated or given placebo).

In a randomized human trial, young healthy volunteers received grape seed phytosome once daily for 5 days. The blood TRAP (Total Radical‐trapping Antioxidant Parameter) was measured at several time intervals during 1st day, then also on 5th day. After 30 minutes of administration on 1st day, blood TRAP levels were significantly elevated over the control which received conventional standardized grape seed extract ^[30].

The complexation of green tea polyphenols with phospholipids strongly improves their poor oral bioavailability. A study on absorption of phytosomal preparations was performed in healthy human volunteers along with non complexed green tea extract following oral administration. Over the study period of 6 hours the plasma concentration of total flavonoids was more than doubled when coming from the phytosomal versus the non‐phytosomal extract. Antioxidant capacity was measured as TRAP (Total Radical‐trapping Antioxidant Parameter). The peak antioxidant effect was a 20% enhancement and it showed that the phytosome formulation had about double the total antioxidant effect ^[31].

The comparative uptake of silybin from the phytosome form versus the non-phytosome form were investigated in two human studies. In the first, young healthy subjects (ages 16-26, n=8) took single 360-mg doses of silybin by mouth, either as the phytosome or as conventional silybin. After eight hours the plasma silybin level achieved from the phytosome was almost three times that of the non-complexed silybin. By measuring the total area under the curve (AUC), it was determined that silybin is absorbed 4.6-times better from its phytosome than its conventional form ^[32].

The Leucoselect® phytosome is prepared at a ratio of one part GSP (Grape Seed Polyphenol) to three parts phosphatidylcholine by weight. The Leucoselect GSP in phytosome form have demonstrated potent antioxidant effects ^[33]. Cigarette smoke is a well-proven source of oxidative stress. Each puff of cigarette smoke contains trillions of carbon and oxygen-centered oxidative species. In a randomized, double-blind, crossover trial, male heavy smokers over the age of 50 (n=24) received Leucoselect phytosome at 300 mg/day of GSP or a placebo for four weeks. The supplement significantly improved low density lipoprotein (LDL) cholesterol resistance to oxidation. Thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation and oxidative stress, was significantly reduced in the LDL (p<0.05 versus placebo); and the lag phase of LDL time to oxidation, a measure of LDL antioxidant resistance, was prolonged in comparison with placebo (p<0.005) ^[34].

Francesco and his co-workers ^[35] studied on a recently developed coated tablet MonCam containing phytosomes of Green tea extract (Greenselect® Phytosome). It was tested in obese subjects (n=100) of both genders on a hypo-caloric diet. Fifty (50) subjects received MonCam plus hypo-caloric diet and other 50 received only hypo-caloric diet. After 90 days significant weight loss (14kg) with reduction in body mass index were observed in the group taking green tea whereas only 5 kg weight loss in the diet only group. So MonCam was reported to be an effective way of reducing weight.

In a longer-term human study, 105 healthy volunteers received 135 mg green tea catechin (GTC) daily for two weeks, either as the conventional, decaffeinated GTC preparation or as its phytosome derivative. The non-phytosome form slightly (but not significantly) elevated red blood cell (RBC) membrane vitamin E content and failed to alter the membrane polyunsaturated fatty acid (PUFA) level, a predictor of membrane fluidity. By contrast, the GTC phytosome significantly elevated both vitamin E and PUFA levels. These effects would tend to make the RBC membrane more fluid and more resistant to oxidative damage ^[36].

In a new comparative study in humans, the overall curcuminoid absorption was about 29-fold higher for Meriva® (27.2 for the low dosage, 31.5 for the high dosage), compared to the unformulated curcuminoid mixture, while a 50 to 60 fold higher absorption has been shown for demethoxycurcumin and bisdemethoxycurcumin. The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clinical efficacy of Meriva® at doses significantly lower than the unformulated curcuminoid mixtures ^[37].

Similar results have been also seen comparing the absorption of (-)-epigallocatechin 3-O-gallate (EGCG), the main constituent of Greenselect® Phytosome. Twelve healthy male volunteers were randomly divided in two groups. One received a single dose of Greenselect® (containing 240 mg of tea catechin). The second group received 1,200 mg of Greenselect® Phytosome (containing 240 mg of tea catechin). EGCG was chosen as the biomarker for absorption. The peak concentration at 2 hours is more than doubled with Greenselect® Phytosome in comparison to the simple Greenselect®. Further, the plasma levels of EGCG remain considerably higher with Greenselect® Phytosome ^[38].

The inflammatory response of the 18β-glycyrrhetic acid phytosome were assessed in the experimental model of Croton oil-induced oedema reduction. At the same dose level, the action of the 18β-glycyrrhetic acid phytosome was found to be greater and to last longer than that of 18β-glycyrrhetic acid alone. This means that the Phytosome not only increases the active ingredient tolerability and absorption, but also improves its efficacy ^[14].

The bioavailability of the curcumin phytosome preparation (Meriva®, from Indena SpA) has been tested in rats against non-phytosome curcumin extract .The rats were fasted overnight, then received by mouth either the phytosomal or the non-phytosomal preparation. Blood samples were obtained at 15, 30, 60, or 120 minutes after oral gavage. Curcumin complex was administered by oral gavage at 360 mg/kg body weight, in either phytosome or nonphytosome form. Curcumin I was identified in the rat blood samples along with its metabolites curcumin glucuronide, curcumin sulfate, tetrahydro-curcumin, and hexahydrocurcumin. The phytosome preparation displayed superior curcumin plasma absorption from the first 30 minutes. In the period 0-120 minutes the AUC values were 5.6 times better for the curcumin phytosome compared to the nonphytosome preparation (actual data 26.7 mcg/min/mL versus 4.8 mcg/min/mL). In this study, the liver also accumulated significantly more curcumin I from the phytosome compared to the non-phytosome. ^[39]

CONCLUSION:

The effectiveness of herbal extracts in terms of potency can be improved by the value added phytosome formulations which is a patented technology (Indena, Italy) also known as herbosome. For gastrointestinal absorption a drug should have sufficient water solubility and lipid solubility. The polyphenolic flavonoids are well known for their diverse therapeutic effects but either less water solubility or insufficient lipid solubility are the hurdles in developing dosage form. Problems of this type are avoidable through the benefits of this new technology. Therapeutic effect of herbal constituent can be obtained at significantly lower dose in comparison to conventional herbal extract. The review enlightened the ongoing research and also through rays of hope that in near future many of the traditional herbal extract can be converted to effective modern medicine.

The review encouraged us to develop Rutin into phytosome to improve its solubility, permeability and bioavailability. Rutin exhibits multiple pharmacological activities including antibacterial, anti-tumour, anti-inflammatory, anti-diarrhoeal, anti-ulcer, anti-mutagenic, vasodilator and immune-modulator^[45]. Rutin water solubility was determined as 0.0639 ± 0.0088 mg/ml and only 0.54 ± 0.007 mg/ml is soluble in phosphate buffer pH 7.4. The n-octanol / phosphate buffer (pH 7.4) partition coefficient of rutin found to be 2.74 ± 0.82. The 1:1 (rutin:phosphatidylcholine) phytosome complex showed n-octanol/phosphate buffer (pH 7.4) partition coefficient of 0.722 ± 0.056. Rutin phytosome is more soluble as we found 1.4902 ± 0.004 mg/ml in phosphate buffer pH 7.4. These findings have correlation with the report of Singh et al 2012 ^[9]. They evaluated the antioxidant activity of the prepared rutin-phospholipid complex and reported that antioxidant activity of rutin was maintained even after being complexed with the phospholipid and finally

Table 1: Successful Products: ^{[40- 44]}

SL No	Source	Phytoconstituent	Phytosome	Dose	Utilization
1	Gingko biloba	(a) Dimeric flavonoids18 (b) Terpenoids (gikgolides and bilobalide)	Ginkoselect^® Phytosome	120 mg	Vasoactive agent, Anti-inflammatory agents, cognition enhancer
2	Silybum marianum	(a)Flavolignan (Silybin) (b)Flavanolignan(Silymarin)	Silybin Phytosome TM	120 mg	(a)Antioxidant and Hepatoproptective(b)Anti-inflammatoryAnti-aging
3	Crataegus oxyacantha	Flavonoids	Hawthorne Phytosomes	100 mg	Antioxidant, cardio-protective
4	Camellia sinensis	Catechins and their gallate derivatives.	Greenselect® Phytosome	50-100 mg	Antioxidant, cardio-protective,
5	Terminalia serica	Sericosides	Sericosides Phytosome	--	Skin restructuring, capillary protecting, wound healing, anti-oedema,anti-inflammatory
6	Panax ginnseng	Ginsenosides	Ginseng PhytosomeTM	150 mg	Nutraceutical, immunomodulator, anti-ageing
7	Vitis vinifera	Procyanidine	Grape seed phytosome	50-100 mg	Cardio-protectant, anti-inflammatory, antioxidant.
8	Serenoa repens (Bartr)	Phytosterol	Sabalselect ® Phytosome	--	Non-cancerous prostate enlargement.
9	Olea europaea	Verbacoside, tyrosol, hydroxytyrosol	Oleaselect TM Phytosome	--	Antioxidant, inhibit harmful oxidation of LDL cholesterol, anti-inflammatory
10	Echniacea angustifolia	Echinacosides and high molecular weight polysaccharide (inulin)	Echinacea Phytosome^TM	--	Neutraceutical, Immunomodulator
11	Glycerrhyza glabra	Glycerrhetinic acid	Glycerrhetinic acid Phytosome^TM	--	Anti-inflammatory
12	Centella asiatica	Asiatic acid, Madecassic acid	Centella terpenoid Phytosome^TM	60-120 mg	Skin disorder, antiulcer, wound healing, anti-hair loss agent
13	Citrus aurentium	Naringenin	Naringenin Phytosome^TM	100 mg/kg	Anti-oxidant
14	Swertia alternifolia	Xenthones 26	Swertia Phytosome^TM	--	Anti-oxidant
15	Serena repens	Phytosterol	Sabaselect Phytosome ^TM	320 mg	Non-cancerous prostate enlargement
16	Melilotus officinalis	Melilotoside, terpenoids	Lymphoselect Phytosome	6-20 mg	Anti-inflammatory, thromboflabitis, anti-edema
17	Santalum album	Xemenynic acid, ethyl xemenynate	Ximiline and ximenoil Phytosome^TM	--	Improves microcirculation
18	Vaccinum myrtellus	Anthocyanoside	Mirtoselect Phytosome^TM	---	Antioxidant, anti-inflammatory, diabetic retinopathy
19	Aesculus hippocastenum	Saponins	Escin β sitosterol Phytosome^TM	3% gel	Anti-edema, vasoactive properties

Figure 3: Skin permeation profile of Rutin and Rutin Phytosome in transdermal patch. All data are Mean ± SD (n = 3).

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Received on 23.08.2013 Modified on 05.09.2013

Research J. Pharm. and Tech. 6(11): November 2013; Page 1295-1301