INTRODUCTION:

¹The concept of multicomponent therapy is beneficial when the selected agents possess differing mechanisms of action that provide additive or synergistic efficacy.² Medicinal plants have attracted many scientists as an effective therapy for the treatment of many diseases. This may be due to many reasons like the side effects of conventional medicine, efficiency of plant-derived drugs and growing interest in natural products. Herbal Therapy is the result of the growing interest of scientists in medicinal plants. In this therapy, instead of a single photochemical, extracts of plant parts such as roots or leaves are used. Herbalists think that the different phytochemicals present in many herbs interact enhancing the therapeutic effects of the herb and dilute its toxicity. According to them, herbal synergism cannot be duplicated with synthetic chemicals as phytochemical interactions and trace components may alter the drug response in many ways. Photosomes “phyto” means plant while “some” means cell-like. Phytosomes are little cell like structure. This is advanced forms of herbal formulations which contains the bioactive phytoconsituents of herb extract surrounds and bound by a lipid. Recently, these preparations are used effectively in the treatment of many conditions like functional dyspepsia, irritable bowel syndrome etc.³

ANCIENT HISTORY AND ITS DEVELOPMENT:

The basis of concept of modern medicine development remains rooted in traditional medicine and therapies. ⁴

In different parts of the world like ancient China, Egypt, Africa, America and India, plants had been used for medicinal purposes long before recorded history. Chemical analysis first became available in the early 19^th century which started the extraction and modification of herbal ingredients. Later, chemists began making their own version of plant compounds, and over time, the use of herbal medicines declined in favor of drugs.⁵ Before the 20th century medicines relied almost exclusively on multicomponent medicines, obtained from natural sources. In contrast, the modern pharmaceutical industry almost exclusively uses single-ingredient drugs, otherwise known as new chemical entities (NCEs).⁶ They are particularly important in treating infectious diseases such as HIV, tuberculosis, malaria and complex chronic diseases like cancer and metabolic syndrome. In particular, a number of plant extracts and natural products work synergistically with existing antibiotics, restoring antibiotic activity against resistant strains of bacteria such as Staphylococcus aureus and Escherichia coli.⁷ The use of MCH preparations have accelerated in recent years due to high cost of modern medicine and increased public interest in natural products. Approximately 25% of modern drugs used in the United States have been derived from plants.⁸

NEED OF HERBAL PLANTS NOVEL DRUG DELIVERY SYSTEMS:

Several researchers are working towards developing novel drug delivery systems like mouth dissolving tablets, sustained and extended release formulations, mucoadhesive systems, transdermal dosage forms, microparticles, microcapsules, nanoparticles, implants, phytosome, liposomes, microspheres etc. of herbs. Some of them are at the laboratory stage and some have reached to the market, (the world's first poly-herbal mouth dissolving tablet). But there are many challenges with herbal drugs which need to be overcome like difficulty of conducting clinical research in herbal drugs, development of simple bioassays for biological standardization, development of pharmacological and toxicological evaluation methods, investigation of their sites of absorption, toxic herbal drugs in use, discovering various animal models for toxicity and safety evaluation, legal and regulatory aspects of herbal drugs and so on.⁹

PHYTOSOME:

The term “phyto” means plant while “some” means cell-like. ¹⁰ Phytosomes are little cell like structure. This is advanced forms of herbal formulations which contains the bioactive phytoconsituents of herb extract surrounds and bound by a lipid. Most of the bioactive constituents of phytomedicines are water-soluble compounds like flavonoids,¹¹terpenoids glycosides out of these flavonoids are a major class of bioactive compounds possesses broad therapeutic activities.¹² Because of water soluble herbal extract and lipophilic outer layer phytosomes shows better absorption which result better bioavailability and actions than the conventional herbal extracts containing dosage form.¹³

ADVANTAGES OF PHYTOSOMES:

Phytosomes have the following advantages ^15-16

· As the absorption of active constituents is improved, its dose requirement is also reduced.

· It enhances the absorption of lipid insoluble polar phytoconstituents through oral as well as topical route showing better bioavailability, hence significantly greater therapeutic benefit.

· Chemical bonds are formed between phosphatidylcholine molecule and phytoconstituent, so the phytosomes show better stability profile.

· Added nutritional benefit of phospholipids.

· Phosphatidylcholine used in preparation of phytosomes, besides acting as a carrier also acts as a hepatoprotective, hence giving the synergistic effect when hepatoprotective substances are employed.¹⁴

· It enhances the absorption of herbal constituent and hence the bioavailability.

· It gives nutritional benefit of phospholipid.

Table no 1: Liposomes herbal formulation and their applications.

Name of Bioactive component.	Application	Reference
Essential oil from Atractylodes macrocephala Koidz	Increase in solubility and bioavailability	17
Essential oil of O. dictamnus	Increase in activity	18
Extracts of Tripterygium wilfordi	Reduction in side effects	19
Quercetin	Increase in bioavailability and reduction in side effects	20
Silymarin extract	Increase in hepatoprotective activity	21
Taxanes	Decrease in toxicity	22
Capsaicin	Increase in permeation as prolongation of action	23
Essential oil of Artemisia arborescens L	Increase in stability	24

LIPOSOMES:

Liposomes are the biodegradeable, colloidal and spherical vesicles (0.05-5.0 μm in diameter) composed of a bilayer membrane entrapping an aqueous core. Liposome membranes can be composed of naturally-derived phospholipids with mixed lipid chains and a variation of head groups or of pure synthetic lipids with defined acyl chains and head groups. Drugs with widely varying lipophilicities can be encapsulated in the liposomes, either in the phospholipids bilayer, in the entrapped aqueous volume or at bilayer interface. Liposomes usually formed from phospholipids have been used to change the pharmacokinetic profile of not only drugs, but herbs, enzymes etc. Liposomal based drug delivery is advantageous specifically it enhancing the therapeutic index of anti-cancer agents, either by increasing the drug concentration in the tumour cells and by decreasing the exposure to normal cells. Various targeting strategies can be exploited using liposomal drug delivery system . There are lots of herbal liposomal formulations have been reported for herbal drugs where liposome are able to enhance product performance by solubility enhancement, improving bioavailability, targeting at site of action and prolonged release of drug. Application of liposome’s is shown in table no 1.

Table no 2: Microsphere herbal formulation and their applications.

Name of Bioactive component/ Plant	Application	Reference
Silymarin	Sustained release	25
Zedoary turmeric oil	Increase in bioavailability and sustained release occurs	26
Extract of Piper sarmentosumn	Used for industrial scale	27
Campothecin	Significant decrease in dose	28

MICROSPHERES:

Microspheres are spherical particles consisting of size ideally 1-300 μm. Each particle is matrix of the drug dispersed in the polymer and drug is released as a first order process. The polymers used for the fabrication of the microspheres are biodegradable or non biodegradeable. Various polymers have been used for fabrication of these microparticulate carriers such as Albumin, Gelatin, Modified Starch, Polypropylene, Dextran, Polylactic acid and Polylactide- co-glycolide etc. The drug release is controlled by the dissolution and degradation of the matrix. Application of microsphere in herbal formulation is shown in table no 2.

Table no 3: Nanoparticle herbal formulation and their applications.

Name of Bioactive component/ Plant	Application	Reference
Paclitaxel	Reduction in side effects	29
Curcumin	Increase in solubility	31
Cuscuta chinensis	Increase in solubility	32
Triptolide	Increase in solubility	33
Zedoary turmeric oil	Increased stability and drug loading	34
Quercetin.	Increased drug release and antioxidant effect	35
Taxol	Sustained release	36

NANOPARTICLES:

Nanoparticles are the submicron size particles having size range 10 to 1000 nm. The main advantages of the nanoparticles are their stability and long term storage. The particle size and surface characteristics of nanoparticles can be easily modified for controlled and targeted drug delivery.³⁵ Application of nanoparticle in herbal formulation is shown in table no 3.

PATENTED TECHNOLOGIES OF PHYTOSOMES:

In the field of phytosomes formulation research studies carried out by a number of academic scientist as well as by industrial laboratories here some patents for phytosomes and other related technologies along with their applications and innovations are listed in Table 4.

ROLE OF HERBAL EXTRACT IN NOVEL DRUG DELIVERY SYSTEMS:

Extraction process is the initial crucial step in preparation of plant formulations. Modern methods of extraction are effective in advancing the development of traditional herbal remedies For ancient time mankind is using plant source to alleviate or cure illnesses.⁴³ Plants constitute a source of novel chemical compounds which are of potential use in medicine and other applications. Plants contain many active compounds such as alkaloids, steroids, tannins, glycosides, volatile oils, fixed oils, resins, phenols and flavonoids, which are deposited in their specific parts such as leaves, flowers, bark, seeds, fruits, root, etc, which can obtain by extractiob process which will help full for the treatment the disease.⁴⁴ There are lots of technique for extraction process like soxhlet extraction, thermal desortion, maceration, steam distillation,percolation etc apart from all these technique soxhlet extraction is commonly use in the lab scale and industrial point of view soxhlet extraction process are as follow.

SOXHLET EXTRACTOR

It is a laboratory apparatus⁴⁴ invented in 1879 by Franz von Soxhlet.⁴⁵ It was originally designed for the extraction of a lipid from a solid material. However, a Soxhlet extractor is not limited to the extraction of lipids. Typically, a Soxhlet extraction is only required where the desired compound has a limited solubility in a solvent, and the impurity is insoluble in that solvent. If the desired compound has a significant solubility in a solvent then a simple filtration can be used to separate the compound from the insoluble substance.

PROCEDURE:

The sample is placed in the thimble.

· A solid material containing some of the desired compound is placed inside a thimble made from thick filter paper, which is loaded into the main chamber of the Soxhlet extractor. The Soxhlet extractor is placed onto a flask containing the extraction solvent Soxhlet is then equipped with a condenser.

· The solvent is heated to reflux. The solvent vapour travels up a distillation arm, and floods into the chamber housing the thimble of solid. The condenser ensures that any solvent vapour cools, and drips back down into the chamber housing the solid material.

· The chamber containing the solid material is slowly filled with warm solvent. Some of the desired compound will then dissolve in the warm solvent. When the Soxhlet chamber is almost full, the chamber is automatically emptied by a siphon side arm, with the solvent running back down to the distillation flask. The thimble ensures that the rapid motion of the solvent does not transport any solid material to the still pot. This cycle may be allowed to repeat many times, over hours or days.

· During each cycle, a portion of the non-volatile compound dissolves in the solvent. After many cycles the desired compound is concentrated in the distillation flask. The advantage of this system is that instead of many portions of warm solvent being passed through the sample, just one batch of solvent is recycled.

· After extraction the solvent is removed, typically by means of a rotary evaporator, yielding the extracted compound. The non-soluble portion of the extracted solid remains in the thimble, and is usually discarded. Mechanism of extraction process is shown in the figure no 1 and 2.

Figure no 1: Extraction progres

Figure no 2: mechanism of Soxhlet extractors

CONCLUSION:

Herbal drugs or plant possess a lot of therapeutic potential that should be explored via application of novel drug delivery technology. Large molecular size, lipid solubility, degradation in acidic stomach are certain problems which limit the therapeutic activity of these extracts in vivo though these possess excellent bioactivity in vitro. Application of novel drug delivery systems. A number of plant constituents like flavanoids, tannins, terpenoids etc. showed enhanced therapeutic effect at similar or less dose when incorporated into novel drug delivery vehicles as compared to conventional plant extracts. Hence there is great potential in development of novel drug delivery system for valuable herbal drugs as it provides efficient and economical drug delivery and the trends of incorporating NDDS for herbal drugs have also been adopted at industrial scale like liposomes, microspheres and nanoparticles give greater effects with least toxicity. Recent technology of drug delivery when applied to botanicals open new avenues to explore maximum therapeutic potential of plant substances of polar nature. Phytosomal complexes were first investigated for cosmetic applications, but mounting evidence of potential for drug delivery has been cumulated over the past few years, with beneficial activity in the realms of cardiovascular, hepatoprotective , anti-inflammatory, and anticancer applications etc. Standardized plant extracts or mainly polar phytoconstituents like flavonoids, terpenoids, tannins, xanthones when complexed with phospholipids like phosphatidylcholine give rise to a new drug delivery technology called phytosome showing much better absorption profile following oral administration owing to improved lipid solubility which enables them to cross the biological membrane, resulting enhanced bioavailability. Phytosomes have improved pharmacokinetic and pharmacological parameter, which in result can advantageously be used in treatment of various acute diseases as more amount of active constituent becomes present at the site of action (liver, brain, heart, kidney etc). Herbal extract play a very important role in the cosmetic products which are used to protect the skin against exogenous and endogenous harmful agents and enhance the beauty and attractiveness of skin.

ACKNOWLEDGEMENT:

The authors would like to acknowledge the assistance provided by kind cooperation of Secretary Shri Keshavrao Mankar Bhavabhuti Shikshan Sanstha “Shri Laxmanrao Mankar Institute of Pharmacy ” Amagoan, Gondia Maharashtra, INDIA.

REFFERENCE:

1. Liu Y, Hu B, Fu C, Chen X. Combination Database, Bioinformatics. 26(4); 2010: 587- 588.

2. Swarnlata Saraf and K. Dashora, Multi-Component Drug Delivery System: An Emerging Trend, Pharma Voice, 2006: 1-151.

3. W. Roscha, T. Liebregtsb, K.-J. Gundermannc, B. Vinsond and G. Holtmannb, Phytotherapy for Functional Dyspepsia: A Review Of The Clinical Evidence For The Herbal Preparation STW 5, Phytomedicine. 13; 2006: 114-121.

4. Bhushan Patwardhan, Ashok D. B. Vaidya and Mukund Chorghade, Ayurveda and Natural Products Drug Discovery, Current science. (6); 2004: 86.

5. Stephen J. Currier, Paul D. Johnston, and Kenneth J. Gorelick, Herbal Medicines, Science & Medicine, January/February 2000.

6. Kevin Spelman, MS; JJ Burns, ND; Douglas Nichols, ND; Nasha Winters, ND; Steve Ottersberg, MS; Mark Tenborg, ND, Modulation of Cytokine Expression by Traditional Medicines: A Review of Herbal Immunomodulators, Alternative Medicine Review.11:2006.

7. Farnsworth N. R. Screening Plants for New Medicines, Chapter 9 in Biodiversity, ed. E.O. 1988.

8. Wilson. M. M. Pandey, S. Rastogi & A. K. Rawat: Indian Herbal Drug for General Healthcare: An Overview, The Internet Journal of Alternative Medicine.6(1); 2008.

9. Devi V.K., Jain N, Valli K.S., Importance of Novel Drug Delivery Systems in Herbal Medicines, Phcog Rev. 4; 2010: 27-31.

10. Cott J. Natural Product Formulations Available in Europe for Psychotropic Indications. Psychopharmacol Bull. 31: 1995:745.

11. Bombardelli E, Curri SB, Della RL, Del NP, Tubaro A, Gariboldi P. Complexes Between Phospholipids and Vegetal Derivatives of Biological Interest. Fitoterapia. 60; 1989: 1-9.

12. Dang Yi. New product concept. UPC code 0300540111783. 2000. 4. Manach C, Scalbert A, Morand C. Polyphenols: Food Sources and Bioavailability. Am J Clin Nutr. 79; 2004: 727-747.

13. Mascarella S. Therapeutic and Antilipoperoxidant Effects of Silybin-Phosphatidylcholine Complex in Chronic Liver Disease, Preliminary Results. Curr Ther Res. 53; 1993: 98-102.

14. Kidd P, Head K. A Review of the Bioavailability and Clinical Efficacy of Milk Thistle Phytosome: A Silybinphosphatidylcholine Complex. Altern Med Rev. 10: 2005:193-203.

15. Bombardelli E, Spelta M, Loggia Della R, Sosa S, Tubaro A. Aging Skin: Protective Effect of Silymarin- Phytosome. Fitoterapia. 62;1991: 115-22.

16. Bombardelli E, Mustich G. Bilobalide Phospholipid Complex, Their Uses and Formulation Containing Them. U.S. Patent EPO- 275005. 1991.

17. Wen Z, Liu B, Zheng Z, You X, Pu Y, Li Q. Preparation of Liposomes entrapping essential oil from Atractylodes macrocephala Koidz by modified RESS technique. Chem Eng Res Design. 88 (8A); 2010:1102-1107.

18. Li HR, Li SF, Duan HQ. Preparation of liposomes containing extracts of Tripterygium wilfordii and evaluation of its stability. Zhongguo Zhong Yao Za Zhi. 32(20); 2007:2128-31.

19. Priprem A, Watanatorn J, Sutthiparinyanont S, Phachonpai W and Muchimapura S. Anxiety and cognitive effects of Quercetin liposomes in rats. Nanomedicine 4; 2008:70-78.

20. Mohamed S, El-Samaligy, Nagia NA, Mahmoud EA. Evaluation of hybrid liposomes-encapsulated silymarin regarding physical stability and in vivo performance. Int J Pharm. 319; 2006: 121-129.

21. Mahajan A, Mangat P, Bhatia A, Katare OP. A novel herbal capsaicin loaded liposomal formulation: design, development and evaluation. Pharmaceutical sciences, section11. July 2010. Available from: URL: http:// www.puchd.ac.in/csc2007/abstract /section_11- PHARM.pdf

22. Straubinger RM, Balasubramanian SV. Preparation and characterization of Taxane containing liposomes. Methods Enzymol 391; 2005: 97-117.

23. Sinico C, Logu AD, Lai F et al. Liposomal incorporation of Artemisia arborescens L. essential oil and in vitro antiviral activity. Eur J Pharm Biopharm. 59; 2005:161- 168.

24. Garg R, Gupta GD. Gastroretentive floating microspheres of Silymarin: Preparation and in vitro evaluation. Trop J Pharm Res. 9(1); 2010: 59-66.

25. You J, Cui FD, Han X, Wang YS, Yang L, Yu YW, Li OP. Study of the preparation of sustained release microspheres containing zedoary turmeric oil by the emulsion solvent diffusion method and evaluation of the self emulsification and bioavailability of the oil. Colloids Surf B Biointerfaces. 48(1); 2006:35-41.

26. Chan ES, Yim ZH, Phan SH, Mansa RF, Ravindra P. Encapsulation of herbal aqueous extract through absorption with ca-alginate hydrogel beads. Food and Bioproducts Processing. 88 (40239); 2010:195-201.

27. Chao P, Deshmukh M, Kutscher HL, Gao D, Rajan SS, Hu P et al. Pulmonary targeting microparticulate campothecin delivery system: anticancer evaluation in a rat orthotopic lung cancer model. Anticancer Drugs. 21(1); 2010: 65-76.

28. Trickler WJ, Nagvekar AA, Dash AK. A novel nanoparticle formulation for sustained Paclitaxel delivery. AAPS Pharm Sci Tech. 9; 2008:486-493.

29. Bisht S, Feldmann G, Soni S et al. Polymeric nanoparticle encapsulated curcumin: a novel strategy for human cancer therapy. J Nanobiotech. 5:3; 2007.

30. Yen FL, Wu TH, Lin LT, Cham TM, Lin CC. Nanoparticles formulation of Cuscuta chinensis prevents acetaminophen induced hepatotoxicity in rats. Food Chem Toxicol. 46; 2008: 1771-1777.

31. Mei Z, Chen H, Weng T, Yang Y, Yang X. Solid lipid nanoparticle and microemulsion for topical delivery of triptolide. Eur J Pharm Biopharm. 56; 2003: 189-196.

32. Lertsutthiwong P, Noomun K, Jongamonngamsang N, Rojsitthisak P. Preparation of alginate capsules containing turmeric oil. Carbohydr Polym.74; 2008: 209-214.

33. Tzu-Hui W, Feng-Lin Y, Liang-Tzung L, Tong-Rong T, Chun-Ching L, Thau-Ming C. Preparat ion, Physicochemical characterization and antioxidant effects of quercetin nanoparticles. Int J Pharm. 346(1-2); 2008:160-8.

34. Fu RQ, He FC, Meng DS, Chen L. Taxol PLA nanoparticles. ACTA Academiae Medicinae Militaris Tertiae. 28; 2006: 1573-74.

35. Zhang J, Jasti B and Li X. Fromulation and Characterization of silibinin-loaded Sterically Stabilized Solid Lipid Nanoparticles. Drug delivery. 15; 2007: 381-387.

36. Jiang YN, Yu ZP, Yan ZM, Chen JM. Studies on preparation of herba epimedii flavanoid phytosomes and their pharmaceutics. Zhongguo Zhong Yao Za Zhi. 26(2); 2001: 105-8.

37. Di Pierro F. Compositions comprising Gingko biloba derivatives for the treatment of asthmatic and allergic conditions. EP1813280, 2007.

38. Bertelli V. Fatty acid monoesters of sorbityl furfural and compositions for cosmetic and dermatological use. EP1690862, 2006.

39. Franceschi F, Giori A. A phospholipid complex of olive fruits or leaves extracts having improved bioavailability. EP1844785, 2007.

40. Doering T, Traeger A, Waldmann-Laue M. et al. Cosmetic and dermatological composition for the treatment of aging or photodamaged skin. EP1640041, 2006.

41. Kleinman H K, Goldstein A L, et al. Treatment of skin, and wound repair, with thymosin beta 4. U. S. Patent No-20070015698, 2007.

42. Bombardelli E, Patri G F, Pozzi R. Complexes of saponins with phospholipids and pharmaceutical and cosmetic compositions containing them. EP0283713, 1988.

43. Tonthubthimthong P, Chuaprasert S, Douglas P, Luewisutthichat W. Supercritical CO2 extraction of nimbin from neem seeds an experimental study. J. Food Eng. 47;2001: 289-293.

44. Laurence M. Harwood; Christopher J. Moody (13 Jun 1989). Experimental organic chemistry: Principles and Practice (Illustrated edition ed.). WileyBlackwell. pp. 122–125. ISBN 0-632-02017-2.

45. Soxhlet, F. Die gewichtsanalytische Bestimmung des Milchfettes, Polytechnisches J. (Dingler's) 1879, 232, 461.

Received on 13.06.2013 Modified on 01.07.2013

Research J. Pharm. and Tech. 6(9): September 2013; Page 962-966

Title of patent	Innovation	Patent No	Reference
Compositions comprising Ginkgo biloba derivatives for the treatment of asthmatic and allergic conditions	Compositions containing fractions deriving from Ginkgo biloba, useful for the treatment of asthmatic and allergic conditions	EP1813280	37
Fatty acid monoesters of sorbityl furfural and compositions for cosmetic and dermatological use	Fatty acid monoesters of sorbityl furfural selected from two diff series of compounds in which side chain is a linear or branched C3 -C19 alkyl radical optionally containing at least one ethylenic unsaturation	EP1690862	38
		EP1690862	38
Phospholipid complexes of olive fruits or leaves extracts having improved bioavailability	Phospholipids complexes of olive fruits or leaves extracts or compositions containing it having improved bioavailability	EP/1844785	39
Cosmetic and dermatological composition for the treatment of aging or photodamaged skin	Composition for topical treatment of the skin comprises a substance that stimulates collagen synthesis and a substance that enhances the interaction between extracellular matrix and fibroblasts Cosmetic or dermatological composition for topical treatment	EP1640041	40
Treatment of skin, and wound repair, with thymosin beta 4	Compositions and methods for treatment of skin utilizing thymosin β4.	US/2007/ 0015698	41
Saponins with phospholipids and pharmaceutical and cosmetic compositions containing them	Complexes of saponins with natural or synthetic phospholipids have high lipophilia and improved bioavailability and are suitable for use as active principle in pharmaceutical, dermatologic and cosmetic compositions	EP0283713	42