Novel Approaches for Dermal and Transdermal Delivery of Herbal Drugs

Manju R Singh, Mukesh K Nag, Satish Patel, S. J. Daharwal, Deependra Singh*

University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur

ABSTRACT:

In recent times, the utilization of herbal bioactives is increased worldwide because of their incredible therapeutic effects and negligible side effects as compared to the synthetic medicines. However, delivery of herbal drugs has need of modifications with the intention to accomplish sustained and controlled release. Previously herbal bioactives were not considered for development as novel formulations due to lack of scientific justification, processing, standardising, extracting and authentication difficulties. Also, many herbal drugs and herbal extracts regardless of their remarkable activity but show less in-vivo activity due to their poor lipophilicity or improper molecular size, resulting in less absorption and hence reduced bioavailability. Now with the innovation in the technology, novel drug delivery systems unlock the door in the direction of the development of herbal drug delivery systems with enhancing bioavailability, therapeutic effect and reduced toxicity. Many novel carriers such as nanoparticles, phytosomes, liposomes, transferosomes, etc. have been reported for successful modified delivery of various herbal drugs e.g. tacrolimus, quercetin, silybin, ginkgo, ginseng, Berberine etc. The aim of this review is to summarize various novel approaches, which have been developed for dermal and transdermal delivery of herbal drugs delivery to achieve better therapeutic response.

KEYWORDS: Herbal Drugs, Drug delivery, Dermal delivery, Transdermal delivery, Nanoparticle, Liposomes.

1. INTRODUCTION:

Herbs and herbal drugs have created interest among the people by its clinically proven effects in different health problems. Herbal drug therapy for skin disorders has been utilized for many years. Even our biologically close primitives, the apes, make use of herbal self-medication¹. In addition, the overuse of synthetic drugs, which results in higher commonness of adverse drug reactions, has moved humans to revisit to nature for safe remedies. Traditional medicines, because of their long usage in human subjects hold promise for development of safe and effective medicaments for human ailments. Main problem with herbal drugs is improper molecular size, poor bioavailability and solubility parameter. Novel drug delivery system is a new approach to drug delivery. It helps the synthetic and herbal drug to act longer and more efficiently. It overcomes restrictions of older methods of drug administration. It also overcomes the limitations of herbal drugs. In novel drug delivery system, control of the distribution of drug is achieved by incorporating the drug in carrier system or in changing the structure of the drug at molecular level. The present article was likely to endow with an outline of different types of novel drug delivery systems incorporating bioactives and potential advantages of such systems.

2. HERBAL DRUGS:

Herbal formulation mean a dosage form consisting of one or more herbs or processed herbs in specified quantities to provide definite nutritional, cosmetic and other health benefits meant for diagnosis and treatment of diseases and to alter the structure or physiology. Herbal formulation are prepared by subjecting whole plant, scrappy plants, plants parts to treatments such as extraction, distillation, expression, fractionation, purification, concentration. These include powdered herbal materials, tinctures, extracts, essential oils, expressed juices and processed exudates².

2.1 ADVANTAGES AND LIMITATIONS OF HERBAL DRUGS

Mostly herbal drugs are well tolerated by the patient, having fewer unintended consequences and fewer side effects than synthetic medicine, and may be safer to use. Herbal drugs are more effective for long-standing health complaints that do not respond well to conventional medicine. One example is the herbs and alternative remedies used to treat arthritis, Vioxx, a recognized prescription drug used to treat arthritis, were recalled due to increased risk of cardiovascular complications. Herbal management for arthritis, on the other hand, have lesser side effects. Such management include dietary changes like adding simple herbs, eliminating vegetables and reducing white sugar consumption. Cost of herbal drugs is much less than prescription medications. Research, testing, and marketing add significantly to the cost of prescribed medicines. Herbal drugs as compared to synthetic drugs tend to be inexpensive. Herbs are available without a prescription. Simple herbs, such as peppermint, Ocimum, ginger, turmeric, coriander, etc can be cultivated at home³.

Modern medicine treats sudden and serious illnesses and accidents much more effectively than herbal or alternative treatments. Self-treatment with herbal drugs may consist of many risk factors. Moreover, with no proper direction of doses may lead to overdose. Consumption of herbal drugs without correct identification of plant i.e. use of wrong part of plant may lead to poisoning. Because of herbal products are not strictly regulated, consumers may buy inferior quality herbal drugs. The quality of herbal products may show a discrepancy among batches, brands or manufacturers. This can make it much more difficult to prescribe the proper dose of an herb. Not all herbal drugs are safe; some may be poisonous or may cause allergenic reactions. Curative period is usually longer in comparison to conventional medication. Immense patience while undergoing herbal treatment is needed.

3. IMPORTANCE OF NOVEL DRUG DELIVERY SYSTEMS FOR HERBAL DRUGS

Herbal drugs are becoming more popular in the modern world for their application to cure variety of diseases with less toxic effects and better therapeutic effects. Novel drug delivery system is valuable in delivering the bioactive at controlled rate and delivery of bioactive at the target that reduces the adverse effects with the increase in bioavailability of the bioactive. In novel drug delivery system, control of the distribution of drug is achieved by incorporating the drug in carrier system or in changing the structure of the drug at molecular level. There is a great limitation for herbal drugs that many compounds will be destroyed in the highly acidic pH of the stomach, degrade by liver causing decrease level of bioactive to therapeutic level. Drug delivery system used for administering the herbal medicine to the patient is traditional and outdated, resulting in poor efficacy of the drug. Inclusion of novel drug delivery system to plant bioactive reduces the drug deprivation or pre-systemic metabolism and adverse and improves efficacy and administration. For a long time herbal medicines were not considered for development as novel formulations owing to lack of scientific justification and processing problems, such as standardization, extraction and identification of individual drug components in complex polyherbal systems. Modern phytopharmaceuticals research can solve the scientific needs (such as determination of lethal dose, therapeutic dose, pharmacokinetics parameters, mechanism of action, site of action, suitable route of administration etc.) of herbal medicines to being included in novel drug delivery system, such as solid lipid nanoparticles, solid lipid microspheres, micro-emulsions, dermal and transdermal patches, solid dispersions, liposomes, phytosomes, ethosomes, nanoparticles and so on⁴. Various advantages of novel drug delivery systems over conventional system are enhancement of solubility, increased bioavailability, protection from toxicity, enhancement of pharmacological activity, enhancement of stability, improved tissue macrophages distribution, sustained and controlled delivery, and safeguard from physical and chemical degradation (Table 1).

4. DERMAL AND TRANSDERMAL ADMINISTRATION

Human skin is the largest organ in our body. It is a well structured organ that shield the organism against environmental factor and regulate the temperature and water loss from the body. Due to large surface area, it is a perfect target for administered drugs for both topical and systemic action. It consists of three main layers; the epidermis, the dermis, and the hypodermis. Stratum corneum the outermost layer of epidermis is composed of dead and keratinized cells, and consequently it is an inimitable barrier to route of drugs through the skin²⁸. The drugs from topical formulations have to cross all the way through this layer to reach inner layers of the skin and to reach systemic circulation. The nature of drug and the types of the formulations have an efficient role in both dermal and transdermal delivery²⁹. There are two approaches in topical administration i.e. dermal and transdermal. If the applied formulation makes sure localization of drugs in dermal layers then it is dermal administration. While in transdermal application, the drug reaches the dermis of skin by means of a carrier system and then reaches to blood circulation²⁸. The availability of drugs to blood circulation is minimized in dermal application. The merits of transdermal application include controlled drug delivery, better patient compatibility and avoid the hepatic first-pass effect³⁰. Herbal drugs administered dermally and transdermally infiltrate slowly and in minute quantities into the blood circulation. These systems as well avert high local drug amount in the gastrointestinal tract and direct toxicity.

5. HERBAL DRUG NOVEL CARRIERS AND THEIR USES

Various strategies in case of novel herbal drug delivery system includes different types of formulations (Figure 1) are discussed below.

5.1 NOVEL DERMAL CARRIERS

5.1.1 ETHOSOMES

Ethosomes are customized lipid vesicular carrier system represent ethanol in relatively high concentration and are very effectual in delivering drugs into and across the skin. With the help of transdermal therapeutic system, it is possible to avoid the side effects that occur in the case of oral administration. Ethosomes were extending, as novel lipid carriers comprises of ethanol, phospholipids and water. It also helps to improve the delivery of various drugs to the skin. It facilitates drugs to reach the deep skin layers and blood circulation. Due to more amount of ethanol, the lipid membrane is filled less tightly in comparison with conventional vesicles, but it has equivalent stability³¹. For the delivery of miscellaneous group of proteins and peptides, ethosomes are preferable. Ethosomes mainly administered in the form of gel, cream for patient comfort.

Table 1: Different Novel carrier for bioactives and effect observed

S.N	Herbal Drug	Limitation of conventional form	Novel carrier	Effect observed	Ref.
1.	Tacrolimus	Normal skin transport	Liposome	Facilitated entry into the tough barrier consisting of stratum corneum. Better solubility of drug	5
			Nano-lipid carrier	Provide good occlusion property and solubility	6
2.	Coal tar	Skin irritation	Phospholipid carrier	Provide good occlusion property and solubility	7
3.	Anthralin	Irritation & staining	Liposome	Increase the stability of drug. Increases the penetration of drug through skin.	8
			Niosome	Enhance stability of drug	9
			Lipsome	Increases drug uptake and target deeper skin laye.	10
4.	Vit. D analogue	Local irritation	Nanostructured lipid carrier	Enhanced skin permeation and negligible skin irritation	11
5.	Corticosteroids	Skin irritation	Nano-capsule suspension	Greater stability of drug	12
			PEG-nlc’s	High entrapment efficiency and improved drug stability	13
6.	5-amiolevulinic acid	Poor skin penetration	Liposome	Enhance drug uptake	14
			Liposome	Compatible with skin lipid
			Ethosome	Better skin permeation and targeting deeper skin layer	15
			Nano-emulsion	optimize topical drug permeation negligible skin disruption and acceptable safety	16
7.	Temoporfin	Low aq. Solubility	Liposome	Higher rate of drug transfer across skin	17
			Invasome	Enhanced drug uptake	18
8.	Psoralens	Low penetration	Microemulsion	Enhanced drug uptake and provide photostability	19
9.	Cyclosporin	Limited cutaneous permeation	Microemulsion	Increase the stability of drug	20
			PLGA-nanopartice	Rapid dissolution of drug and good stability	21
10.	Acitracin	Scaling, erythema, burning, stinging	Nanostructured Lipid carrier	No major systemic side effects, the main topical side effect was irritation	22
11.	Methotrexate	Low penetration	liposome hydrogel	Enhance drug uptake	23
			Deformable liposome	Better skin permeation and targeting deeper skin layer	24
			Niosome	Enhance stability of drug	25
			Micro-emulsion	Enhanced drug uptake and provide photostability	26
			Nanogel	Greater stability of drug	27

Table 2: Different types of novel herbal formulation

S.N	Bioactive	Pharmacological action	Applications of liposome formulations	Ref.
Ethosomes
1.	Sophora alopecuroides	Anti-endotoxic, anti-cancer and antinflammatory	enhances delivery of drugs through the stratum corneum barrier into the deep layer	31
2.	Matrine	Antibacterial, antiinflammatory, anti-rheumatism and anti-tumour	Increase percutaneous permeation and improve anti-inflammatory effect.	49
Liposomes
3.	Magnolol	Inhibiting vascular smooth muscle cells proliferation	Enhance the therapeutic efficacy	50
4.	Nux vomica	Anti-tumour, analgesic and anti-inflammatory Activities	Increase stability of formulations	51
5.	Quercetin	Antioxidant activity	Enhance therapeutic efficacy	52
6.	Diospyrin	Anti-cancer activity	Enhancement of its anti-tumour effect	53
7.	Myrtus communis	Antioxidant and antimicrobial activity	Increase in its activities	54
8.	Artemisia arborescens	Antiviral activity	Increase in antiviral activity and stability	55
9.	Puerarin	Anti-arrhythmia activity	modify their surface charge and membrane integrity	56
Phytosomes
10.	Quercetin	Antioxidant activity	Enhanced therapeutic efficacy	57
11.	Oxymatrine	Anti-viral	Improvement of bioavailability	58
12.	Ginkgo biloba	Cardioprotective, anti-asthmatic and anti-diabetic	Induced hepatoprotective effect	59
13.	Marsupium	Anti-viral	Increase in bioavailability	60
14.	Embelin	Antibacterial and anti-fertility activities	Increase in solubility	61
15.	Naringenin	Anti-inflammatory, anti-carcinogenic and anti-tumour activity	Increase in bioavailability; prolong the duration of action	62
16.	Silybin	Hepatoprotective and antioxidant	Increase in therapeutic effect	63
Solid Lipid Nanoparticle
17.	Curcumin	Anti-tumour, antioxidant and anti-inflammatory activities	Increase in stability	39
18.	Curcuminoids	Anti-malarial activity	Increase in activity	64
Nanoparticles
19.	Berberine	Antineoplastic activity	H. pylon growth inhibition	65
20.	Quercetin	Antioxidant	Improve stability	66
21.	Hypocrellins	Antiviral activity	Improved stability and hydrophilicity	67
22.	Silybin	Anti-hepatotoxic activity	Shows sustained release and targeting system	68
23.	Ginseng	Antioxidant activity	Improvement in stability and action	69
24.	Salvia miltiorrhiza	Anti-angina activity	Improve bioavailability	70
25.	Paclitaxel	Anti-tumour activity	Show sustained release	71
Microsphere
26.	Ginsenoside	Anti-cancer activity	Enhance solubility and stability	72
27.	Ouercetin	Antioxidant and anti-inflammatory activities	Enhancing its bioavailability and sustain release the formulation	73
28.	Zedoary oil	Hepatoprotective	Sustained-release and higher bioavailability	74
29.	Rutin	Cardiovascular and cerebrovascular diseases	Targeting into cardiovascular and cerebrovascular regions	75
Emulsion
30.	Azadirachta indica	Acaricidal, anti-fungal, antibacterial activities	Reduce the toxicity	76
31.	Matrine	Antibacterial, anti-inflammatory, anti-Viral	Sustained-release formulation	77
32.	Berberine	Anti-neoplastic activity	Sustained-release formulation
33.	Rhubarb	Cathartic and laxative activity		78
34.	Docetaxel	Anti-cancer activity	Increase in the residence time	79
35.	Quercetin	Antioxidant	Enhance penetration into stratum corneum and epidermis	80
36.	Silybin	Hepatoprotective	Sustained-release formulation	81

5.1.2 LIPOSOMES

Liposomes are concentric bi-layered vesicles in which aqueous volume is entirely enclosed by a membranous lipid bi-layer mainly composed of natural or synthetic phospholipids. The liposomes are spherical shape particles that encapsulate the solvents that are internally freely afloat. Liposomes are composed of phospholipids, which are amphipathic molecules as they have both hydrophobic tail and hydrophilic polar head³². The polar end is made of molecules, is phosphoric atom-bound to a water soluble molecule. Liposomes are synthetic microscopic vesicle consisting of one or more concentric spheres of lipid bilayer enclosing aqueous compartments. Liposome has properties that allow it to improve the ingredient solubility, bioavailability, bio-distribution, changed pharmacokinetics and in vitro and in vivo stability. Liposome systems can improved the therapeutic efficacy of drugs³². It used to carry vaccines, drugs, enzymes, or other substances to target cells or organs. As drug carrier systems for topical treatment, liposomes are reported to be superior over conventional topical preparations. Phospholipids, being the major component of liposomal systems, are easily integrated with the skin lipids and maintain the desired hydration conditions to improve drug penetration and localization in the skin layers^{33, 34}. Liposomal encapsulation of retinoid, or tretinoin reduced the local irritation³⁵. Liposomal encapsulation of tacrolimus in topical formulation enhanced its penetration through skin. These characteristics may allow liposomal tacrolimus to be effective against psoriasis without the need of occlusive dressings. If liposomal tacrolimus penetrate into the blood stream, reports with other models suggest that it will be less toxic than free tacrolimus. This will be more important to patients who require higher concentrations of ointment to large areas of skin⁵.

5.1.3 PHYTOSOME

Phospholipids-based drug delivery system has been found promising for valuable and efficient herbal drug delivery. Phytosomes are recent forms of herbal products that are better absorbed, exploit to produce improved results than those produced by conventional herbal extracts. Phytosomes show improved pharmacokinetic and therapeutic profiles than conventional herbal extracts. Phytosomes are prepared by use of polyphenolic phytoconstituents with phosphatidyl choline in the ratio of 1:2 or 1:1. The Phytosomes protects herbal extract components from destruction in digestive secretions and gut bacteria by forming little cell, which is accomplished of being relocated from a hydrophilic environment into the lipid-friendly environment and finally reaching blood. The flavonoid and terpenoids constituents of plant extracts provide themselves quite well for the direct binding to phosphatidylcholine. Phytosomes results from the effect of a required amount of phosphatidyl choline with the standardized extract or polyphenolic constituents (like simple flavonoids) in a non-polar solvent³⁵. The phytosomes technology produces a little cell and the plant extract or its active bioactive is protected from destruction by gastric secretions and gut bacteria owing to the gastroprotective property of phosphatidylcholine.

5.1.4 SOLID LIPID NANOPARTICLES

It is a colloidal carrier used especially for the delivery of lipophilic compounds. It was prepared by different methods - the homogenization and the warm micro-emulsion. The average mean size of solid lipid nanoparticles ranges from 50 nm to 1000 nm. Solid lipid nanoparticles are composed of lipid matrix, which becomes solid at room and at the body temperature³⁶. The main features of solid lipid nanoparticles with look upon to parentral application are the excellent physical stability, protection of incorporated labile drugs from degradation. The SLNs are prepared by different methods such as homogenization and the warm micro-emulsion high-speed stirring ultra-sonication and solvent-diffusion method. Lipids show compatibility with lipophilic drugs and increase the entrapment efficiency and drug-loading into the SLN³⁷. They are more stable than liposomes in biological systems due to their relatively rigid core consisting of hydrophobic lipids surrounded by a monolayer of phospholipids³⁸. These aggregates are further stabilized by the inclusion of high levels of surfactants. Because of their easiness of biodegradation, they are less toxic than polymer or ceramic nanoparticles. Solid lipid nanoparticles can be used to deliver drugs orally, topically, or via inhalation³⁹.

5.1.5 NANOPARTICLES

Nanoparticles are nanosized structures composed of synthetic or semi-synthetic polymers. Nowadays, nanoparticles of herbal medicines have engrossed much attention. Nanoparticles are colloidal systems with particles varying in size from 10 nm to 1000 nm. It is an effective system as the formulation is encapsulated in it easily and can easily reach the target site⁴⁰. The nano-particulate system of formulation shows advantage, as its solubility is increased and the drug can reach the target site, as compared to other systems. Microencapsulation of herbal extract in nanoparticles is a valuable way used to shield drug or bioactives against deterioration, volatile losses, or untimely interaction with other ingredients. The advantages of the nanoparticles are that it improves the absorbency of the herbal formulation, reduces the dose of formulation and increases its solubility⁴¹.

5.1.6 MICROSPHERE

Microsphere comprises of small spherical particles, with diameters in the micrometer range, typically 1 μm to 1000 μm (1 mm). Microspheres are also referred as micro-particles. Microspheres can be prepared from a range of natural and synthetic materials. Glass microspheres, polymer microspheres and ceramic microspheres are commercially available. Microspheres are divided into biodegradable or non-biodegradable microsphere. Biodegradable microspheres include albumin microspheres, modified starch microspheres, gelatin microspheres, polypropylene Dextran microspheres, polylactic acid microspheres, etc. Solid and hollow microspheres vary widely in density and therefore are used for different applications. Hollow microspheres are typically used as additives to lower the density of a material. In addition, reports on immune microsphere and magnetic microsphere are also common in recent years. Immune microsphere possesses the immune competence because of the antibody and antigen being coated or adsorbed on the polymer microspheres⁴².

5.1.7 NIOSOME

The low cost, greater stability and ease of storage of non- ionic surfactants lead to the utilization of these compounds as alternative to phospholipids, the main constituent of liposomes . Niosomes are microscopic lamellar structures formed on admixture of a non ionic surfactant, cholesterol and a charge inducing agent, with subsequent hydration in aqueous media. Niosomes comprises of an architecture consisting of both hydrophobic and hydrophilic moieties, and as a result can accommodate drug molecules of varying solubilises. Niosomes have been evaluated in many pharmaceutical applications and were reported to reduce systemic toxicity by drug encapsulation and minimize clearance of such agents from the body by slow drug release. Developed dithranol entrapped in liposomal and niosomal vesicles (0.5%), and found both of them superior to conventional formulation, while liposomes showed better results than niosomes employing mice skin. Marianecci et al. investigated the niosomes made up of surfactants (Tween 85 and Span 20) and cholesterol for the delivery of ammonium glycyrrhizinate (AG), useful for the treatment of various inflammatory based diseases⁴³.

5.1. 8 TRANSFEROSOMES

Transferosomes are phospholipid vesicles that act as potential carriers for the transdermal delivery of the drug as they overcome the difficulty of penetration through the stratum corneum and can easily penetrate through the intracellular pores of the skin due to their flexibility⁴⁴. Increased penetration through stratum corneum results from hydration or osmotic force in the skin. Patel et al. prepared transferosomes containing the Curcumin gel and an increase in the permeation was observed when compared with the simple gel through the skin⁴⁵. Since ultra deformable vesicles have the capability of delivering the large molecules, they can be used to deliver vaccines topically. Transferosomes containing proteins like integral membrane protein, human serum albumin, gap junction protein are used for this purpose^{46, 47}.

5.1.9 EMULSIONS

Emulsion is a biphasic system in which one phase is intimately dispersed in the other phase in the form of minute droplets ranging in diameter from 0.1 μm to 100 μm. In emulsion, one phase is always water or aqueous phase, and the other phase is oily liquid, i.e., non-aqueous. Among them, the micro-emulsion is also called nanoemulsions, and the sub-micro-emulsion is also called lipid emulsion. Emulsion is targeted or distributed well due to attraction to lymph. Micro-emulsions are solutions containing nanometre-sized droplets of an immiscible liquid dispersed in an aqueous buffer. The droplets are coated with a surfactant to reduce the surface tension between the two liquid layers. Micro-emulsion is a clear, thermodynamically stable, isotropic mixture of oil, water and surfactant, frequently in combination with a co-surfactant. In addition, emulsions produce targeted sustained release, improve the penetrability of drugs into the skin and mucous and reduce the drugs' stimulus to tissues⁴⁸.

A variety of herbal novel formulations has been studied, which are summarized in Table 2.

6. CONCLUSION:

Herbal bioactives is now world widely accepted as a suitable alternative system of treatment in the form of pharmaceuticals, Nuetraceuticals, functional foods etc. However, the drug delivery system for herbal bioactives is relatively traditional and outdated. An extensive research is going on in the area of novel drug delivery and targeting for plant actives and extracts, as they possess a lot of therapeutic potential. Yet, research in this area is still at the exploratory stage. Hence, there is an immense potential in development of novel dermal drug delivery system for valuable herbal bioactives as it provides proficient and economical drug delivery.

7. ACKNOWLEDGEMENT:

The authors are thankful to Director, University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G.) for providing necessary facilities relating to present work and UGC-MRP 41-748/2012 (SR); CGCOST (CCOST/650/2011); UGC-MRP 39-169/2010 (SR); CGCOST (CCOST/660/2011) for financial assistance for the studies.

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Received on 22.09.2013

Modified on 20.10.2013

Accepted on 01.11.2013

© A&V Publication all right reserved

Research Journal of Pharmacognosy and Phytochemistry. 5(6): November –December 2013, 271-279