A REVIEW ON CHITOSAN-BASED HERBOSOMES A NANO-DRUG DELIVERY TO CURE ALZHEIMER’S DISEASE

A REVIEW ON CHITOSAN-BASED HERBOSOMES A NANO-DRUG DELIVERY TO CURE ALZHEIMER'S DISEASE

S. Riyazullah and P. R. Kumar and K. Bhaskar Reddy

Department of Pharmacognosy, Sri Venkateswara College of Pharmacy, RVS Nagar, Chittoor, Andhra Pradesh, India.

ABSTRACT: The discovery of drugs for Alzheimer’s disease (AD) therapy that can also permeate the blood-brain barrier (BBB) is very difficult owing to its specificity and restrictive nature. The BBB disruption or drug administration directly into the brain is not an option due to toxic effects and low diffusion of the therapeutic molecule in the brain parenchyma. A promising approach for systemic drug delivery to the central nervous system is the use of nanosized carriers. The therapeutic potential of certain nanopharmaceuticals for AD has already been demonstrated in-vivo after systemic delivery. Herbosomes have an enhanced absorption rate, producing excellent bio-availability, good penetration power.  Herbosome technology is one of such systems that incorporate phospholipids into standardized active ingredients of herbal extracts, thus effectively enhancing the bioavailability of water-soluble bioactive constituents of phytomedicines such as flavonoids, phenolics and hydrophilic compounds. These phytoconstituents have been established to exhibit a variety of biological activities that have pharmacological benefits. However, poor absorption of these phytoconstituents limits their bioavailability. The poor absorption is principally due to the failure of these constituents to reach their site of action before being degraded as well as their inability to pass through the small intestine due to their multi-ring structures and the lipid nature of the intestinal wall. This review chronicles the recent advances made in herbosome technology, highlighting the concepts, applications, and future perspectives of herbosome use.

Keywords: Herbosomes, Phytomedicine, Lipid based delivery systems, Phytosomes, Phyto-phospholipid complex

INTRODUCTION: Alzheimer’s disease (AD) is a neurodegenerative disorder of the human brain causing dementia.

The majority of the 35 million people who have dementia worldwide are thought to have AD (World Alzheimer's Report from Alzheimer's Disease International).

The initial clinical symptoms of the disease are almost imperceptible and typically involve lapses of memory for recent facts and poor judgment ¹. The performance of complex work tasks and ability to acquire new information may be reduced. After a couple of years cognitive functions are affected and patients show spatial disorientation, apathy, general disinterest, and difficulty in performing simple tasks such as preparing meals or managing bank accounts. Patients frequently lose emotional control, which may be accompanied by physical or verbal aggression. Symptoms of depression may prevail in the early stage of illness. With the progression of the disease, patients develop motor problems showing difficulty for walking and manual activities like writing. Recent memory is severely affected. Over several years, the disease leads to a gradual deterioration of the life of the patients, who manifest marked dementia with profound memory and cognition losses. Many patients become immobile and succumb to respiratory difficulties. AD is neuropathologically characterized by neuritic plaques and neurofibrillary tangles in regions of the brain particularly related to memory and cognition ².

Phytomedicines have been used for the treatment of various ailments since ancient times. In recent years there has been an increase in research output relating to natural products chemistry, especially in Nigeria and Africa in general. Various plant materials have been observed to exhibit a variety of biological activity such as antilipidemic activity, hepatoprotective activity, immunomodulatory activity and in treating multiple Neurodegenerative Diseases. Currently, as many as one-third to approximately one-half of all the drugs available are derived from plants or other natural sources ³.

The drug formulations of traditional systems of medicine like the African, Chinese and Indian systems usually contain crude extracts of different herbs that incorporate undesirable and toxic principles and active principles. With phyto and analytical chemistry developments, specific ingredients or a group of similar ingredients from plants are being extracted, isolated, and tested for their different therapeutic applications ⁴. The bioactive components of these herbs have been identified as mostly flavonoids, tannins, glycosides, phenolics, and other hydrophilic molecules. Nevertheless, isolation and purification of individual components from whole herbal extracts often lead to partial or total loss of therapeutic activity. The chemical complexity of the crude or partially purified extract appears to be crucial for the bioavailability of the active constituents; hence standardization of herbal extracts has become imperative ⁵. Although having excellent bioactivity in-vitro,  plant extracts often exhibit poor effectiveness in herbal extracts because the bioactive components cannot be absorbed into the blood by simple passive diffusion, and the bioactive phytoconstituents are mostly water-soluble; hence, their poor lipid solubility limits their ability to pass across lipid bio-membranes.

This has restricted the use of pharmacologically effective polyphenolic plant actives for treating different disorders. Moreover, when taken orally, bioactive phytoconstituents are destroyed by or lost to the gastric environment, or they may be rendered less effective by interaction with other drugs or nutraceuticals ⁶. To counter these problems, pharmaceutical research has been geared towards the development of novel lipid-based drug delivery systems to improve the bioavailability of drugs while maintaining the therapeutic activity of the drug. One delivery system designed to improve the in-vivo solubility and hence bioavailability of poorly soluble herbal drugs involves the incorporation of standardized herbal extracts intoherbosome or phytosome ^{7, 8}.

In view of their ampiphilic properties, herbosomes are more bioavailable (as demonstrated by pharmacokinetics and activity studies in animals) when applied topically or orally, compared with simple herbal extracts due to their enhanced capacity to cross into the blood through the lipid-rich biomembranes ^{5, 8}. The active components of the herbal formulation are also well protected from destruction by the gastric environment ⁹. Lipid drug delivery systems have advantages over Chitosan-based polymer systems. The advantages include heightened drug absorption, reduced side effects, controlled drug release, and site-specific targeting. Also, most lipid formulations have high stability, high carrier capacity, the feasibility of incorporating both hydrophilic and hydrophobic substances, and the feasibility of variable routes of administration ⁹.

Nanotherapeutic Approaches for AD Treatment and Prevention: Three types of barriers protecting the central nervous system (CNS) have been described: the Blood-Brain Barrier (BBB), the blood-cerebrospinal-fluid barrier (BCSFB) and the ependymal barrier. The BCSFB is localized in the choroid plexis epithelium in the ventricles, while the ependymal barrier plays the role of an obstacle between the cerebrospinal fluid (CSF) and the brain tissue. The BBB regulates the exchanges occurring between the CNS and the blood circulation ¹⁰. Although the BBB performs vital duties for the brain, such as protecting it from toxic compounds and mediating hemostasis, it interferes with the effective delivery of drugs to the CNS. Only highly lipid-soluble compounds with a molecular weight (MW) less than 400 Da are permitted to cross through the BBB ¹¹. Based on multiple reports, the BBB is altered in AD.

BBB disruption may be both a contributing factor to and a consequence of AD. Three types of BBB damage are found to contribute to the onset of AD, including leakage of undesired compounds from the blood to the CNS, dysfunction in the transport system, and changes in protein expression in endothelial cells ¹². BBB disruption may facilitate drug delivery since these disruptions are followed by increased BBB permeability, decreased expression of efflux transporters, and decreased CSF reabsorption. However, in some cases of AD, the impaired BBB leads to a reduced distribution of drugs in the CNS, and is a disadvantage for drug delivery ¹³. To overcome the BBB obstacle, nanotherapeutic approaches that can be applied within non-invasive frameworks have shown promise due to nanoparticles' high surface-to-volume ratio and the potential for surface functionalization with desired ligands. Nanotherapeutic approaches that have employed different mechanisms, including targeting Aβ, targeting cholinesterase and dissolving clots of fibrinogen, exhibited significantly better outcomes than current therapies.

Three methods have been used for targeting Aβ plaques: genetically inhibited or regulated expression of the Aβ peptide, inhibition of the fibrillation process, and clearing accumulated Aβ amyloids from the brain. Nanotechnology-based therapeutics provide delivery of the cholinesterase inhibitor Rivastigmine to the brain of Wistar rats by employing modified poly(n-butyl cyanoacrylate) NPs with polysorbate 80 and also chitosan NPs via intravenous and intranasal administration, respectively ¹⁴.

Alternative Therapy Using Medicinal Plants in Treatment of AD: Due to severe side effects of current therapies, alternative therapies such as the use of medicinal plants for the treatment of AD and other diseases are a vital focus of researchers (Ali M. et al., 2017; Ayaz et al., 2017a; Sadiq et al., 2018). The medicinal plants have been reported to enhance the memory and learning process that normally declines with AD (Ahmad et al., 2016; Ayaz et al., 2017b; Zohra et al., 2018). From the current literature, we have summarized potential anti-Alzheimer compounds isolated from various medicinal plants Table 1. Currently, several studies report on the phytochemicals that have been clinically proven with significant anti-AD potentials. Some of these bioactive compounds and their mechanisms of action against AD have been discussed in the following sections.

TABLE 1: THE MAJOR MEDICINAL PLANTS WITH POTENTIAL BIOACTIVE COMPOUNDS AND THEIR MECHANISMS OF ACTION AGAINST AD

Herbosomal Technology:

The Principle of Herbosome Technology: The flavonoid and terpenoid Phyto-chemical constituent extracts provide them for the direct complex with phosphatidylcholine. Herbosome results from a stoichometric amount of the phospholipid (phosphatidylcholine) reaction to the standardized extract or polyphenolic constituents in a non-polar solvent ²⁰. Phosphatidylcholine is a bifunctional compound and this (phosphatidyl) moiety being lipophilic, and the choline moiety being hydrophilic in nature. In particular, the choline head of the phosphatidylcholine molecule binds to these compounds while the lipid-soluble phosphatidyl portion comprising the body and tail, which then envelopes the choline-bound material. Hence, the Phytoconstituents build up a lipid compatible molecular complex with phospholipids, also called as phytophospholipid complex.

Mode of Phytophospho Lipid Complex Formation: The poor absorption of flavonoids or phytochemicals is likely due to two main factors. First, multiple ring molecules are not quite small enough to be absorbed from the intestine into the blood by simple diffusion, nor does the intestinal lining actively absorb them, as occurs with the standardized extract or polyphenolic constituents (like simple flavonoids) in a non-polar solvent. Phosphatidylcholine is a bifunctional compound, the phosphatidyl moiety being lipophilic and the choline moiety being hydrophilic in nature. Specifically, the choline head of the phosphatidylcholine molecule binds to these compounds while the lipid-soluble phosphatidyl portion comprising the body and tail, which then envelopes the choline bound material. Hence, the phytoconstituents produce a lipid compatible molecular complex with phospholipids, also called as phytophospholipid complex. Molecules are anchored through chemical bonds to the polar choline head of the phospholipids, as can be demonstrated by specific spectroscopic techniques. Precise chemical analysis indicates the unit pyrosomes is usually a flavonoids molecule linked with at least one phosphatidylcholine molecule. The result is a little microsphere or cell is produced ²¹.

Herbosome Formulation: Herbosome is a patented process developed in the year 1989 by Indena, an Italian pharmaceutical and nutraceutical company. They patented the technology as T ®. This phytosome is a cell-like structure, a combination of soy lecithin with standardized extracts containing polyphenolic compounds, vastly improving their absorption and utilization ²². Herbosomes result from the chemical reaction of a stoichiometric amount of the phospholipid to the standardized herb extract or specific active phytoconstituents and are generally prepared by solvent evaporation or anti-solvent precipitation techniques using alcoholic or organic solvents as reaction media. The supercritical fluid technique has also been incorporated into herbosome technology (for preparing puerarin–phospholipid complex) by researchers such as Li and coworkers ²³. In the more frequently used solvent evaporation technique, the drug (standardized extract or isolated bioactive phytoconstituents) and the phospholipids are placed in the same flask containing a suitable solvent system. The reaction is carried out at suitable fixed temperature for a fixed duration of time to get the maximum possible yield and drug entrapment ². The optimum ratio of phospholipid to drug is 1:1, although different molar ratios ranging from 0.5:1 to 3:1 have also been employed with success ^{24, 25}. The herbosome complex thus formed can be isolated by precipitation with an aliphatic hydrocarbon or lyophilization or spray drying ²⁶. The common stages for the preparation of herbosomes are shown in Fig. 3. Usually, Aprotic solvents like acetone, methylene chloride, ethyl acetate, dioxane etc., are used as reaction media for formulating herbosomes; however, they have been largely replaced by protic solvents 14 like ethanol. Other Solvents such as tetrahydrofuran, dichloromethane, and n-hexane have also been used by researchers ^{24, 27, 28}. Most of the recent works have been carried out using absolute ethanol as the reaction medium.

The common criterion for the selection of phospholipids for herbosome formulation was the ratio of phosphatidyl group present in them. The most commonly used phospholipids are those derived from soya beans containing higher proportions (that is, about 76%) of phosphatidylcholine with a high content of polyunsaturated fatty acids like linoleic acid about 70%, linolenic acid, and oleic acid. The phospholipids of the soya bean have been the phospholipid of choice because the higher content of phosphatidylcholine in them offers compatibility and similarity with the mammalian plasma membrane ²². Soy lecithin, phosphatidylserine, and 1, 2-distearoyl-sn-glycero-3- phosphocholine have also been used.

FIG. 1: COMMON STAGES FOR PREPARATION OF HERBOSOME ⁶

Evaluation and Characterization of Herbosomes: Factors such as size, membrane permeability, the amount and purity of preparatory materials, the percentage of entrapped phytochemicals, and chemical composition determine how a herbosome would behave in a biological system. A variety of techniques have been employed for the study and characterization of herbosomes. Transmission Electron Microscopy and Scanning Electron Microscopy have been used to visualize the herbosome after formation to assess its size and shape.

The formation of the phyto-phospholipid complex can be confirmed by FTIR spectroscopy, X-ray diffraction, NMR, and Molecular imaging techniques, while the drug content of the complex can be quantified used HPLC. Other techniques used include Dynamic light scattering (DLS) coupled with a computerized inspection system and Photon correlation spectroscopy to determine the particle size and Zeta potential of the complex and Ultracentrifugation to determine the entrapment efficiency of an extract by a herbosome.

Applications of Herbosomes: Herbosomes formulations in solutions, emulsions, creams, lotions, gels etc., have gained importance in various fields like the pharmaceutical, veterinary, cosmetic, and nutraceutical fields. Companies involved in producing and marketing herbosomal products include Indena in Milan, Italy; Jamieson Natural Sources in Ontario, Canada; Thorne Research in Dover, England and Natural Factors in Canada. The herbosome process has been applied to many popular herbal extracts, including Gingko bilboa, grape seed, hawthorn, olive fruits and leaves, green tea, ginseng, kushenin, marsupsin, and curcumin ²⁹. These phytosomes are significantly more bioavailable and hence therapeutically more effective than the standardized extracts or their conventional forms and are useful in various disorders. Maiti et al. ³⁰, have demonstrated the improvement in pharmacokinetic profile of curcumin on carbon tetrachloride-induced acute liver damage in rats by preparing its complexation with phospholipids.

The antioxidant activity of the herbosome was significantly higher than that of pure Curcumin at all dose levels tested ^{22, 31, 30} Maiti et al. ¹⁹, also demonstrated the improvement in pharmacokinetic profile of naringenin herbosome. The developed naringenin herbosome exhibited better antioxidant activity than the free compound with a prolonged duration of action ^{31, 32}. Yanyu et al. have evaluated the bioavailability of silybin– phospholipid complex against silybin-N- methylglucamine. The phospholipid complex showed prolonged plasma therapeutic level and increased bioavailability ³³. Chen et al. ²¹ demonstrated the pharmacokinetic profile of quercetin, kaempferol, and isorhamnetin present in Ginkgo biloba extract after oral administration in rats by formulating its phospholipid complex. The results demonstrated an immense increase in bioavailability of the extract in its phospholipid complexed form ^{22, 34}. Other therapeutically efficient phytosome complexes from different plant extracts/ active compounds developed in recent years are summarized in Table 1, along with the improved pharmacodynamic and pharmacokinetic profiles of the crude drug and their clinical utility.

Benefits of Herbosome Formulations:

1. Potential enhancement of bioavailability.
2. Herbal herbosome process produces a little cell whereby the valuable components of the herbal extracts are protected from destruction by digestive secretions and gut bacteria.
3. Pharmacologically Assured delivery to the different biological tissues.
4. No compromise of nutrient safety.
5. Less dose requirement is due to absorption of chief constituent.
6. Drug loading efficiency is so high and more over predetermined because drug itself in conjugation with lipids is forming vesicles.
7. No problem of drug entrapment.
8. Herbosomes shows better stability profile because chemical bonds are formed between phosphatidylcholine molecules and phytoconstituents.
9. Phosphatidylcholine used in the herbosome process which acting as a carrier and also nourishes the skin, because it is essential part of cell membrane.
10. Herbosome is also superior to liposomes in skin care products.
11. Significantly gives greater clinical benefit than liposome’s.
12. The structure of herbosome elicits peculiar properties and advantages in cosmetic application.
13. Significantly Enhanced ability of herbosome to cross cell membranes and enter cells.
14. Their low solubility in aqueous media allows the formation of stable emulsions or creams.

CONCLUSION: A wide number of phytochemical constituents are Isolated from herbal drugs mostly the flavonoids and the terpenoids fraction furnishes with a number of applications. The poor absorption and the poor bioavailability associated with the polar phytoconstituents limit its use. The poor bioavailability can be removed by formulating an appropriate drug delivery system like Herbosome (Phospholipids) based drug delivery system has been found promising for better and effective drug delivery and can increase bioavailability rate and extent of drug absorption across the lipoidal biomembrane. Herbosome is one of the phospholipids-based herbal drug delivery systems with a better absorption and stability profile than other phospholipids-based drug delivery systems. The Herbosome can play a vital role in the value delivery of phytoconstituents such as the flavones and the xanthones. Apart from the use of herbosome also has a wide scope in herbal formulations and cosmetics as well. Many areas of herbosome will be revealed in the future as part of their pharmaceutical use.

ACKNOWLEDGEMENT: Nil

CONFLICT OF INTEREST: Nil

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How to cite this article:

Riyazullah MS and Kumar PR and Reddy KB: A review on chitosan based herbosomes a nano-drug delivery to cure alzeimer’s disease. Int J Pharmacognosy 2020; 8(7):298-04. doi link: http://dx.doi.org/10.13040/IJPSR.0975-8232.IJP.8(7).298-04.

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