Introduction

Since ancient times humans rely on plants for their livelihood. Nature has furnished a complete storehouse of remedies in the form of herbs [1]. The knowledge of herbal medicines encompassed over thousands of years so that most of the phytoconstituents are utilized for ensuring health care. In twentieth century, bioactive compounds are explored due to their therapeutic potential to treat several diseases such as cancer, cardiovascular, neurodegenerative diseases and many more [2]. These phytoconstituents/bioactive compounds are reported to posses pharmacological activity but due to their poor physicochemical, pharmacokinetic (solubility and bioavailability) and pharmacodynamics properties, they are unable to meet the desired delivery [3,4,5].

Herbal extracts/plant actives have various hurdles like physicochemical considerations that may result in poor and/or variable solubility, chemical instability in the acidic pH and metabolism, poor permeation through the intestinal wall [5]. Many herbal extracts containing phytoconstituents like flavonoids, tannins, terpenoids and polyphenolics are highly soluble in water but are nevertheless poorly absorbed either due to their multiple-ring large size molecules (500–4000 Da), which cannot be absorbed by diffusion or due to poor absorption through lipid-rich membranes of the small intestine. [3, 6] Similarly, some phytoconstituents like Silybin, Triterpenes, Ginkgolides, Bilobalide, Curcuminoids etc. have low aqueous solubility and minimum absorptivity, leading to drug levels below therapeutic concentration in the blood. Taken as a whole, these findings lead to the conclusion that phyto-formulations must have a good balance between hydrophilicity and lipophilicity.

Therefore, recent research is more focused on the designing of novel carrier systems, including surfactant and polymer/lipid-based systems for the effective delivery of phytoconstituents. However, there is still lack information about the physicochemical stability as well as the targeted delivery of these herbal drugs [1, 2, 5]. The physicochemical properties depend on various factors like pKa of the compound, log P value, gastrointestinal pH, size of the particle and surface area. The process of absorption also depends on the surface area, gastro intestinal track length and blood flow [7,8,9].

Nano-sized particulate, colloidal, and vesicular carrier drug delivery systems are emerging trends that have grained potential to address these associated limitations. Novel drug delivery system (NDDS) refers to a combined approach that is based on various streams like biological science, physical science, biotechnology, polymer science, applied chemistry and pharmaceutical sciences; thus the nano-sized drug delivery systems (ranging from 1 to 100 nm) for bioactive compounds have great future for overcoming the limitation associated with them thereby enhancing the utilization of herbal molecules [5, 8]. Pharmaceutical nanomedicine can deliver bioactive compounds or plant extracts into the body with their desired therapeutic efficacy. These modern approaches are termed as novel drug delivery systems (NDDS), which contain polymeric/lipidic nanoparticles, nanoemulsions, liposomes, niosomes, phytosomes, transferosomes, microspheres, self-emulsifying drug delivery system, hydrogel and cyclodextrin complexation [3, 5]. Thus, the encapsulation of herbal extracts or plant actives into novel carrier systems reduces the metabolic degradation and accumulation of drugs at the nonspecific target site which improves their efficacy. This also contributes towards the patients’ compliance in case of pediatrics and geriatrics [9].

In the past few years, considerable attention has been focused on the expansion of novel nanomedicine [10,11,12]. These techniques have reported remarkable advantages over the conventional formulation. Modern drug delivery systems led to an enhancement of solubility and stability, improved bioavailability and reduced toxicity along with the improved kinetics and dynamics of the herbal formulation [3, 5, 13]. In the present review emphasis on various aspects like recent advancement in novel strategies for phyto-formulations, their limitations and applications in drug delivery are covered. This review aims to provide exhaustive information about the findings related to such systems which will be beneficial for pharmaceutical researchers, academics and industrialist. The novelty being focusing on those many bioactive compounds which are yet to be explored for their physical, chemical, kinetics, dynamics and therapeutic effect. The overall finding report use of liposomes and self-emulsifying drug delivery system as the most preferred system for delivery of herbal compounds.

Novel strategies for delivery of herbal extract/ bioactive

Vesicular nano-carrier drug delivery system

In the current scenario drug targeting and desired (sustained/controlled) delivery are key requirements to improve the quality of therapy. Researchers have focused on formulation studies of vesicular nanocarrier systems like Phytosomes, Liposomes, Niosomes, Transferosomes as these are promising materials to overcome the shortcomings associated with conventional medicines [14, 15].

Colloidal particulate drug delivery system

Nanotechnology deals with the size range of one thousand millionths of a particular unit i.e.,

1 nm = 109 m, which offers an advanced drug delivery system for preventing and treating various diseases [10]. The different types of colloidal particulate drug delivery systems like Solid lipid nanoparticles, Metal nanoparticles, Microspheres and Emulsions are discussed below [3, 10].

Other drug delivery system

Besides vesicular and colloidal systems hydrogels and cyclodextrin contributes as another drug delivery system [16, 17].

Vesicular nano-carrier drug delivery system

Phytosome

Definition

Phytosome is a patented technology developed by INDENA which is a leading Italian manufacturing company of pharmaceuticals and nutraceuticals [3]. This technology has emerged as an advanced herbal drug delivery system with improved stability, bioavailability and target specificity of active plant constituents. According to the known definition, it consists of two words “Phyto” and “Some” here “Phyto” means plant and “Some” means cell-like structure [18].

Description

Phytosomes are reported as ideal vesicular drug delivery systems (VDDS) capable of delivering both water-soluble (like flavonoids, tannins, terpenoids, etc.) and lipid-soluble (polyphenols-sparingly soluble in both water and lipids) compounds along with phospholipid [19]. Phosphatidylcholine a bifunctional moiety with hydrophilic choline and lipophilic phosphatidyl part is important characteristic of phytosomes [20]. The phospholipid and phytoconstituent exist in specific stoichiometric proportion of 2:1 or 1:2. The average phospholipid complexes have particle size range 50 nm to 100 μm [21, 22]. The Phyto-phospholipid complex structure by micelle formation is depicted in Fig. 1 [2, 3]. Improved stability and solubility due to the chemical linkage, improved membrane permeation ability as well as improved bioavailability with the desired therapeutic effect are the advantages of phytosomes, which prove it as most acceptable system for delivery of herbal bioactives [23, 24].

Fig. 1
figure 1

Phyto phospholipid complex structure by micelle formation (Phytosome) [3] [2]

Full size image

Method of preparation

In phytosome formulation therapeutic agents, carrier material and solvent are the most important components. The selection of standardized herbal extract or an active phytoconstituent depends on its hydrophilicity or lipophilicity. The choice of carrier phospholipid depends on its chemical stability. The phospholipids commonly used are phosphatidylserine/ phosphatidylcholine/ phosphatidylethanolamine [3, 21]. In phospholipid complexation strategy the choice of solvent depends on the solubility of both herbal bioactive and phospholipids. Several types of research suggest that the use of either aprotic or protic solvents as well as a mixture of solvents for better dissolution of compounds. Aprotic solvents like dichloromethane, diethyl ether, dichloromethane, dioxane, chloroform and n-hexane are replaced with alcohol (ethanol) which is considered safe. In the first step of phytosome preparation 2–3 mol of natural or synthetic phospholipid is mixed with 1 mol of herbal extract/phytoconstituent and then dissolved in organic solvent like dioxane, acetone, methylene chloride, hexane and ethyl acetate. The organic solvent is then removed completely along with the aqueous content by a rotary vacuum evaporator. Phytosomes are isolated by precipitation with non-solvent, lyophilization, spray drying or vacuum drying. The diagrammatic representation is depicted in fig. 2 [18, 21, 24, 25].

Fig. 2
figure 2

Processing steps for preparation of phytosomes [18, 21, 24, 25]

Full size image

Applications

Phytochemicals such as polyphenols, flavonoids, tannins, terpenoids, nitrogen/sulphur-containing compounds delivered as phytosomes which posses antimicrobial, antioxidant and anti-inflammatory properties [15]. Recently curcumin, resveratrol and many other polyphenolic compounds have been investigated for their use in preventive of cancer and cardiovascular diseases [7]. Research evidence suggests that phytosome tailored drug delivery system helps to overcome the limitations associated with herbal extract/bio-actives [10, 18]. Commercial products of phytosomes along with their pharmaceutical applications are listed in Table No.1-(1.1.1-a) & the recent findings of herbal constituents by phytosomal delivery system is enlisted in (1.1.1-b) [31,32,33,34,35,36,37,38,39,40].

Liposome

Definition

Liposomes are spherical shaped vesicular drug delivery systems comprising of concentric bilayers capable of encapsulating both hydrophilic and lipophilic material in a single structure [3]. They are self-assembled lipid bilayer membranes vesicles which are formed by phospholipids and cholesterol [10, 18]. This colloidal system is designed with a unique framework by interaction with water, polar lipids and form self-organized colloidal particles. As drug carriers, liposomes are extremely versatile [2, 41]. They can carry hydrophobic drugs within the non-polar lipid membrane core and hydrophilic drugs in the aqueous interior pocket consequently; the water-soluble compounds are entrapped in the aqueous compartment and lipid-soluble compounds aggregate in the lipid section. The size of the liposomes ranges from 50 nm to more than 1 μm, depending upon their respective composition and preparation method [42].

Description

Liposomes are bilayer lipidic vesicular carrier system which can be prepared using various phospholipids like phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylglycerol and other molecules such as cholesterol. There are various types of liposomal vesicles like small unilamellar vehicles (SUV-100 nm), large unilamellar vesicles (LUV-200 to 800 nm), multilamellar vesicles (MLV-500 to 5000 nm), long-circulating liposomes (usually surface-grafted with certain polymers), immunoliposomes (carrying antibodies) [18, 43, 44]. Various types of liposomal vesicles are depicted in Fig. 3.

Fig. 3
figure 3

Structure of new generation liposome carrier system. (A) Conventional liposome (B) Cellular membrane coated liposome (antibody) (C) Polymer functionalized liposome (D) Different lamellar vesicles liposome (E) Core- shell lipid polymer liposome (F) Surface modified immuno liposome (G) Multi lamellar liposome. [18, 43, 44]

Full size image

The conventional liposomes have certain limitations (leakage and fusion, short half-life, less stability, etc.) so these liposomes are tailored into advanced carrier systems as new generation liposomes. These spherical vesicular systems effectively provide improved sustained/controlled release, longer stability, drug loading efficacy, target selectivity, prolonged action and higher drug entrapment efficiency of bioactive components [5, 45].

Method of preparation

The synthesis of the liposome is complex process due to complications in attaining nano size, stability and effective encapsulation efficiency. The methods for synthesis of liposomes are classified based on mechanical methods, organic solvent replacement method and fusion method.

  • Mechanical methods -

  • Film method and

  • Ultrasonic method [3, 10]

  • Organic solvent replacement method

  • Reverse-phase evaporation and

  • Ether vaporization method [18, 41, 46]

  • The fusion of prepared vesicles or size transformation method

  • Freeze-thaw extrusion method and

  • Dehydration–rehydration method [32, 47, 48].

New generation liposome - PEGylated Liposomes.

In PEGylation of liposomes has gained much attention as compared to the conventional and targeted liposomes. Poly-(ethylene glycol) (PEG) has been widely used as a polymeric steric stabilizer to improve the blood circulation time of liposomes. It can be incorporated on the liposomal surface in different ways, but the most widely used method is to anchor the polymer in the liposomal membrane via a cross-linked lipid (i. e, PEG- distearoyl-phosphatidylethanolamine [DSPE] [3, 43].

PEG is a linear polyether diol with advantages of biocompatibility, solubility in aqueous and organic media, lack of toxicity, very low immunogenicity, antigenicity and good excretion kinetics. For example, when liposomes are covalently bound to PEG for reducing the identification by macrophages, the stability and circulation half-lives were increased. Daniel Bobo et al., reported, several liposomal formulations which had been approved by the USFDA like Doxil, DaunoXome, and Abraxane etc. and some of nano-liposomal formulations like CPT-11, SPI-077, and CPX-35 are in different clinical trial phases [49].

Long circulating liposomes are composed of poly (ethylene glycol) (PEG). This PEG is grafted on the exterior surface of liposome. The circulation time of the vesicles can be prolonged depending upon both the amount of grafted PEG and the length or molecular weight of the polymer. For example, Marcel B. Bally et al., reported that 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE) when modified with PEG(DSPE-PEG 2000) showed increased plasma circulation longevity as compared to 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC). Similarly, longer-chain PEGs (i.e., PEG 1900 and PEG 5000) have maximum blood residence time as compared to short-chain PEG (i.e., PEG 750 and PEG 120). PEG 2000 containing liposome exhibit increased blood circulation time compared to formulations containing PEG 350 to 750 [50, 51].

Surface modification of liposomes with PEG can be achieved in several ways: -

  • by physically adsorbing the polymer into the surface of the vesicles,

  • by incorporating PEG-lipid conjugate during liposome preparation, or

  • by covalently attaching reactive groups on the surface of the preformed liposome.

Liposomes can serve as the carriers system for antitumor drugs, anti-fungal drugs, analgesic drugs, gene therapy and vaccines. Surface modification of liposomes with PEG is illustrated in Fig. 4 [43].

Fig. 4
figure 4

Systemic presentation of modification of convention liposome into PEG coated liposome for specific target delivery of active component.. [3] [43]

Full size image

Applications

Liposomes are increasingly used to deliver several herbal products for the prevention or treatment diseases [29]. Presently, the liposomal delivery system finds wide application in food processing, cosmetic formulation and pharmaceutical industries [15]. Liposomal phytoconstituents delivery can help in achieving consistent stability, bioavailability, and therapeutic effects of herbal products. The list of phytoconstituents liposomal delivery system is summarized in Table No.1- (1.1.2) [52,53,54,55,56,57,58,59,60].

Niosome

Definition

Niosomes are bilayer amphipathic vesicular carriers similar to liposomes, in which phospholipids are replaced with nonionic surfactants. Niosomes can entrap hydrophilic, amphiphilic, and lipophilic molecules and can exhibit longer circulation time compared to liposomes [3, 14, 61].

Description

Niosomes are bi-layered structure, hydrophilic and hydrophobic ends of their surfactant tend to arrange into external and internal sites, respectively [2, 10]. These vesicular carriers are compatible with intracellular tissues, non-toxic, biodegradable, non-immunogenic and can deliver various therapeutic agents, including proteins, herbal extract and bio-actives to their target site of action [61]. Niosomes have structural similarities with liposomes; however, liposomes have some limitations like leaking, fusion, less economic and stability issues [52]. Niosomes formulations can successfully overcome these disadvantages and are widely acceptable systems. Niosomes as delivery system offers several advantages like reduced dose, highly stable in varying pH, targeted drug delivery, reduced side effects, increased efficacy and osmotically active [61]. Delivery of active drug substance by noisome is represented in Fig. 5 [3, 14, 61].

Fig. 5
figure 5

Delivery of active drug substance by Niosome. [3, 14] [61]

Full size image

Method of preparation

Niosomes are formulated by the non-ionic surfactant, cholesterol and di-ethyl ether with successive hydration in the appropriate media. This vesicular system can deliver hydrophilic/lipophilic and synthetic drugs as a unilamellar or multilamellar vesicle [61,62,63]. The different methods for preparation of niosomes are represented in Fig. 6. Thin-film hydration method and reverse phase evaporation method are discussed below-.

Fig. 6
figure 6

Methods of Preparation for Niosomes. [42] [61] [63] [64]

Full size image

Thin-film hydration method

This method is suitable for multilamellar niosomes. In this method, the surfactants, cholesterol, and additives are dissolved in an organic solvent. Excess of solvent is removed by rotatory vacuum evaporator to obtain a thin film. Dried surfactant film could be rehydrated by the aqueous phase. After hydration, multilamellar niosomes vesicles are obtained [61].

Reverse phase evaporation method

This method is applied for large unilamellar vesicles of niosomes. For this, all ingredients are dissolved in a mixture of ether and chloroform and added to the aqueous phase containing the drug. The mixture is sonicated for emulsification and evaporated to get unilamellar vesicles [42].

Applications

Niosomes have a wide range of biological applications such as target specificity, maximum stability and retention of drugs in blood circulation, sustain/controlled release of drugs and as diagnostic imaging agents. In addition to the pharmaceutical application, noisome also act as an excellent carrier for anti-inflammatory drugs, anticancer drugs, hormones and natural compounds such as plant extracts or their active components [61]. The term phyto-niosomes describes niosomes containing various herbal drug extracts such as Ginkgo biloba extract, marigold extract etc. [63, 64]. Pereira M.C. et al. introduced a novel vesicular carrier system for cancer by formulating coated niosomes which provides long circulation time and uniform bio distribution throughout the entire tumor cells. Rinaldi F. et al. studied and investigated the better anti-inflammatory activity of ibuprofen and lidocaine containing noisome as compared to the free drug. Some of the reported work on niosome delivery system is summarized in Table No.1-(1.1.3) [63,64,65,66,67,68,69,70,71].

Transfersomes

Definition

Transfersomes are defined as specially designed highly deformable vesicles, consisting of at least one inner aqueous compartment enclosed by lipid vesicles. They are like liposomes in morphology, but, functionally, they are suitably deformable to go through membrane pores [3]. Transferosome is a trademarked technology of the German company IDEA AG. It consists of two words “transferred” and “some” where “transferred” means carrying and “some” means body [5, 10, 72, 73].

Description

Transfersomes consist of phospholipid, surfactant, and water [1, 3]. They are elastic and extremely adaptable aggregates and this property assist in their quick penetration through the intercellular lipid pathway of the subcutaneous tissue. They have a diameter of approx. 100 nm [18, 22]. Tranferosomes can encapsulate both hydrophilic and hydrophobic moieties (herbal/synthetic) in their structural framework are highly biocompatible, sustained release and effectively used in topical application [3, 10]. The technologies (Freeze-thaw method, Ethanol injection method, Vortexing sonication method, Reverse-phase evaporation method and Rotary film evaporation method) are popular for the preparation of transfersomes. [61, 72]. Rotary film evaporation method and reverse-phase evaporation method are discussed below-.

Method of preparation

Rotary film evaporation method

This method was invented by Bangham. It is also known as the hand-shaking method. For the preparation of transferosomes all ingredients phospholipids and surfactants are dissolved in a mixture of solvent (chloroform and methanol) into a round bottom flask. After constant rotation film is prepared on the walls of the flask. This film is then hydrated using aqueous media containing drug resulting in formation of bilayer vesicles due to the swelling of lipid [72].

Reverse-phase evaporation method

In this method, surfactant-containing aqueous media and lipids containing organic solvents are collected in a round-bottomed flask. Then drug is added to the lipid or aqueous medium based on its solubility. The mixture is sonicated fallowed by removal of solvent under low pressure [72, 73].

Applications

Transfersomes have been used as carriers for delivery of different therapeutic agents, including proteins, nutraceuticals, insulin, antigens, peptides, albumin, analgesics, sex hormones, anticancer drugs and phytoconstituents/herbal extracts. The example of drugs delivered as transfersomes are mention in Table 1-(1.1.4) [74,75,76,77,78].

Table 1 Listing of recent work on vesicular nano-carrier drug delivery system to solve the hurdles related with herbal drug
Full size table

Colloidal particulate drug delivery system

Polymeric nanoparticles

Definition

Nanonization deals with several issues like low oral bioavailability, low solvency, poor ingestion etc. [3, 10]. Polymeric nanoparticles are the structure of solid colloidal particles with a size dimension of 10 to 1000 nm (1 μm). There are several types of nanomaterials such as polymeric nanoparticles, solid lipid nanoparticles, metal nanoparticles, etc. which if investigated could be an interesting approach in drug delivery systems. Usually, these nanoparticles are coupled with nonionic surfactants to reduce the interaction with the immunological system and the functional groups attached with them. Based on the structure, nanoparticles are broadly known as nanospheres and nanocapsules. The system in which the drug is enclosed into a cavity surrounded by a unique polymer membrane is known as nanospheres, whereas the matrix systems in which the drug molecule is dispersed are nanocapsules [17, 22].

Description

Nanoparticles are an effective delivery system which requires synthetic polymer, proteins, lipid and carbohydrates for the delivery of drug component. Several herbal compounds such as curcuminoids, praziquantel and paclitaxel are delivered as polymeric nanoparticles with 400 nm size range. Polymeric nanoparticles are synthesized by using biocompatible polymers that facilitate controlled drug delivery with target specificity and prolong stability [3, 81]. Nowadays various advanced polymers are extensively used in polymeric nanoparticles such as poly-L-lactic acid (PLA) and copolymers with glycolic acid (PLGA). Besides there, the other widely used polymers are poly (ε-caprolactone) (PCL), methacrylic acid copolymers, and acrylic or methacrylic esters, triglycerides, lecithin natural or synthetic lipids are used [79, 80]. Bisht et al. synthesized curcumin-loaded polymeric nanoparticles using copolymers of N-isopropyl acrylamide (NIPAAM), with N-vinyl-2-pyrrolidone (VP) and poly(ethylene glycol)monoacrylate (PEG-A). Solvent evaporation and electrospinning method are discussed for the preparation of polymeric nanoparticles [82, 83].

Method of preparation

Solvent evaporation

In this method, the polymer is first dissolved in ethyl acetate (better toxicological profile in comparison to Dichloromethane and chloroform), therefore the resulting solution is emulsified with an aqueous phase. Then the mixture is typically processed using a surfactant and high-speed homogenization or ultra-sonication, to obtained dispersion of nanodroplets. By using a continuous magnetic stirring solvent is completely evaporated. After the solvent has evaporated, the solidified nanoparticles can be washed and collected by centrifuging, followed by freeze-drying for long term storage.

Electrospinning

This technique is highly versatile for fabrication of nanofibrous materials. It is one of the widely adopted encapsulation technique for thermosensitive bioactive agents. The electrostatic force is used to draw a fine nanofiber out of polymer solution droplet, which flies toward the nearest lower electrical potential target. The electrospinning apparatus consist of three main components: a high voltage power supply, a polymer solution reservoir (e.g., a syringe) with or without a flow control pump, and a metal collecting screen. The concentration of polymer, molecular weight, and fiber morphology (low viscosity), electrical conductivity (higher molecular weight polymer) and effect of solvents are the critical parameter to be considered in the preparation of nanofibres containing bioactive components.

The three stages of method includes –

  • The polymeric solution is kept in a reservoir and connected to a power supply to establish a charged polymer jet.

  • Charging the polymer solution could be done either with a syringe with a metal needle or a capillary with a metal tip in the polymer solution.

  • The fiber collecting screen is expected to be conductive and it can either be a stationary plate or a rotating platform or substrate. The plate can produce non-woven fibers, whereas a rotating platform can produce both nonwoven and aligned fibres. [84, 85].

Applications

To improve the nanosize range and specificity several metal ions have been used for the preparation of nanoparticles such as gold, silver, zinc and platinum. Recently the phyto extracts of Cucurbita pepo, Malvacrispa, Acalyphaindica, Zingiberoffcinale, Syzygiumcumini leaf extract Cymbopogon citrate, Abelmoschusesculentus, Pelargonium graveolens, Cassia auriculata and Punicagranutum were successfully delivered as gold nanoparticles. Similarly several phytoconstituents such as Acoruscalamus, Boerhaaviadiffusa Tea extract, Tribulusterrestris, Cocousnucifera, Abutilon indicum, Pistaciaatlantica, Ziziphoratenuior, Cymbopogancitratus, Acalyphaindica, Premnaherbacea, Calotropisprocera, Centellaasiatica, Argyreia nervosa, Psoraleacorylifolia, Brassica rapa, Cocciniaindica, Vitexnegundo were delivered as silver nanoparticles [5, 27, 45].

Dube, A. et al., formulated chitosan nanoparticles for enhanced intestinal absorption of both (+)-catechinand(−)-epigallocatechin gallate. The cumulative amounts transported after encapsulation were significantly (p < 0.05) higher, i.e. 302.1 ± 46.1 vs 206.8 ± 12.6 ng/cm2 and 102.7 ± 12.4 vs 57.9 ± 7.9 ng/cm2 for catechin and epigallocatechin gallate, respectively. The mechanism by which absorption was enhanced was stabilization of catechins after encapsulation (99.7 ± 0.7 vs 94.9% ± 3.8% and 56.9 ± 3.0 vs 1.3% ± 1.7% of the initial catechin and epigallocatechin gallate concentration respectively) [86]. Konecsni, K., et al., formulated rutin loaded chitosan (CH)-tripolyphosphate (TPP) nanoparticles. Theses nanoparticles are prepared by using 4.0:1.0 of CH:TPP mass ratio. The particles carried a high positive charge which promoted mucoadhesion. These are some examples of polymeric nanoparticles loaded with herbal bioactive [87]. The polymeric particles for herbal constituents are listed in Table 2-(2.1.1) [82, 86,87,88,89,90,91,92,93,94].

Table 2 Listing of recent work on colloidal particulate drug delivery system to solve the hurdles related with herbal drug
Full size table

Microspheres

Definition

Microspheres are spherical shaped micro sized particles with diameter 1–1000 μm protecting the drugs efficiently [3]. Microparticles are classified into two types; microcapsules (distinct capsule wall) and microspheres (dispersed throughout the matrix) [5]. The natural and synthetic polymers used for formulation of microspheres are polylactide-co-glycolide, albumin, polypropylene, gelatine, dextran, modified starches, polylactic acid. This delivery system is capable of controlling the release pattern of herbal components for a longer period i.e. can provide prolong release(sustain/control) [15, 61].

Description

Microspheres are classified as biodegradable and non-biodegradable. Syringeability and target specificity made this delivery system more popular for bio-actives delivery of bioactives. In the last few decades, many herbal extract/phytoconstituents are such as zedoary oil, tetrandrine, quercetin and Cynarascolymus extract are delivered as microspheres [80].

Method of preparation

The following methods are used for the preparation of the microspheres. Some of them are discussed below-

  • Solvent evaporation

  • Single emulsion technique –

    • Thermal cross-linking

    • Chemical cross-linking agent

  • Double emulsion technique

  • Polymerization technique –

    • Normal phase polymerization- Bulk, Suspension, Emulsion.

    • Interfacial polymerization

  • Spray-drying technique

  • Wet inversion technique

  • Complex coacervation

  • Hot melt microencapsulation

  • Extrusion spheronization

  • Quasi-emulsion solvent diffusion method [95,96,97].

Solvent evaporation technique

This is the most popular and commonly used technique. It utilizes both microencapsulation and the o/w emulsion, system for the preparation of microspheres. This method is used for the formulation of microparticles with low drug loading capacity [95, 97].

Double emulsion technique

This method is also called the hydrous technique and is applicable for water-soluble drugs. This technique is carried out in fallowing steps-

  1. 1.

    Formation of primary emulsion (drug + aqueous solution of polymer)

  2. 2.

    Formation of double emulsion (addition of aqueous solution of polyvinyl alcohol)

  3. 3.

    Formation of multiple emulsion (addition of large aqueous phase (w/o/w))

  4. 4.

    Solvent evaporation (microsphere in solution)

  5. 5.

    Separation, washing and drying. (Collection of microspheres)

Wet inversion technique

This technique is carried out in the following steps –

  1. a.

    Addition of polymeric solution (dropwise through the small-sized nozzle) with acetic acid in an aqueous solution of a counterion such as sodium tripolyphosphate.

  2. b.

    After the formation of microsphere addition of cross-linking agent (ethylene glycol di glycidyl ether)

  3. c.

    Microspheres are then washed and freeze-dried [97].

Applications

Novel carrier drug delivery systems are specially designed to achieve increase drug concentration at the target site, to reduce side effects and to improve bioavailability. The microspheres are promising carriers for the effective delivery of various herb extract/bioactive as well as synthetic drugs [75]. Zeng H. et al., prepared microspheres of locust bean gum (LBG) and poly(vinyl alcohol) (PVA) was developed for oral controlled release of buflomedil hydrochloride (BH) by emulsion crosslinking method using glutaraldehyde as crosslinker. Hence, microspheres of LBG and PVA can be used as a potential carrier for controlled oral delivery of highly water-soluble drugs like BH. Some of the recent literature is mentioned in Table 2- (2.1.2) [96, 98,99,100,101,102,103,104,105,106].

Emulsion

Definition

As per the known definitions, Emulsion refers to isotropic dispersed systems of two immiscible liquids [1, 3]. They consist of an oily system dispersed in an aqueous system or vice-versa. One of them is internal phase and the other is continuous phase. In o/w emulsion water in the continuous phase whereas in w/o emulsion oil in the continuous phase. The emulsion is composed of natural/synthetic oils, solid/ liquid surfactants, and/or one or more hydrophilic solvents and co-solvents/ surfactants [3]. Its appearance is translucent to transparent liquid. Emulsions are generally classified ordinary emulsion (0.1–100 μm), microemulsion (10–100 nm), sub-micro-emulsion (100–600 nm), etc. [107].

Description

As a vesicular drug delivery system emulsion have a greater affinity towards lymphatic fluids. Hence nano-diametric vesicles can easily cross membrane barriers and enhance the efficacy of drug. Now-a-day’s research is being focused to reduce the size of the globules to make the delivery system more stable for desired and improved pharmacokinetics of the drug. Various surfactants including polysorbate 20, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 60 castor oil, and PEG 300 caprylic and co-surfactants like ethanol, glycerine, poloxamer 407 and propylene glycol are widely used for micro-emulsion preparation.

The small droplet size of emulsion facilitated maximum surface area for the better penetration of herbal extract/poor aqueous soluble drug. The lipophilic drugs being delivered by o/w or o/w/o emulsion, while water-soluble drugs are delivered by w/o or w/o/w emulsion [107, 108].

Multiple emulsion

Multiple emulsion are also known as “emulsions of emulsions” in which w/o/w emulsions consist of water droplets dispersed within larger oil droplets, which are dispersed in an aqueous continuous phase while o/w/o emulsion consists of larger water droplets enclosing smaller oil droplets, which are dispersed in a continuous oil phase [6].

Various advancements in emulsifying drug delivery systems were done in the last decade as microemulsion/nanoemulsion, self-emulsifying drug delivery system, etc. [109]. Various herbal extract and phytoconstituents are effectively delivered by emulsion drug delivery. Most of the phytoconstituents like bruceajavanica oil, silybin, wurenchun, Ginkgo biloba extracts, curcumin, apigenin, camptothecinlutein, kaempferiaparviflora, honokiol, wurenchun, ligusticum chuanxiong oil and zedoary oil are delivered as emulsion. The mechanism of drug absorption by emulsifying drug delivery is represented in fig.7 [5, 20, 110].

Fig. 7
figure 7

The mechanism of drug absorption by emulsifying drug delivery. [5] [20, 110]

Full size image

Self-emulsifying drug delivery system (SEDDS)

SEDDS are defined as lipid-based drug delivery systems having drug, oil, surfactant, co-surfactant, co-solvent as main components. SEDDS is classified into self-micro emulsifying drug delivery systems (SMEDDS) and self-nano emulsifying drug delivery systems (SNEDDS). Pouton C.W. et al., explained the successful absorption of the drug by SMEDDS from the gastrointestinal fluid. Droplet size that provides a larger surface area for rapid absorption, greater solubility and thus prevents from enzymatic degradation (prevent the first-pass metabolism). [107, 108] The ability to formulate SMEDDS depends on the solubility of the drugs in the excipients. The optimal solubility parameter (log p) of the poor water-soluble compounds lies in the range of 2 to 4. Majority of drugs are lipophilic with poor bioavailability which needs a smart carrier system for their effectiveness. Hence SEDDS acts as a promising carrier for effective drug delivery [62].

Method of preparation

Various emulsification methods are used for the preparation of SEDDS. The key components which facilitate the effective penetration of drug at their target site –

  1. 1.

    Oils [Labrafaclipophile WL139, Oleic acid, Captex 200],

  2. 2.

    Surfactants [carboxyl (RCOO-) sulfate (ROSO3-), polyoxyethylene (Tweens)]

  3. 3.

    Co-solvents [propylene glycol, and polyethylene glycol]

  4. 4.

    Co-surfactant [Ethanol] [108].

Applications

Emulsifying drug delivery has wide applications as transdermal, parenteral, pulmonary and ocular drug delivery for the alternative tool of oral drug delivery. As stated in the literature, the emulsifying drug delivery system is a better approach to delivery systems for low solubility and/or low permeability drugs, to facilitate their dissolution and absorption [45]. Several approved formulations available in the market are Neoral (Cyclosporine A), Norvir (Ritonavir) are Fortovase (Saquinavir). Wenli Liu et al. developed a self-micro emulsifying drug delivery system of baicalein to improve its oral bioavailability and solubility. S. hanmugam S et al. developed Solid Self Nano Emulsifying Drug Delivery System (SSNEDDS) in which bioactive carotenoid lutein incorporated with phosphatidylcholine enhanced bioavailability and solubility [79]. Amnon Hoffman et al., reported that high lipophilic compounds such as with higher log p value (about ~7and ~ 6) were also effectively delivered by nano emulsifying drug delivery systems such as cannabinoids Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). Recent research work reported work of phytoconstituent by emulsifying drug delivery system is summarized in of Table 2-(2.1.3) [111,112,113,114,115,116,117,118,119,120].

Other drug delivery system

Hydrogel

Definition

Hydrogel are cross linked water swollen hydrophilic polymeric network which can hold a large amount of water in their three-dimensional structure. It is also known as “Biomacromolecular hydrogels.” They have wide range of applications in case of phytoconstituents delivery, synthetic drug delivery, diagnosis, cellular immobilization, separation of molecules and regulation of the barrier material for better absorption. Furthermore, they have been also applied in various fields like food industries, tissue engineering (artificial muscles), wound dressing, chemical valves, contact lenses and biomedical implant devices [3, 107, 121].

Description

In the last few decades, hydrogels have been successfully investigated as a high mechanical strength framework system. Ionic interaction and hydrogen bonding of cross-linking agents also assist insolubility improving in water. Varieties of natural and synthetic polymers like polysaccharides (e.g., alginate chitosan, hyaluronic acid, dextran, synthetic polymers such as polyethylene glycol, polyethylene oxide, polyacrylic acid, polyvinyl alcohol (PVA), poly-dimethyl aminoethyl methacrylate, poly lactic-co-glycolic acid, polycaprolactone, polypeptides and polyurethane, etc. Polymers are cross-linked using glutaraldehyde, N,N′-Methylenebisacrylamide, ethylene glycol di-methacrylate etc. are used in formulation of hydrogel. PVA chains cross-linked using glyoxal, glutaraldehyde, or borate. Poly(ethylene oxide) (PEO) and poly(ethylene glycol) (PEG) have gained attention recently for biomedical applications because of the nontoxic behavior of PEG, and its wide use in PEGylation of nanoscale drug carriers. Absorption of the active component through hydrogen is shown in Fig. 8 [122, 123].

Fig. 8
figure 8

Absorption of active component through hydrogen drug delivery system [122] [123]

Full size image

Classification of hydrogels

Depending on their method of preparation -

  • Homopolymer hydrogels;

  • Copolymer hydrogels;

  • Multipolymer hydrogels; and

  • Interpenetrating network (IPN) hydrogels.

Ionic hydrogels-

  • Neutral hydrogels (uncharged);

  • Anionic hydrogels (having negative charges only);

  • Cationic hydrogels (having positive charges only); or.

  • Ampholytic hydrogels (having both positive and negative charges).

  • Based on physicochemical structural features of the network, hydrogels.

  • Amorphous hydrogels (having covalent cross-links); or

  • Semicrystalline hydrogels (may or may not have covalent cross-links) [3, 121, 123, 124].

Applications

Hydrogels are used for delivery of chemotherapeutic agents, herbal bioactive, tissue engineering, diagnosis, cellular immobilization, separation of molecules [107]. Some of the examples are enlisted in Table 3-(3.1.1) [16, 125,126,127,128,129,130,131,132,133].

Table 3 Listing some of other drug delivery system to solve the hurdles related with herbal drug
Full size table

Cyclodextrins

Definition

Cyclodextrins (CDs) are a family of cyclic oligosaccharides, obtained by enzymatic degradation of starch, composed of α (1–4)-linked D-glucopyranose units. They have cyclic structure, with hydrophilic outer core and hydrophobic inner cavity. They can effective encapsulate or supra molecular complex guest molecule with proper dimensions, leading to the formation of “inclusion complex”. [3, 17, 134].

Description

CDs have truncated cone structure with the ability to self-assemble and form aggregates in aqueous media. Formation of water-soluble drug/CD complexes can increase drug permeation through biological membranes. The stoichiometry of drug/CD complexes is most frequently 1:1. Natural CDs that is αCD, βCD and γCD have somewhat limited solubility in water so that verities of polymeric materials are used to modify natural CDs to obtain water-soluble CD derivatives. For example, hydroxypropylated CD derivatives (e.g., HPβCD and HPγCD- propylene oxide), carboxymethylated CDs (e.g., CMβCD- monochloroacetic acid), randomly methylated CDs (e.g., RMβCD- methyl iodide) and sulfobutylether CDs (e.g., SBEβCD and SBEγCD-4-butane sultone). These tailored CDs derivatives are currently applied in academic researches and industries. Presently researchers are focusing on use of CD polymers, inclusion complexes and other CD-based materials for solubility enhancement of poorly water-soluble drugs/ herbal bioactive as well as for drug stabilization, protection from light, thermal and oxidative stress, taste masking of drugs, and reduced dermal, ocular or gastrointestinal irritation etc. [135, 136].

Applications

Cyclodextrins have versatile applications in the field of research, a large number of phytoconstituents and synthetic drugs are successfully delivered with the help of inclusion complex. Cyclic oligosaccharides have a great ability to enhance the effective delivery of bioactive components in the physiological system. Most of the isolated phytoconstituents are having such problems enzymatic degradation, poor aqueous solubility and bioavailability; these all issues are effectively resolved by using cyclodextrins. Polymeric CDs are not only used in medical technology they are also applicable for food engineering, environmental pollution control technologies and oilfields industries [17, 135]. Recently reported work on cyclodextrins for phytoconstituents delivery is given in Table 3-(3.1.2) [136,137,138,139,140,141,142,143,144,145].

Conclusion

Numerous attempts have been made in the creation of powerful nanotechnologies which have been an essential part to tackle worldwide difficulties related to food processing, drug targeting, strength and adequacy of natural nutraceutical and pharmaceutical segments. These specialized developments have numerous applications in farming, food processing, sustenance bundling, nutraceutical supplements delivery of active constituents, etc. at present the enormous therapeutic efficacy of phytoconstituents is being explored by encapsulating them into the novel micro or nano-sized carrier system. The phytoconstituents have certain limitations like low solubilization, poor absorption, low bioavailability such hurdles can be effectively overcome by using an advanced delivery system. In the present article, we have summarized some of the recently reported research works of several phytoconstituent categories such as flavonoids, terpenoids, tannins, glycoside, alkaloids sugars, and xanthones, which have been successfully delivered to the target site. The efficacy of phytoconstituents at the desired target site such as liver, brain, heart, kidney and tumor cells was improved as reported in the literature. The nanotechnology delivery system improves the utilization of phytoconstituents in various fields like food industries, cosmetic industries, agriculture sector and especially highlights the increased utilization in pharmaceutical industries.

Nowadays, several advance strategies have been developed by researchers for the effective delivery of phytoconstituents into the physiological system which have produced better pharmacokinetic properties, bioavailability profile and subsequently desired pharmacological action is obtained. Researchers have worked for the development of better drug delivery tools for the phytoconstituents which are capable of overcoming the limitations of conventional therapy. In this review article, we have discussed several novel strategies for the delivery of phytoconstituents using Liposomes, Niosomes, Phytosomes, Transferosomes, Nanoparticles, Microemulsion, Microspheres, Hydrogel, and Cyclodextrins. An attempt to feature the fundamental application of phytoconstituents has been made successfully. Novel medication delivery has improved the problems of phytoconstituents associated with their properties. Here, the attempt to address a novel drug delivery system as a promising tool for the better and effective delivery of nutraceuticals and pharmaceutical components will help the readers, researchers and academicians to overcome the limitations issues. Effectiveness, stability studies, and shelf life of herbal drugs can be extensively improved by formulation development. Therefore, it can be hoped that the special structural features and properties of the novel carriers will contribute in the coming years for maximum efficacy of phytoconstituents and the benefit of humanity at large scale.

Future prospects

In the era of a novel drug delivery system plant, constituent delivery is extremely encouraging for further research to improve the carrier materials. Some of the Modern tailored delivery approaches have proved appropriate carrier system which can easily reduce the toxicity of drugs and boost up their activity thus, improve the overall quality of the isolated phytoconstituents. Herbal drug designing has a huge therapeutic prospective which needs to be investigated through novel approaches to have high efficacy of poor soluble bioactive/ drug (hydrophilic/lipophilic). They need to be evaluating for the short term and long term effects of their products. Current advancement should be focused on the commercial development of the bioactive phyto molecules. The cost of the delivery system needs to be minimized which will render the formulation as economic. The current market and research status of the novel delivery development system for phytoconstituents need to be explored for several therapeutic agents. The development of phytoconstituent delivery can help in achieving consistent quality, bioavailability, and therapeutic effects of herbal drugs and products. In the future, these phytoconstituents can be isolated and investigated for pharmacological and therapeutic activity through in-vivo models. However, the conventional available herbal products or phyto formulation can be redesigned into vesicular carrier drug delivery systems with improved physicochemical properties, pharmacokinetics and pharmacodynamics aspects.