Microencapsulation of bioactive compounds and enzymes for therapeutic applications

CHAPTER

Microencapsulation of bioactive compounds and enzymes for therapeutic applications

17

Ragini G Bodade1, Anand G Bodade2 1

Department of Microbiology, Savitribai Phule Pune University, Pune, Maharashtra, India; 2Department of Transfusion Medicine, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra, India

1. Introduction Microencapsulation, a rapidly expanding technology, deals with the covering of tiny solid, liquid, and gaseous particles by a continuous film of synthetic or natural polymer, thereby protecting them from the adverse environment and enabling a controlled release of particles at the desired time, rate, dose, and site of action. The resulted structure is termed as microparticles (microcapsules, microspheres, and microemulsions). Microparticles exist in a variety of size, compositions, and functions. The size diameter 1e1000 mm is termed as microparticles and more than 1 mm as macroparticles. The particle size less than 1 mm is termed as nanoparticles, nanocapsules, and nanospheres (Peanparkdee et al., 2016). Structurally each of the microparticles or microcapsules consists of an active inner core material and outer coat or shell material that covers or protects the core material. Microsphere has only a homogeneous structure (Fig. 17.1). The core or inner phase contains solid, liquid, or gaseous material, whereas the outer soft or hard film called as shell/coating or membrane made by coating materials like ethyl cellulose, sodium carboxyl methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, gelatin (GE), poly(lacticco-glycolic acid) or (PLGA), chitosan, and polyesters. the liquid core is either dispersed or dissolved form, while solid core is a mixture of active constitutes like stabilizers, diluent, or excipients. Different core materials like active pharmaceutical ingredients, proteins and peptides, food materials, dyes, pigments, volatile oils, catalysts, and pesticides encapsulated within the coat or shell materials (Jyothi et al., 2010). Likewise, different bacterial and animal cells also immobilized and applied in the field of cell and tissue engineering to treat different diseases (Tomaro-Duchesneau et al., 2013). A number of objectives have been achieved by microencapsulation techniques including protection of the core material, material structuration, and controlled release of the encapsulated product. The microsize of the particles makes them efficient in distribution throughout the system and thus improves the drug absorption. The compounds that are difficult to administer because of insolubility, volatility, reactivity, hygroscopicity, and physical state are at the higher priority for microencapsulation. It also protects labile compounds from external environments, viz., oxygen, light, heat, humidity, gastric pH, and host’s immune system, thus improves product quality (Gholse and Yeole, 2013 and Tomaro-Duchesneau et al., 2013). Biopolymer-Based Formulations. https://doi.org/10.1016/B978-0-12-816897-4.00017-5 Copyright © 2020 Elsevier Inc. All rights reserved.

381

382

Chapter 17 Microencapsulation of bioactive

FIGURE 17.1 Structures of microparticles (left: microcapsule and right: microsphere).

In the current chapter, microencapsulation techniques for therapeutic applications of bioactive compounds and enzymes in disease treatments are described in detail.

2. Types of microencapsulation Historically the microencapsulation procedure was first introduced by Bungen burg de Jong and Kan in 1931 using GE sphere and is still widely used in the food, pharmaceutical, and cosmetic industries to maintain the stability, efficiency, and bioactivity of the compounds (Suganya and Anuradha, 2017). Although controlled drug delivery concept using microencapsulation was introduced in 1970s, still it is under study (Gupta and Day, 2012). Morphology of the microcapsules can be affected by selection of the techniques and nature of core and wall material. The synthesized different forms of the microcapsules may be mononuclear, poly/ multinuclear, matrix, multiwall, and irregular type (Das et al., 2011). Principle materials used for microencapsulation are different types of carbohydrate polymers, proteins, and lipids as per Table 17.1. Selection of coating material for microencapsulation depends on its inertness toward core material, availability, chemical compatibility, and stability. It also possesses some physicalechemical properties including cohesiveness, permeability, sorption, solubility, clarity, and stability for target-selected delivery (Bansode et al., 2010; Wazarkar et al., 2016). Different mechanisms have been achieved for controlled and sustained release of core material. Under a specific environmental condition like temperature, the coating material dissolves in water or solvent and results in gradual release of the core material by simple dissolution mechanism. High pressure or cracks on the wall results in release of the material during rupture mechanism. While in diffusion mechanism, a concentration gradient is achieved in core and surrounding environment and causes release of core material (Hu et al., 2017). However, a single type of microencapsulation method cannot be universally applied for a variety of drug materials. Therefore, development of a microcapsule method for a given drug requires understanding of drug physiochemical characteristics, compatible polymer, and encapsulation. The encapsulation techniques for drugs are emerging widely as ideal method due to its wide applications in food, cosmetic, and pharmaceutical industry. Microencapsulation drug delivery system is a promising option for developing oral drug formulation. Major of the drugs studied for encapsulation are from BCS class II group, which comprises mainly low solubility and high permeability drugs. Therefore, bioavailability, stability, and controlled release of drug could be possible by varied encapsulated methods. This will eliminate the drug easily from absorption site and for those having reduced bioavailability (Sachan et al., 2014). Microencapsulation is classified as chemical (emulsification, polymerization, and liposomes), physical (freeze-drying/lyophilization, spray drying, cocrystallization, fluidized-bed coating, or

3. Microencapsulation of bioactive compounds and bioactive extracts

383

Table 17.1 Materials used for microencapsulation. Sr. No.

Source

Material

1

Plant and plant exudates

2 3

Marine extracts Animal and microbial

4

Other materials

Starch and its derivatives (amylose, amylopectin, dextrin, maltodextrins, polydextrose), celluloses (ethyl cellulose, carboxymethyl cellulose, methyl cellulose, cellulose acetate phthalate) and their derivatives (gum arabica, galactomannans), pectin, and soybean-soluble polysaccharides Carrageenan, alginate Dextran, chitosan, xanthan and gellan, caseins, albumin, gelatin and gluten, fatty acids and fatty alcohols, waxes (beeswax, carnauba wax, candelilla wax), steric acids, glycerides, and phospholipids PVP, paraffin, PEG, inorganic materials

extrusion), and physiochemical/biological method type (coacervation and solgel encapsulation), and each of these gives different morphology of the particles (Table 17.2) (Madene et al., 2006, Nedovic et al., 2011, Laouini et al., 2012 and Lam and Gambari 2014).

3. Microencapsulation of bioactive compounds and bioactive extracts Bioactive compounds extracted from different parts of the plants have been used in food and pharmaceutical industries as health-promoting agents. They are obtained easily from the plant extracts prepared from plant parts by solvent extraction method. In pharmaceutical industry, bioactive compounds revealed to be effective in treatment of cancer, obesity, infection, and cardiovascular diseases. Moreover, they are also investigated for their health-promoting effects on animals (Pangestuti and Kim, 2011 and He and Giusti, 2010). Bioactive extracts and individual bioactive compounds are microencapsulated by immobilization methods using different wall materials as per Table 17.3 and Fig. 17.2. Moreover, effect of oral delivery of microcapsules prepared by alginate, polylysine, and pectin revealed no direct effect on microbial load of the gastrointestinal tract (Afkhami et al., 2007). Natural polyphenols and polyherbal formulations (PHFs) possess dynamic medicinal and therapeutic properties. Plants contain large quantities of pigments, especially chlorophylls, carotenoids, and anthocyanin are responsible for colourization of plant flowers, fruits, and leaves. In food industry these pigments are used as colorant, flavoring agent, and taste enhancer. Anthocyanin is a water-soluble nontoxic polyphenol used widely as colorants in foods and drinks. However, several factors such as pH, light, storage temperature, free radicals, chemical structure, concentration, oxygen, and solvents affect its stability and bioavailability and thus require encapsulation (Carocho et al., 2015; Zhao et al., 2015; Joana Gil-Cha´vez et al., 2013). Recently its importance in treatment of cardiovascular, neurological, cancer, and diabetes diseases has been investigated (Yousuf et al., 2016). Encapsulation of anthocyanin by spray drying technique using maltodextrin (MD) and gum arabic (GA) has been studied for its stability (Burin et al., 2011 and Mazuco et al., 2018). Jaboticaba extract (Myrciaria cauliflora and Myrciaria jaboticaba), a rich source of anthocyanin, can be microencapsulated with MD and GA by spray drying method to improve its physicalechemical characteristics as well as minimal color loss (Silva et al., 2013). Santos et al. (2013) assessed encapsulation using polyethylene glycol (PEG), supercritical CO2 as solvents, and ethanol as cosolvent to retain its stability and protection from

384

Table 17.2 Common techniques for microencapsulation in food and pharmaceutical industry. Type of encapsulation

1

Spray drying

2

Freeze-drying/ lyophilization

3

Coacervation

Principle

Material used

Homogenized core and wall material in suitable solvents is fed into a spray dryer and atomized with a nozzle. Water gets evaporated due to high temperature with simultaneous precipitation of capsules at the bottom.

Gum arabica, maltodextrins, saccharose, cellulose, gelatin, lipids, soy proteins

The homogenized material is freezed by reducing the surrounding pressure and allowing the frozen water to sublimate directly from solid phase to gas phase by providing enough heat. Phase separation of one or more hydrocolloids from a polymeric solutions layer around the core material is suspended in the same reaction mixture under the specific conditions, viz., pH, temperature, ionic strength.

Dextran, chitosan, polyvinyl alcohol, gelatin, carrageenan, gum arabica, soy protein, guar gum

Chitosan, heparin/gelatin, gum arabica/gelatin, gliadin, carrageenan, polyvinyl alcohol, soy protein, guar gum/dextran, gelatin/carboxymethyl cellulose

Advantages

Disadvantages

for · Used hydrophobic and

of product · Loss · Degradation of

· · · · ·

hydrophilic polymers Suitable for heat labile and highly viscous solutions (300mpa) Economically feasible Inexpensive, simple, rapid High drug-loading efficiency For thermosensitive compounds (water-soluble natural aromas and essence, drugs)

· For thermosensitive ·

compounds (flavor compounds) High encapsulation efficiency and targeted and controlled release

· ·

heat-sensitive products For limited wall materials Fiber formation sometimes achieved

Expensive and timeconsuming

Expensive

Chapter 17 Microencapsulation of bioactive

Sr. No.

4

Liposomes

Phospholipid bilayers are dispersed in aqueous environment, encapsulation, and core.

targeted and · Site efficient

· ·

5

6

Emulsification

Polymerization

Mixture of emulsion is prepared by two immiscible liquids, which are either used directly as liquids or dried in the powder form. The reactive monomers get polymerized on the surface of droplet or particle to form a capsule shell.

Oil and Water system

Ethyl cellulose, carboxymethyl cellulose, methyl cellulose, cellulose acetate phthalate, gelatin

controlled drug delivery Both hydrophilic and hydrophobic compounds can be encapsulated Stable and easy production

Both hydrophilic and hydrophobic food compounds can be encapsulated

Micro- to nanosized particles will be formed

low · Expensive, reproducibility, low drug entrapment, difficulties in particle size control, and short circulation halflife of vesicles Issues with sterilization and stability Droplets are bigger in size and need separation Always coupled with other encapsulation method Difficult to control the polymerization

· · ·

3. Microencapsulation of bioactive compounds and bioactive extracts

Cholesterol and natural and/ or synthetic phospholipids (phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylinositol)

385

Table 17.3 Microencapsulated plant extracts and bioactive compounds. Technique

Material

Application

1

Anthocyanin

Spray drying method

Maltodextrin Gum arabic

Nutraceutics

2 3

Spray drying method Encapsulation

Maltodextrin and gum arabic Margarine

Nutraceutics Nutraceutics

Silva et al. (2013) Zaidel et al. (2014)

4 5

Jaboticaba extract Roselle and red cabbage extract Bilberry extract Jamun extract

With whey protein and citrus pectin Gum arabica and maltodextrin

Nutraceutics Nutraceutics

6

Black carrot extract

Encapsulation Spray and freezedried method Spray drying method

Maltodextrin 20e21 DE

Nutraceutics

7

Spray drying method

Maltodextrin/soybean protein isolates

Antioxidant

Spray drying method

Maltodextrin/dextrose and gum acacia and tricalcium phosphate Maltodextrin/dextrose and gum acacia

Antioxidant

Nayak & Rastogi (2010)

Nutraceutics

Tonon et al. (2010)

10

Pomegranate extract Garcinia indica Choisy fruit pulp Euterpe oleracea Mart. juice fruit pulp Jussara pulp

Mueller et al. (2018) Preetha and Preetha (2017) Ersus and Yurdagel (2007) Robert et al. (2010)

Spray drying method

Santana et al. (2016)

11

Betacyanin

Spray drying method

Cosmetics Antioxidant Antioxidant

12 13

Beetroot extract Cactus pear extract

Spray drying method Spray drying method

Antioxidant Antioxidant

Pitalua et al. (2010) Robert et al. (2015)

14 15

Spray drying method Coacervation

Antioxidant Nutraceutics

Tupuna et al. (2018) Aditya et al. (2015)

16

Norbixin Curcumin and catechin b-Carotene

· ·

Antiangiogenic activity

· Spada et al. (2012) · Aissa et al. (2012)

17

Lycopene

Spray drying method

· Modified starch with trehalose and · Alginate galactomannans

Antioxidant Nutraceutics

· Rocha et al. (2012) · Calvo et al. (2017)

8 9

Spray drying method

· Spray drying method · Freeze-drying method

Gum arabic and modified starch, whey protein concentrate, soy protein isolate Maltodextrin (25 and 10 DE) and starch b-Cyclodextrin and maltodextrin Gum arabic Maltodextrin, inulin, and soybean protein isolate Maltodextrin and gum arabic Olive oil, soybean oil, and sunflower oil Starch Gum arabic

· ·

Reference et al. (2011) · Burin and Wrolstad · Giusti (2003)

and Corke (2000) · Cai · Chong et al. (2014)

Chapter 17 Microencapsulation of bioactive

Core material

386

Sr No

18

21

Grape waste

19

Freeze-drying method

Gum arabic, gelatin, and maltodextrin

Spray drying method drying · Spray method · Freeze-drying method drying · Spray method · Freeze drying

Hussain et al. (2018)

Maltodextrin

Antioxidant Antidiabetic Antioxidant

Gum arabic and maltodextrin

Antioxidant

Rezende et al. (2018)

· Alginateechitosan · Guar gum and 5% polydextrose

method

22 23

24 25

Chlorogenic acid

· Paeonia rockii roots sidoides · Lippia Cham. hystrix · Citrus fruit extract

Spray drying method Spray dry method

· Chitosan arabic · MD/gum · Glucomannan/gum arabic

26

Gallic acid Quercetin Vanillin Tea extract

Spray dry method

27

Punicalagins

Spray dry method

28

Capsaicin

Coacervation

Gelatin and gum acacia

· ·

Spray dry method Spray dry method

b-Cyclodextrin

Acetylated starch and inulin Inulin

· b-Cyclodextrin · Chitosan · Maltodextrin

Antioxidant, antibacterial, antiinflammatory, and antiplatelet activity Antimicrobial Antioxidant Antimicrobial Antioxidant

Antioxidant Antioxidant Improvement of bone quality Cytotoxicity Antioxidant a-Glucosidase activity Antimicrobial Antioxidant

Da Costa et al. (2018)

et al. · Moschona (2018) · Kuck and Noren˜a (2016)

Zhao et al. (2010)

· Sansone et al. (2014) et al. · Fernandes (2012) · Adamiec et al. (2012) Robert et al. (2012) Sun-waterhouse et al. (2013) Haidong et al. (2011) Liang et al. (2011)

· ·

Cam et al. (2014)

Xing et al. (2004)

Plant Oil Drumstick oil

Spray drying method

Maltodextrin/gum arabic

30

Plant and animal oil

coating · Fluid-bed method

b-cyclodextrin · Hydroxypropyl · Maltodextrin

Cosmetics and anticholesterol Nutraceutics

Premi and Sharma (2017) Anwar et al. (2010) Encina et al. (2016) Continued

387

29

3. Microencapsulation of bioactive compounds and bioactive extracts

20

Polyherbal formulation (PHF) Cupuassu seed extract Acerola pulp

Table 17.3 Microencapsulated plant extracts and bioactive compounds.dcont’d Technique

Material

Application

Reference

31

Flaxseed oil

Spray drying method

Nutraceutics

32

Olive oil

Spray drying method

Antioxidant

Tonon et al. (2011); Carneiro et al. (2013) Calvo et al. (2012)

33

Linseed oil

Spray drying method

Nutraceutics

Gallardo et al. (2013)

34 35

Garlic oil Ginger oil

Coacervation Spray drying method

Maltodextrin/whey protein concentrate Maltodextrin/carboxymethyl cellulose and lecithin Gum arabic/maltodextrin and whey protein isolate Gelatinegum acacia Arabic/maltodextrin and inulin

Antioxidant Antioxidant

36 37 38

Lemon oil Walnut oil Green coffee oil

Spray drying method Spray drying method Spray drying method

Siow and Ong (2013) De Barros Fernandes et al. (2016) Kausadikar et al. (2015) Shamaei et al. (2017) Carvalho et al. (2014)

39

Macadamia nut oil

Spray drying method

40

Brucea javanica oil

41

Nigella seed oil

Coacervation method Spray drying method Spray drying method

42

Eugenol oil

Coacervation

Gelatinesodium alginate

Antioxidant

43

Menthol

Spray drying method

Gum arabic and modified starch

44

Omega-3 fatty acids

Spray dry method, coacervation, spray chilling, extrusion coating, liposomes

Maltodextrin/gum arabic, casein/ methyl cellulose, starch/whey protein

Antimicrobial and anticancer Nutraceutics

Encapsulation

Poly(lactic-co-glycolic acid)-catalase

drying · Spray method

Maltodextrin Skim milk powder and Tween 80 Starch Hi-Cap 100 and Corn syrup/HiCap 100 Sodium caseinate (NaCas) and maltodextrin (MD) Arabic gum and gelatin

· Sodium caseinate and maltodextrin DE 10 arabic/maltodextrin · Gum · Gum arabic/sorghum starch

Nutraceutics Nutraceutics Cosmetics and antioxidant Antioxidant Anticancer Antimicrobial, antioxidant, and nutraceutics

Laohasongkram et al. (2011) Hu et al. (2016)

· Mohammed et al. (2017) et al. (2016) · Edris · Arshad et al. (2018)

Shinde and Nagarsenker (2011) Soottitantawat et al. (2005) Kaushik et al. (2015)

Enzymes 45

Catalase (EC 1.11.1.6)

Treatment of acatalasaemic and oxidative stress

Singhal et al. (2013)

Chapter 17 Microencapsulation of bioactive

Core material

388

Sr No

46

Encapsulation

Artificial cell preparation

Treatment of phenylketonuria

Bourget and Chang (1986)

Encapsulation

Artificial cell preparation

Palmour et al. (1989)

Entrapment method

Liposomes

50

Urease (EC 3.5.1.5)

· Encapsulation · Encapsulation · Solgel method

Liquid-air nozzle method

· Carrageenan · Alginate/bentonite · Silica matrix

Hexamethylenediamine/milk casein

51

Asperginase (EC 3.5.1.1)

Entrapment method

Liposomes [poly(lactic-co-glycolic acid)/polyvinyl alcohol]

52

Superoxide dismutase (EC 1.15.1.1) Papain (EC 3.4.22.2.) and protein hydrolysate

Entrapment method

Liposomes [poly(lactic-co-glycolic acid)/polyvinyl alcohol]

Encapsulation method

Carboxymethylated flamboyant seed gum/sodium alginate

LescheNyhan disease Treatment of hyperuricemia Treatment of lactose intolerance In urea removal from artificial kidney dialysate Treatment of acute lymphoblastic leukemia Treatment of acute and chronic inflammation Nutraceutics

· Spray dry method · Coacervation

· Maltodextrin/modified starch HiCap 100 complex · Gelatin/acacia · Cyclodextrin

47 48 49

53

Micronutrients 54

Vitamin A palmitate

Ascorbic acid

56 57

Squalene Vitamin B12 Vitamin B2 Vitamin B9

· · ·

Watereoil double emulsion method Spray dry method Encapsulation method

Corn oil, polyglycerol polyricinoleate (emulsifier), and gelatin Chitosan Chitosan/alginate Gelatin Lactoferrin/b-lactoglobulin

· · ·

et al. (2017), · Zhang (1998), · Dashevsky · Nichele et al. (2011)

Miyawaki et al. (1979)

De Brito et al. (2019)

Shaheen et al., 2017

Betancur-Ancona et al. (2011) and Ruiz Ruiz et al., 2013

· Gangurde and Amin (2017) et al. · Junyaprasert (2001) and Albertini et al. (2010)

Nutraceutics and antioxidant Antioxidant Antioxidant

· Zhang et al. (2018)

Comunian et al. (2014) Kumar et al. (2017) Estevinho et al. (2016) Azevedo et al. (2014) Chapeau et al. (2016)

· · ·

389

55

Nutraceutics and antioxidant

Zhou et al. (2016)

3. Microencapsulation of bioactive compounds and bioactive extracts

Phenylalanine ammonia-lyase (EC 4.3.1.24) Xanthine oxidase (EC 1.17.3.2) Uricase (EC 1.7.3.3) Lactase (EC 3.2.1.108)

390

Chapter 17 Microencapsulation of bioactive

FIGURE 17.2 Microencapsulated bioactive compounds.

the environmental condition. The result revealed that the supercritical solvent technology and conventional Caealginate encapsulation system protected the anthocyanin pigment from light and temperature significantly. Encapsulation with Caealginate showed less release profile than the PEG (Santos et al., 2013). Zaidel et al. revealed the improved storage and stability characteristics of margarine containing encapsulated anthocyanin from roselle and red cabbage (Zaidel et al., 2014). Bilberry extract has been reported as a rich source of anthocyanins and so investigated for encapsulation with whey protein and citrus pectin (PC) for its bioavailability and intestinal accessibility in humans (Mueller et al., 2018). A comparable result has been observed with the use of spray dried and freeze-dried method for anthocyanin pigment encapsulation from Jamun (Syzygium cumini) extracts. Spray dried powder with GA and MD as wall material gave the homogeneous particle size, low moisture content, and highest encapsulation efficiency (EE) up to 8 weeks of storage (Preetha and Preetha, 2017). Six different anthocyanin pigments have been reported in black carrot (Daucus carota L.). Effects of MD (20e21 DE) as carrier agent by spray dried encapsulation method revealed the highest anthocyanin content and improved shelf life under light illumination and storage temperature (Ersus and Yurdagel, 2007). Bioactive compounds like polyphenols and anthocyanins from pomegranate juice (PJ) (Punica granatum) and ethanolic extracts (PE) were encapsulated with MD or soybean protein isolates (SPI) by spray drying method. MD microcapsules attained significant protection to the polyphenols and anthocyanin’s than SPI during storage conditions (at 60
C for 56 days). Commercial PJ has highest antioxidant activities as compared to other fruit juices, green tea, and red wine. Thus has health benefits and commercial value (Robert et al., 2010). Many of the fruit juice powders obtained by spray drying are sticky, hydroscopic, and less soluble. Use of fruit pulps encapsulated with carrier agents revealed beneficial to handle, package, and transport. Microencapsulation of anthocyanin from Garcinia indica Choisy fruit pulp using MD/dextrose and GA and tricalcium phosphate helps to enhance their antioxidant activity (69.90%) and stability (Nayak and Rastogi, 2010). Similar result was described for anthocyanin from Euterpe oleracea Mart. juice fruit pulp (Tonon et al., 2010). Therefore, encapsulated anthocyanins as food additives protect them in gastrointestinal site and induce safe release for its beneficial health effect (Robert and Fredes, 2015).

3. Microencapsulation of bioactive compounds and bioactive extracts

391

Microencapsulation by spray drying of jussara pulp (Euterpe edulis) using ternary mixtures of GA and modified starch (MS) together with either whey protein concentrate (WPC) or SPI as the carrier agents revealed to give maximum yield (PY), solubility (S), retention of total anthocyanins (RTA), EE, and minimum moisture content. Thereby, the jussara pulp product can be applicable to cosmetics, as colorants, and flavoring agents (Santana et al., 2016). Betacyanin, a close relative of anthocyanin natural pigment, is used as food colorant. Betacyanin from the Amaranthus gangeticus plant extracted and encapsulated using MD as carrier (25 and 10 DE) and starch as coating agent by spray dried method revealed highest pigment retention 97.3% and 88.7%, respectively. The 25 DE/10 DE mixed powders can be stored up to 63.6 weeks without any pigment loss (Cai and Corke, 2000). Furthermore, microencapsulation using b-cyclodextrin and MD was explored by Chong et al. (2014). The result revealed that b-cyclodextrin-encapsulated pigment had shorter range of droplet size and drying time during spray drying method (Chong et al., 2014). Betalains are naturally occurring plant pigments classified as betacyanins and betaxanthins. Betalains-containing fruits are known for their beneficial actions in maintaining the body’s redox balance, decreasing oxidative damage, and improving antioxidant status in humans. Moreover, in humans after ingestion they promote their incorporation into the LDL and red cells, thereby protecting from oxidative damage and hemolysis. Betalains and carotenes from the cactus pear have known for their colorant and health beneficial properties. Beta vulgaris (beetroot) is known for its antioxidant properties due to betacyanins and betaxanthins content. Many of the reported studies revealed its significant role in cancer, coronary diseases, and other degenerative illnesses. Encapsulation by spray drying using GA revealed no significant differences in color, antioxidant activity, betalains concentration, and redox potential up to 45 days. Water adsorption influences the stability of the product during storage (aw < 0.521 for greatest stability) and antioxidant activity (aw > 0.748 for greatest stability). Therefore, betacyanin microcapsules could be interesting food additives for their antioxidant health benefits (Pitalua et al., 2010). Also, indicaxanthin from cactus pear (Opuntia ficus-indica) improved drastically by encapsulation in an MD matrix when stored at 20
C for months (Gandia-Herrero et al., 2010). In another study, pulp and ethanolic extract of cactus pear encapsulated with MD, inulin, and cladode mucilage revealed promising thermal stability and thereby its application as food additives (Saenz et al., 2009; Ota´lora et al., 2015). Moreover, encapsulation within an SPI and polysaccharide (MD or inulin) revealed improved betalains and polyphenol EE, and stability during storage at 60
C (Robert et al., 2015). Carotenoids are natural pigments found in fruits, vegetables, some fungi, and algae. Various carotenoids from different sources are reported for oxygen radicals scavenging activity and thereby reduce oxidative stress in biological system. Moreover, it has potential to reduce cancer, cardiovascular disease, cataracts, and as immune response booster (Gul et al., 2015). Microencapsulation by spray drying and supercritical micronization method using different carrier materials, viz., MD and calciumealginate, revealed its stability against light, oxygen, and increased shelf life (JaniszewskaTurak, 2017; Fratiann et al., 2017). Norbixin, an apocarotenoid, has food additive and antioxidant applications. It effectively deactivates reactive oxygen species (ROS)-induced DNA damages from the cell. Microencapsulation using MD: GA by spray drying improved its thermal stability and shelf life (Tupuna et al., 2018). Encapsulation of curcumin and catechin by water-in-oil-in-water system was study by Aditya et al. (2015). They have been used in food and drink products as supplement to prevent several diseases such as cancer, obesity, infection, and cardiovascular ailments (Aditya et al., 2015). Bcarotene microencapsulation was studied for antiangiogenic activity using starch and GA (Spada et al.,

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2012, Aissa et al., 2012, Thakur et al., 2017 and Correˆa-Filho et al., 2019). Lycopene encapsulated in MS by spray drying was studied by Rocha et al. (2012). The plant pigment is used as colorant in food and can be prevented by oxidation reaction during storage process (Rocha et al., 2012). Release profile of lycopene from pink grapefruit was strongly influenced by encapsulating it with alginate with trehalose and galactomannans. Lycopene is used as food additive, colorant, and flavor modifiers. It is effective in reducing risk of oxidative stress, cancer, cardiovascular, and hepatic fibrogenesis diseases (Calvo et al., 2017). Microencapsulation of PHF made by the root of Chlorophytum borivilianum, Astragalus membranaceus, Eurycoma longifolia, and seeds of Hygrophila spinosa T. Anders was carried out by freezedrying method using GA, GE, and MD polymers. The result revealed excellent antioxidant activity and antidiabetic activity. Microencapsulation of PHF further proved improved bioavailability under intestinal acidic pH (Hussain et al., 2018). Cupuassu (Theobroma grandiflorum Schum.) fruits are known for their intense aroma and nutritional value due to their phenolic contents. Microencapsulation using MD for cupuassu seed extract by spray drying method was investigated for antiradical power and stability at low temperature or under simulated gastrointestinal conditions (Da Costa et al., 2018). Bioactive compounds from acerola pulp (Malpighia emarginata DC), viz., carotenoids (CA), ascorbic acid (AA), phenolic compounds (PC), anthocyanins (A), and residual extracts, retain good antioxidant activity by spray- and freeze-drying encapsulation methods, using GA and MD (Rezende et al., 2018). Phenolic compounds, viz., quercetin, kaempferol, transferulic acid, ellagic acid, and a derivative of caffeic acid, are found in many of the fruit extracts. Grape waste (Vitis vinifera) from wine industry contains high amount of these phenolic compounds and has potential to use in food and pharmaceutical industries after immobilization. Encapsulation of this waste extracts revealed high antioxidant activity, antibacterial activity, antiinflammatory, and antiplatelet activity using alginateechitosan polymer due to its controlled release property (Moschona et al., 2018). Moreover, 5% partially hydrolyzed guar gum and 5% polydextrose has proven to be the best treatment for retention of phenolics and anthocyanins (>80%) and antioxidant activities (45.4%e83.7%) by spray drying encapsulation technique (Kuck and Noren˜a, 2016). Antimicrobial activity of microencapsulated Vitis labrusca solvent extract against Staphylococcus aureus and Listeria monocytogenes and Leishmania arginase enzyme inhibition was reported by (de Souza et al., 2014). Microencapsulated chlorogenic acid from Nicotiana tabacum leaves was developed as food products with antimicrobial properties (Zhao et al., 2010). Moreover, enhanced antifungal activity of Paeonia rockii roots and Lippia sidoides Cham. leaves and antibacterial activity of Citrus hystrix DC fruit skin were reported using chitosan, MD/GA, and glucomannan/GA, respectively (Sansone et al., 2014, Fernandes et al., 2012 and Adamiec et al., 2012). Gallic acid, a natural antioxidant from plant, was investigated for microencapsulation using acetylated starch and inulin revealed higher EE and antioxidant activity (Robert et al., 2012). Health benefits of other polyphenols like quercetin and vanillin revealed significant with inulin as wall material by spray drying microencapsulation method (Sun-waterhouse et al., 2013). Microencapsulation using b-cyclodextrin of Camellia sinensis tea extract has been reported for improvement of bone quality in rat and reduction in blood Ca2þ contents due to its content of catechins, gallic acid, and caffeine (Haidong et al., 2011). Improved cytotoxicity of the tea polyphenols has also been reported using microencapsulation in chitosan and can be used as antitumor agent (Liang et al., 2011). Punica granatum L. peel extract containing polyphenol punicalagins was microencapsulated in MD and revealed enhanced antioxidant and a-glucosidase activity (Cam et al., 2014).

3. Microencapsulation of bioactive compounds and bioactive extracts

393

Enhanced antiinflammatory activity of polyphenols such as caffeic acid, carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-L-homoserine lactone was studied by Coimbra et al. (2011). Capsaicin from chill has application as pharmaceutical, neuroscience, and antimicrobial drugs in medicine. Microencapsulation by coacervation process using GE and GA along with tannins revealed a high drug-loading content (19.84%) and a high EE (88.21%) (Xing et al., 2004). Food-derived micronutrients like Vitamin A from natural foods have been always a growing interest for the health promotion activities. Vitamin A palmitate (VAP) is widely used in cosmetic industry to prepare skin care products. Microencapsulation using MD and MS Hi-Cap 100 by spray dry method significantly increased its antioxidant activity and stability up to 3 months with promising EE (53%e63%) and drug release (80.18%e83.43%) (Gangurde & Amin, 2017). In another study microencapsulation with gelatineacacia complex by coacervation and double-coated alginatee chitosan microcapsule along with stabilizer butylated hydroxytoluene (BHT) improved the VAP stability (Junyaprasert et al., 2001 and Albertini et al., 2010). Microencapsulation of VAP using gcyclodextrin-based metal organic frameworks (g-CD-MOFs) enhances its stability by 1.6-fold than the current market reference product (BASF VAP). Thus, the microencapsulation method revealed useful for its food and pharmaceutical applications (Zhang et al., 2018). Other micronutrient AA (Vitamin C) is a natural antioxidant from fruits and vegetables and was investigated for physicochemical and sensory stability of chicken frankfurters and thereby its health-promoting activity. Encapsulation by watereoil double emulsion method using corn oil, polyglycerol polyricinoleate (emulsifier), and gelatin could allow the incorporation of an antioxidant with vitamin functionality and improved stability (Comunian et al., 2014). One another micronutrient of marine origin squalene has a wide range of health-promoting properties like cardio-protective, antioxidant, chemopreventive, anticancerous, etc. Therefore, squalene has applications in pharmaceutical, cosmetic, and biomedical industries. Kumar et al. studied oxidative stability of squalene by encapsulating in chitosan by spray drying method (Kumar et al., 2017). Vitamin B12 (cobalamin), Vitamin B2 (riboflavin), and Vitamin B9 (folic acid) also known for their health benefits are microencapsulated by chitosanealginate, GE, and lactoferrin/b-lactoglobulin, respectively, for their stability, bioavailability, and shelf life (Estevinho et al., 2016; Azevedo et al., 2014 and Le-gang et al., 2012, Chapeau et al., 2016). Many of the plant oils have nutritional value but are unstable due to their oxidative deterioration nature and consequent production of undesirable flavor. Encapsulation of such oils to minimize the oxidative reaction and to improve the physiochemical characteristics, viz., viscosity, stability, droplet size, and dry powder characteristics, are mostly affected by the type of carrier agent and techniques. Carrier agents used for encapsulation of these oil-based components include mostly GA, MD, WPC, skim milk powder (SMP), and sodium caseinate (NaCas). Drumstick oil or ben from Moringa oleifera (MOO) resembles to olive oil in fatty acid composition and contains high amount of useful behenic acid and oleic acid. High oleic contents of MOO attributed an increase in HDL cholesterol and decrease in serum cholesterol and triglycerides level. Therefore, are applied in cosmetics, skincare formulations, and folk medicines (Nadeem and Imran, 2016). Encapsulation of drumstick oil with MD: GA revealed better thermal and oxidative stability, thus has therapeutic values (Premi and Sharma, 2017). Other reported oils encapsulated by spray drying include fish oil (Anwar et al., 2010; Encina et al., 2016), flaxseed oil (Tonon et al., 2011; Carneiro et al., 2013), olive oil (Calvo et al., 2012), linseed oil (Gallardo et al., 2013), garlic oil (Siow and Ong 2013), and ginger oil (De Barros Fernandes

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et al., 2016). Thus, encapsulated oils revealed applications as food additive and therapeutics. Lemon oil, a flavoring agent in the tea and beverages encapsulated by spray drying techniques using MD, was developed by Kausadikar et al. (2015). Walnut oil contains health-beneficial essential fatty acids, oleic acid, linoleic acid, tocopherols, and phytosterols. Walnut oil has been effective in reducing the risk of cardiovascular and cancer diseases. Shamaei et al. (2017) evaluated the emulsion prepared using SMP and Tween 80 as wall material, with 91% encapsulated efficiency and its possible nutraceutical application (Shamaei et al., 2017). Green coffee oil from Coffea arabica and Coffea canephora contains high amount of diterpenes (cafestol and kahweol), palmitic acid, oleic acid, stearic acid, and linoleic acid. Due to its emollient properties including antioxidant and solar UV light absorption property it can be applied as active ingredients in cosmetics products. Green coffee oil microparticles of MS Hi-Cap 100 and corn syrup/Hi-Cap 100 has stabilized by lecithinechitosan through electrostatic layer-by-layer deposition technique to exhibit the highest oxidative stability and controlled release of sun protective factor (Carvalho et al., 2014). The macadamia nut oil (Macadamia integrifolia) contains high amount of monounsaturated fatty oils (70%) and is widely used in treatment of cardiovascular diseases by reducing the blood cholesterol level. Encapsulation by NaCas and MD in 1: 4 proportions improves quality and shelf life of macadamia by preventing oxidative reaction (Laohasongkram et al., 2011). Brucea javanica fruit possesses anticancer, antiinflammatory, antimalarial, and detoxification activities. Brucea javanica oil (BJO) extracted from dried ripe fruit contains stearic, oleic, and linoleic acids. Encapsulation of BJO extract prevents its off flavors, volatilization, and degradation effectively. Improved anticancer activity of encapsulated BJO microcapsules by complex coacervation method and spray drying method was evaluated by Hu et al. (2016). At the optimal conditions, the EE (82.9%) and stability against oxidation was remarkably achieved for cancer treatment using arabic gum and gelatin as coating materials (Hu et al., 2016). Nigella sativa seed is used traditionally to treat fever, headache, diarrhea, anxiety, asthma, and stroke. The Nigella seed oil (NSO) shows excellent source of essential fatty acids and lipid-soluble bioactive compounds. Thymoquinone is the active compound from NSO and possesses excellent antioxidant and antiinflammatory properties. Thymoquinone encapsulation using NaCas and MD DE 10 by spray drying method was assessed for its oxidative stability, morphology, and bioavailability by Mohammed et al. (2017). A similar study on oleoresin from N. sativa L. emulsified using GA/MD (1:1 w/w) by spray drying method was carried for its application in processed food and nutraceutical (Edris et al., 2016). In another study, microencapsulated oleoresin by GA and sorghum starches were studied for antioxidant activity and antimicrobial activity against Escherichia coli and Bacillus cereus (Arshad et al., 2018). Eugenol is a phenylpropanoid containing oil derived from clove and cinnamon and used in medicine as local antiseptic and analgesic agent. Its derivatives are also used in perfumeries, flavorings, and as essential oils. Microencapsulation of eugenol with GEesodium alginate complex by coacervation is expected to offer protection against oxidization and volatilization (Shinde and Nagarsenker, 2011). Menthol, a cyclic monoterpene alcohol from peppermint, possesses biological activities, viz., antibacterial, antifungal, antipruritic, anticancer, and analgesic. Microencapsulation of menthol with GA and MS by spray drying method affects its handling and storage conditions (Kamatou et al., 2013 and Soottitantawat et al., 2005). Omega-3 fatty acids, polyunsaturated fatty acids, implicated in the prevention of diabetes, coronary artery disease, arthritis, cancer, hypertension, other inflammatory, and autoimmune disorders. Many studies encourage the involvement of omega-3 fatty acids for healthy retina and brain development of fetus in pregnant and lactating women. Microencapsulation of omega-3 fatty acids using spray dry

4. Microencapsulation of therapeutic enzymes

395

method, coacervation, spray chilling, extrusion coating, and liposomes was also successfully studied for their oxidative deterioration and stability (Kaushik et al., 2015).

4. Microencapsulation of therapeutic enzymes Enzymes are biocatalyst responsible for conversion of substrate to product at varied biological conditions. However, enzymes become nonfunctional under stressed environmental factors like temperature, pH, mechanical process, and others due to change in conformation. Enzymes possess varied applications in detergent, pharmaceutical, and food industry. Microencapsulating the enzyme in order to improve its use in industrial process and commercial products is today’s need. Their encapsulation can be achieved by two strategies: surface immobilization by chemical or physical interaction on a solid support and by encapsulation inside the matrices such as hydrogels or within solid membranes (Trusek-Holownia and Noworyta 2015). Both Spray drying and liposome methods have been revealed advantageous for encapsulation of therapeutic enzymes and for their controlled release, using different wall materials and carrier agents (Andrea et al., 2016). Moreover, it can prolong the enzyme stability and in vivo half-life when injected intramuscularly, subcutaneously, or intraperitonially, or administered orally as an ingestible product to carry out its intended functions. Therefore, encapsulation gains importance in treatment of type 1 diabetes, Alzheimer’s disease, Parkinson’s disease, renal disease, cancers, and other disorders (Karamitros et al., 2013, Tomaro-Duchesneau et al., 2013 and Szilasi et al., 2012). Catalase (E.C. 1.11.1.6) an antioxidant enzyme plays important role in detoxifying the hydrogen peroxide production during stress-induced diseases, viz., Zellweger syndrome, acatalasemia, or Wilms tumoreaniridia syndrome (WAGR syndrome). Moreover, it is responsible for cell proliferation by inducing genetic instability and oncogenes activation. Therapeutic application of catalase as future therapeutic target in the context of cancer by using prooxidant approaches has a significance (Glorieux and Calderon, 2017). Chang and Poznansky (1968) reported microencapsulation of catalase in treatment of acatalasaemic mice. This prevents enzyme leakage and its involvement in immunological reactions (Chang and Poznansky, 1968). Poly(lactic-coglycolic acid)ecatalase-loaded nanoparticle protects human neurons from oxidative stress and UV-induced epidermal damage (Singhal et al., 2013 and Hammiller et al., 2017). Microencapsulation of the phenylalanine ammonia-lyase enzyme (EC 4.3.1.24) effectively depleted phenylalanine in phenylketonuric rats within 6 days in vivo study. Here the phenylketonurictreated rats showed no signs of abnormal behavior and weight loss as compared to phenylketonuricnontreated rats as enzyme is protected by low gastrointestinal pH and other proteolytic enzymes action (Bourget and Chang, 1986). Deficiency of the enzyme hypoxanthine phosphoribosyltransferase (HPRT) gives rise a disease called LescheNyhan syndrome. It is also associated with hyperuricemic condition. Encapsulation of xanthine oxidase (EC 1.17.3.2) enzyme protects the condition effectively (Palmour et al., 1989). Moreover, uricase (EC 1.7.3.3) entrapment inside the lipid vesicle membrane along with catalase in bicine buffer as alkaline enzymosomes provides enhanced thermal, hypothermal, acidebase, and proteolytic stabilities, in vitro and in vivo kinetic characteristics, and uric acid lowering properties (Zhou et al., 2016 and Tan et al., 2010). In adult human milk, tolerance caused due to lactose is treated by lactase enzyme/b-galactosidase (E.C.3.2.1.108) that catalyzes conversion of milk lactose to glucose and galactose. Microencapsulation

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protects lactase from highly acidic gastric fluids and allows it to reach in small intestine effectively. Oral delivery of lactase fabricated in carrageenan-based hydrogel beads revealed greater encapsulation, protection, and targeted enzyme delivery (Zhang et al., 2017). Study on microencapsulation of lactase in alginate and bentonite at low pH (4.61) revealed reduction in the protein loss without lowering the enzyme activity (Dashevsky, 1998). While lactase entrapment in a silica matrix by the sol-gel method prolongs its therapeutic action and stability in extreme pH and temperature conditions (Nichele et al., 2011). Microbial urease (EC 3.5.1.5) has been identified as emerging pathogenic factor in bacterial and fungal infection (Mora and Arioli, 2014), and induction of kidney struvite stone formation (Schwaderer and Wolfe., 2017). It is also used in urea removal from artificial kidney dialysate. Oral microcapsule containing urease and an adsorbent, zirconium phosphate, was evaluated for urea removal in stirred batch by Wolf and Chan (1987) and found effective in reducing dialysis treatment times (Do
gac¸ et al., 2014; Wolfe and Chang, 1987). In vivo study of microcapsule containing urease as intraperitoneal injection into dogs of 0.25 mL/kg resulted in rise of the arterial blood ammonia level due to enzyme activity (Chang, 2013). In another study, alginate microparticles cross-linked with Baþþ ions has been revealed as an alternative matrix for urease nanoencapsulation and its possible biomedical applications (Saxena et al., 2017). Urease microencapsulation by liquid-air nozzle method using hexamethylenediamine and a protective protein provides 78% retained initial activity (Miyawaki et al., 1979). Acute lymphoblastic leukemia (ALL) is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells. Asperginase (EC 3.5.1.1), an antitumor enzyme, hydrolyzes asparagine into aspartic acid and ammonia, thus inhibiting the protein synthesis in leukemic cells (Batool et al., 2016). However, treatment with asperginase is hampered by anaphylactic toxic reactions and development of resistance to the enzyme. Liposome-entrapped Erwiniae asparaginase investigation using C3H mice bearing 6C3HED asparagine-sensitive lymphoma cells achieved complete cure (Chang, 2013). Currently nanoencapsulation of asperginase using poly(lacticco-glycolic acid) (PLGA) and polyvinyl alcohol (PVA) as a stabilizer gives maximum EE (87  2%) and reduced immunogenic effects using double emulsification method (De Brito et al., 2019). Superoxide dismutase (EC 1.15.1.1) enzyme is prescribed to treat acute and chronic inflammation by inhibiting the generation of molecular oxygen or hydrogen peroxide from superoxide ions produced by proinflammatory cytokine signaling pathway. PEGylated SOD liposomes can decrease inflammation effectively in a rat model of lipopolysaccharide-induced peritonitis by reducing TNF-a and oxidative species. Moreover, liposomes containing catalase and SOD found effective for skin inflammation reduction in a murine ear edema model (Farhadi et al., 2018). Papain (E.C. 3.4.22.2.) and Phaseolus lunatus protein hydrolysate were encapsulated by carboxymethylated flamboyant seed (Delonix regia) gum (CFG) for better protection in a gastric pH and controlled drug release. Both of them can thus be used as a nutraceutical and therapeutic agents (Betancur-Ancona et al., 2011 and Ruiz Ruiz et al., 2013).

5. Challenges and future outlooks Microencapsulation of bioactive compounds, plant extracts, and enzyme as drug has definitely a remarkable therapeutic potential for a wide range of diseases, due to achievement of polymer chemistry and advancement in encapsulation techniques. A large number of the bioactive compounds and plant extracts are encapsulated for their therapeutic applications but found limited for enzymes.

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However, most of the current methods have several limitations related with the complexity in procedure, selection of material, low EE, toxicity with organic solvent on exposure, maintenance of aseptic conditions, burst effect and controlled drug release, targeted delivery, effective cost, ensured product quality, stability during manufacturing process, reproducibility, and scale-up at commercial level. Therefore, still require great efforts to minimize these issues.

Acknowledgments Authors are thankful to Head, Department of Microbiology, SPPU, and Head, Department of Transfusion Medicine, Seth G S Medical College and KEM Hospital for their help in smoothing out the whole manuscript.

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