Physical-Chemical Active Substances Encapsulation Approaches in Pharmaceutical Industry

Physical-Chemical Active Substances Encapsulation Approaches in Pharmaceutical Industry: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Lubomir Lapcik.

Encapsulation is a valuable method used to protect active substances and enhance their physico-chemical properties. It can also be used as protection from unpleasant scents and flavors or adverse environmental conditions. Encapsulation has demonstrated effectiveness and versatility in multiple industries, such as food, nutraceutical, and pharmaceuticals. Moreover, the selection of appropriate encapsulation methods is critical for the effective encapsulation of specific active compounds.

encapsulation
pharmaceutical
physico-chemical properties

1. Introduction

Different substances have great health benefits or function as a drug, but they cannot be used directly or stored for a long period. This is due to their low solubility, low bio-availability, tendency to oxidize, or their strong odor or flavor. Encapsulation is a method that has been known for more than 60 years, but it still holds great interest among researchers [1,2]^[1][2]. Typically, a substance is enclosed by a coating material which forms a barrier to protect the substance from the environment and chemical interaction [3,4,5,6]^[3][4][5][6]. Encapsulated substances can be also called core, fill, or matrix substances. The coating material is called a shell or wall material, as can be seen in Figure 1. Encapsulation can be used for improving the mentioned properties of different substances as well as protecting the core substance from, for example, light, moisture, and changes in pH [2,7,8,9]^[2][7][8][9]. Apart from protecting of core, it can also be used in the prolongation of release. This can be helpful with gradual and controlled release of drugs [10,11]^[10][11].

Figure 1.

Substance encapsulated into a coating material.

Encapsulation can be achieved by many methods, some of which are described in this entreviewy. These methods can be divided into three main types: chemical, physico-chemical, and physico-mechanical [7,12]^[7][12]. This entreviewy does not mention every encapsulation approach since it is a very broad topic, but rather focuses on methods mostly used in pharmaceutical and food industries. The global food encapsulation market has undergone continuous growth and is expected to reach a value of USD 17 billion by 2027 ^[13].

With regard to encapsulation of pharmacologically active substances, it is important to note that this technology can have broader applications beyond just the pharmaceutical and food industries. Encapsulation can also be utilized in various other industries; for example, it can be used in nutraceuticals or in the construction industry as a self-healing material such as concrete [14,15]^[14][15]. Specifically, in concrete, types of bacteria can be encapsulated for a self-healing effect ^[16]. The principle of self-healing materials is applied when the treated material is mechanically damaged; the encapsulate is released after a rupture of capsules and the core material is used to repair the damaged part [17,18,19]^[17][18][19]. In the same industry, the encapsulation is also used for anticorrosive coating. An example of encapsulated food is linseed oil ^[20]. The anticorrosive coating can have three mechanisms of protection. Firstly, it is a basic barrier on top of the material; secondly, the coating material can carry corrosion inhibitors; lastly, the coating can provide cathodic protection ^[21]. Self-healing materials and anticorrosion coatings of materials aim to prolong material use and prevent and avoid structural damage that may occur ^[22]. For example, marine infrastructure such as bridges and tunnels are in hostile environments and are prone to micro-cracks ^[23].

Quantum dots (QDs) are closely examined within chemistry. QDs are between 2 and 10 nm in diameter and have a semiconductor core with a shell, together with ligands ^[24]. Quantum dots can be also used together with encapsulation methods to achieve better properties, which are already unique. Quantum dots are widely used in the biomedical industry [24,25]^[24][25], for example, in biomolecular tracking, tumor imaging, and photodynamic therapy ^[24]. Encapsulated QDs can be used for the detection of heavy metals and other possible harmful substances ^[26]. Table 1 provides specific examples of the encapsulation methods described in this entreviewy, along with several examples from other industries that demonstrate the diversity of encapsulation.

Table 1.

Different methods of encapsulation.

Methodology	Active Substance	Coating	Vehicle Dimension	Field of Application	Enhanced Property	References
Emulsion electro-spraying assisted by pressurized gas	Algae oil	Wheat gluten extract	3.34 ± 1.77 µm	Nutraceutical industry	Oxidation, bioavailability, organoleptic properties, controlled release	^[27]
Extrusion	Polyphenols of Piper Betel leaves	Alginate	-	Nutraceutical industry, food supplementation industry	Stability, oxidation, taste	^[28]
	Polyphenols from Mesona chinensis Benth extract	Alginate	1516.67 ± 40.96 µm	Traditional medicine	Bioaccessibility, bioavailability	^[29]
	Phage SL01	Alginate/k-carrageenan	2.110 ± 0.291–2.982 ± 0.477 mm	Pharmaceutical industry	Bioavailability, better survivability (pH, enzymes)	^[30]
Nanoemulsion	Thyme oil	Chitosan	50.18 ± 2.32 nm	Bioinsecticides, larvicides	Control release	^[31]
Nanoemulsion	Vitexin	Medium-chain triglyceride	108–166 nm	Food application	Water solubility, bioavailability	^[32]
Emulsion	Curcumin	Sunflower oil, carboxy-methylcellu-lose, lecithin	~20 mm	Food delivery	Bioavailability, photochemical stability, less degradation	^[33]
Spray drying	Anthocyanins	Maltodextrin	-	Nutraceutical industry, colorant	Shelf life, stability	^[34]
Spray drying	Saccharomyces boulardii	Rice protein, maltodextrin	-	Functional foods and beverages, supplements, animal feed	Effectiveness, prolongue storage, less degradation	^[35]
Freeze drying	Blackthorn (Prunus spinosa L.) extract	Maltodextrin	-	Functional foods, supplements, pharmaceutical	Shelf-life, bioavailability, physico-chemical and biological degradation	^[36]
Freeze drying	Propolis	Whey protein isolate	99.76 ± 21.56–242.22 ± 81.78 nm	Alternative medicine, food, cosmetic and pharmaceutical industries	Odor, taste, bioavailability	[37,38]^[37][38]
Lipid encapsulation	Gamma-oryzanol	Stearic acid, sunflower oil/rice bran phospholipids, Tween 80	143 ± 3.46 nm	Nutraceutical industry	Water solubility, size	^[39]
Internal phase separation	N-acetylcysteine	Ethylcellulose	100–1000 µm	Nutritional supplement	Bitter aftertaste, astringency, sulfur smell	^[40]
Self-assembly of biopolymers	Anthocyanins	Whey protein isolate, pectin	~ 200 nm	Nutraceutical industry, colorant	Molecular instability	^[41]
Vacuum facilitated infusion	Curcumin	Geotrichum candidum arthrospores	-	Food industry, pharmaceutical industry	Water solubility, chemical stability, Bioavailability	^[42]
Multiple step preparation including modified Störber sol-gel process	Mn₃O₄	Hollow carbon sphere coated by graphene layer	-	Battery industry	Enhancing performance of lithium-ion batteries, specific capacity	^[43]
Synthesis of QD, growth of iron shell, and oxidation to form iron oxide shell	Quantum dots	Iron oxide	~20 nm	Bifunctional markers, virus detection	Optical properties	^[44]
Pelletization process, coating processes	Calcium acetate/sodium carbonate (or composite of two), superabsorbent polymers, poly(ethylene glycol)	Epoxy resin, fine sand	-	Self-healing concrete	Waterproof and alkali resistance, mineralization time, durability	^[14]
Sol-gel method	SiO₂	ZnO	-	Cosmetics, renewable energy, UV-protecting	Photoactivity properties	^[45]

2. Physical-Chemical Approaches in Pharmaceutical Industry

2.1. Encapsulation of Bacteriophages

Encapsulation can be used for the treatment of bacterial infections ^[46]. Due to the still-greater risk of bacteria obtaining resistance to antibiotics, the encapsulation of bacteriophages can be one of the main options to fight bacterial infection without antibiotics ^[46]. Bacteriophages are viruses that can infect and kill bacteria with high specificity and do not threaten healthy human microflora [46,47,48,49]^{[46][47][48][49]}. Without encapsulation, the bacteriophages have lower survivability in gastro-intestinal conditions; specifically, they can be affected by gastric enzymes, bile, and the acidic environment when used orally [46,48,50]^[46][48][50].

2.1.1. Emulsification

This method is based on dispersing one liquid with the active compound into a second liquid that is not miscible, and creating small droplets [51,52,53,54,55]^{[51][52][53][54][55]}. Emulsions tend to be thermodynamically unstable and surfactants as emulsifiers need to be added to decrease surface tension [56,57,58]^[56][57][58]. Solid particles, such as nanoparticles, can also function as a stabilizer and emulsions stabilized in such a way are called Pickering emulsions [56,58,59]^[56][58][59].

The method mentioned by Anna Choinska-Pulit et al. includes a mixture of microorganism cells and polymer, which is added to vegetable oil (canola, sunflower, and corn oil, for example) ^[46]. Mixtures must be homogenous until a water-in-oil emulsion is formed, and stirring of the emulsion is a key step to obtain droplets having the right size and shape. Emulsification creates droplets called capsules, whereas extrusion droplets are called beads. The capsule core is liquid, and the bead core is porous. Capsules are at least 100 times smaller than beads ^[60].

Emulsifiers, for example, guar gum or lecithin, must be included for stabilization. Settling is used to recover hardened capsules. Researchers in the publication from Dini et al. used this method to encapsulate bacteriophages to reduce enterohemorrhagic E. coli in the bovine gastric environment; methoxylated pectin was used as the material for encapsulation and was emulsified by mixing with Tween 20 (Polyoxyethylene sorbitan monolaurate) ^[61]. Homogenization was performed by mixing and oleic acid was added to reach a final concentration of 10 vol%. Additionally, coating was carried out with 0.2 wt% of high-methoxylated pectin or guar gum.

Double water-in-oil-in-water (W/O/W) emulsion was conducted by Kim, S. et al. ^[62]. PLGA microspheres were prepared using a bacteriophage solution of pAh-6C in phosphate buffered saline (PBS), mixed with PLGA, and dissolved in dichloromethane to form a W/O emulsion. To form a double emulsion, the primary W/O was homogenized together with polyvinyl alcohol (PVA). A second set of microspheres comprised PLGA/alginate composite. This composite was prepared by preparing W/O/W as before. Calcium chloride solution was added and homogenized to crosslink the alginate. To the emulsion was added deionized water and, after stirring and evaporating, microspheres were obtained ^[62].

2.1.2. Extrusion

The principle of this method is the forceful flow of material through a slit ^[8]. Extrusion is a suitable method for the preparation of capsules with hydrocolloids by adding microorganisms. The cell suspension is extruded through a syringe needle in the form of droplets into a bath or a hardening solution, which is mostly calcium chloride [46,63,64,65]^{[46][63][64][65]}.

The group of Zhenxing Tang et al. used extrusion as the method to encapsulate Felix O1 bacteriophages into alginate-whey protein microspheres ^[66]. In this work, researchers focused on the growing problem of bacterial contamination in food poisoning. Worldwide treatment of bacterial infections in food animals is carried out using antibiotics, which causes the overuse of these drugs. Bacteriophage treatment can be a good substitute. Encapsulation is needed because gastric acidity decreases the viability of bacteriophages. Within minutes, the phages were found to be inactive in the simulated gastric fluid. The viability of Felix O1 increased to 2 h of incubation in alginate-whey protein microcapsules ^[66]. Encapsulation efficiency describes how much of the core material is successfully entrapped into the capsules. The encapsulation efficiency of bacteriophages is calculated as the quantity released from capsules divided by the initial quantity in the capsules multiplied by 100% ^[67]:

E E = (m_{s} m_{t}) \cdot 100 %

where

m_{i}

is the initial mass and

m_{s}

is the mass of the compound left in solution. Here the encapsulation efficiency reached 99% for mixtures of alginate-whey proteins from 93% of pure alginate microspheres. The extrusion method is simple and cheap but has a big disadvantage for use at a mass-production scale ^[46].

In the publication by Savic et al., researchers encapsulated extracted antioxidants from orange peel into alginate-chitosan microparticles ^[68]. The extrusion method with coaxial airflow was used for encapsulation. To the solution of alginate 1.5% (v/v) was added ethanol extract of orange peels. From the homogeneous solution, which was in a plastic syringe, drops were torn using coaxial airflow. Droplets fell into the crosslinking solution while stirring and solidifying. The crosslinking solution was prepared using calcium chloride 2% (w/v) and chitosan 0.5% (w/v). The chitosan was prepared using 0.5% (v/v) acetic acid. The encapsulation efficiency was 89.2% ^[68].

2.2. Probiotic Encapsulation by Chitosan-Gel Particles

Probiotics are helpful bacteria for maintaining a healthy bowel environment. A problem in administering probiotics is that they are prone to degradation because of humidity and low pH in the human intestines. The group of Albadran H. et al. devised a novel method to encapsulate probiotics in chitosan-coated agar-gelatin particles for releasing probiotics into the large intestine ^[69]. This method should be scalable and thus more suitable than commonly used extrusion methods. Firstly, they prepared agar-gelatin particles loaded with bacteria. This was undertaken by separately dissolving agar and gelatin in deionized water for 2 h at 70–80 °C. Both substances were mixed together at a 1:1 ratio and autoclaved. A small volume of cell suspension was mixed with agar-gelatin and poured into a petri dish, left at room temperature to solidify, and cut into particles having a size of approximately 6 mm. Secondly, particles were coated with chitosan. Agar-gelatin particles were added into the chitosan solution and stirred. Particles were then collected by filtration and washed with phosphate buffered saline (PBS). As a result, particles prepared by the method described by Albadran H. et al. showed great potential for delivery of probiotics into the large intestine ^[69]. Coated particles showed the ability to withstand the environment of simulated gastric fluid (SGF) for 2 h of incubation and 3 h in simulated intestinal fluid (SIF). X-ray diffraction analysis showed a change in the physico-chemical properties of agar. This change caused by thermal treatment resulted in a strong and tight polymer network.

2.3. Nanoemulsion

The definition of a nanoemulsion system can vary as some sources describe that the droplet size is smaller than 500 nm whereas others claim the droplet size is up to 1000 nm [70,71,72,73,74]^{[70][71][72][73][74]}. The system is made of two immiscible liquids, as stated previously, which are stabilized using surfactant [75,76,77,78]^{[75][76][77][78]}. Nanoemulsions, as opposed to macro and microemulsions, have improved physico-chemical stability ^[79]. The immiscible liquids used most are water and oil [74,80]^[74][80]. There are two main types of nanoemulsion. The first type can be formed as oil-in-water (O/W); the second type is water-in-oil (W/O), depending on the dispersed liquid. Apart from these, they are also water-in-oil-in-water (W/O/W), and vice versa, and bi-continuous types [55,72,81,82]^{[55][72][81][82]}. Two main approaches are used for preparation, the so-called high and low-energy methods [83,84]^[83][84]. High-energy methods include high-pressure homogenization, microfluidization, and ultrasonication [74,85,86]^[74][85][86]. With these methods, mechanical energy is used to break large droplets. The main disadvantage of high-energy methods is cost, due to energy demand. Conversely, the advantages are good control of droplet size and possibility of choosing the formulation composition [85,87]^[85][87]. Low-energy methods include the phase inversion temperature and the emulsion inversion point [74,85]^[74][85]. Their principle uses internal chemical energy and formation of droplets with a change in, for example, temperature or chemical composition [86,87,88]^[86][87][88]. Particles are spheres with amorphous, lipophilic, and negatively charged surfaces [73,89]^[73][89]. A significant number of newly investigated drugs have problems with water solubility and thus their bioavailability is very low ^[78]. In the study by Dey et al. ^[90]., it was found that nanoemulsion enhances the absorption of lipids in the small intestine of rats more than conventional emulsion. The group of Oh et al. ^[91]. developed a lecithin nano-liposol system loaded with astaxanthin (ASTA). Like other antioxidants, ASTA is susceptible to degradation and thus needs to be encapsulated. The method used for preparation was emulsion evaporation. Chloroform with different concentrations of ASTA was added to lecithin and mixed for 2 h. The final mixture was then added to deionized water and homogenized. Chloroform was removed by drying. The last steps were carried out using ultrasonication and purification by centrifuge. The best results were achieved with a loading of 15 wt% as it had a similar hydrodynamic diameter to that prior of loading. The diameter was around 140 nm ± 4 nm. The encapsulation efficiency for 15 wt% was 98.8% ^[91]. The publication by Tayeb and Sainsbury describes different uses of nanoemulsion in the pharmaceutical industry ^[78]. For the delivery of the drug, different ways of application can be used, i.e., nasal, ocular, oral, and parenteral [78,92]^[78][92]. The application of drugs through the skin can be challenging because of the protectiveness of skin layers. Nanoemulsion encapsulation can improve both bioavailability and penetration chance because of the nano-dimensions and low surface tension ^[78]. Quercetin as a well-known antioxidant with various health benefits, which can be encapsulated. It is necessary to do so because of its poor water solubility, skin absorption, and penetration ability, which are improved by nanoemulsion encapsulation [78,93,94]^[78][93][94]. Oral drug intake is specific because of the acidic environment and enzymes [95,96]^[95][96]. Encapsulation can decrease the impact of the environment and help with absorption of active substances ^[97].

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