*3.1. Biopolymers in the Pharmaceutical Industry*

mers in drugs and probiotics delivery.

Due to their special properties, biopolymers have slowly begun to replace conventional materials. Whereas in the beginning they were mainly used in the food industry, their

application in other related industries took place relatively quickly. In the pharmaceutical industry, they were initially used for the same purpose as in the food industry, which is as thickening and emulsifying agents, host molecules, bulking agents, or fibers. In addition, their use in cosmetics has increased substantially. According to existing data, it is estimated that the world biopolymer market will reach approximately USD 10 billion by the end of 2021, an increase by approximately 17% between 2017 and 2021. The largest market segment is owned by Western Europe with approximately 41.5% of the global market [72]. In biomedicine, polymers have been used successfully both experimentally and in in vivo applications, wound dressing, tissue engineering, drug delivery, or in medical devices such as electronics, sensors, and batteries. Furthermore, due to their physical, thermal, mechanical, and optical properties, biopolymers are ideal materials widely used for food and pharmaceutical applications [5] (Figure 3). their application in other related industries took place relatively quickly. In the pharmaceutical industry, they were initially used for the same purpose as in the food industry, which is as thickening and emulsifying agents, host molecules, bulking agents, or fibers. In addition, their use in cosmetics has increased substantially. According to existing data, it is estimated that the world biopolymer market will reach approximately USD 10 billion by the end of 2021, an increase by approximately 17% between 2017 and 2021. The largest market segment is owned by Western Europe with approximately 41.5% of the global market [72]. In biomedicine, polymers have been used successfully both experimentally and in in vivo applications, wound dressing, tissue engineering, drug delivery, or in medical devices such as electronics, sensors, and batteries. Furthermore, due to their physical, thermal, mechanical, and optical properties, biopolymers are ideal materials widely used for food and pharmaceutical applications [5] (Figure 3).

Due to their special properties, biopolymers have slowly begun to replace conventional materials. Whereas in the beginning they were mainly used in the food industry,

*Polymers* **2021**, *13*, x FOR PEER REVIEW 6 of 33

*3.1. Biopolymers in the Pharmaceutical Industry* 

**Figure 3.** Specific features of biopolymers. **Figure 3.** Specific features of biopolymers.

The composition and matrix of biopolymers can be manipulated in order to obtain the appropriate functional properties such as microstructure, permeability, and chargeability that are dependent on the internal structure of the polymer. Electrical characteristics influence the bonding of particles in the biopolymer matrix and their capacity to aggregate. The biopolymer fractions that prevent aggregation are the ones with a high electrical charge [58]. Based on these properties, biopolymers are used successfully to obtain nanoparticles, nanoemulsions, nanogels, or hydrogels with applications in the biomedical industry as carrier systems. Among them, polysaccharides are the most widely used category of biopolymers, either individually or in mixtures with other biopolymers to replace the synthetic materials or exist in addition to them. The composition and matrix of biopolymers can be manipulated in order to obtain theappropriate functional properties such as microstructure, permeability, and chargeability that are dependent on the internal structure of the polymer. Electrical characteristics influence the bonding of particles in the biopolymer matrix and their capacity to aggregate. The biopolymer fractions that prevent aggregation are the ones with a high electrical charge [58]. Based on these properties, biopolymers are used successfully to obtain nanoparticles, nanoemulsions, nanogels, or hydrogels with applications in the biomedical industry as carrier systems. Among them, polysaccharides are the most widely used category of biopolymers, either individually or in mixtures with other biopolymers to replace the synthetic materials or exist in addition to them.

#### 3.1.1. Biopolymers for Controlled Drug Release 3.1.1. Biopolymers for Controlled Drug Release

Encapsulation involves the protection of living cells from destruction by entrapment in biopolymer membranes and it is applied in micro and macrocapsules [73]. It is the procedure by which one or more materials, representing the active part or core material, is embedded or coated with another material or system, which is actually a mantle, shell, carrier, or encapsulant [74] (Figure 4). Encapsulation involves the protection of living cells from destruction by entrapment in biopolymer membranes and it is applied in micro and macrocapsules [73]. It is the procedure by which one or more materials, representing the active part or core material, is embedded or coated with another material or system, which is actually a mantle, shell, carrier, or encapsulant [74] (Figure 4).

**Figure 4.** Graphical representation of drug encapsulation (adapted from Madene et al. [74] with **Figure 4.** Graphical representation of drug encapsulation (adapted from Madene et al. [74] with permission from the publisher).

permission from the publisher). A specific feature of macrocapsules is the relatively large difference between the surface area and the volume. Thus, it is necessary to use a large number of nutrients to obtain an appropriate diffusion gradient for the entry of nutrients. This aspect overlaps with the necessary nutrition for the cells. In macrocapsules, living cells are entrapped in large diffusion chambers formed as flat sheets, hollow fibers, and disks with semi-permeable properties [75]. Macrocapsules can be used as intra or extra-vascular devices [76]. In intravascular devices, cells are connected to the bloodstream as a shunt, oriented outside the artificial capillaries. They are found in the vicinity of blood circulation, assisting with the rapid transfer of therapeutic and nutritional substances such as oxygen. The biggest disadvantage is the potential for developing thrombosis. Therefore, research is moving towards their use as extravascular devices with cells entrapped within semi-permeable diffusion chambers and placed transdermally or in the peritoneal cavity without the need for direct circulatory access. This involves a minor surgery and permits a quick and easy substitution in case of graft failure or when the transplant has to be replaced for other reasons [73]. Microcapsules allow for a fast transfer of beneficial substances and accurately mimics the release of substances such as glucose or insulin. Due to their benefits, most A specific feature of macrocapsules is the relatively large difference between the surface area and the volume. Thus, it is necessary to use a large number of nutrients to obtain an appropriate diffusion gradient for the entry of nutrients. This aspect overlaps with the necessary nutrition for the cells. In macrocapsules, living cells are entrapped in large diffusion chambers formed as flat sheets, hollow fibers, and disks with semi-permeable properties [75]. Macrocapsules can be used as intra or extra-vascular devices [76]. In intravascular devices, cells are connected to the bloodstream as a shunt, oriented outside the artificial capillaries. They are found in the vicinity of blood circulation, assisting with the rapid transfer of therapeutic and nutritional substances such as oxygen. The biggest disadvantage is the potential for developing thrombosis. Therefore, research is moving towards their use as extravascular devices with cells entrapped within semi-permeable diffusion chambers and placed transdermally or in the peritoneal cavity without the need for direct circulatory access. This involves a minor surgery and permits a quick and easy substitution in case of graft failure or when the transplant has to be replaced for other reasons [73]. Microcapsules allow for a fast transfer of beneficial substances and accurately mimics the release of substances such as glucose or insulin. Due to their benefits, most studies focused on developing microcapsules with low or non-inflammatory responses. This feature is used successfully in the treatment of endocrine diseases [77].

studies focused on developing microcapsules with low or non-inflammatory responses. This feature is used successfully in the treatment of endocrine diseases [77]. Many biocompatible polymers have been used as encapsulation materials. For this, a biopolymer must meet certain criteria: (i) stable and not interacting with the drug it contains; (ii) not interfering with the function and cellular viability; non-toxic, inexpensive, and biodegradable; (iii) both the biopolymer and its degradation products must be non-antagonistic to the host; (iv) molecular weight, solubility characteristics, glass transition temperature, microstructure, and chemical functionality should allow for proper drug diffusion and release; (v) biosafe and biocompatible; and (vi) when biocompatibility Many biocompatible polymers have been used as encapsulation materials. For this, a biopolymer must meet certain criteria: (i) stable and not interacting with the drug it contains; (ii) not interfering with the function and cellular viability; non-toxic, inexpensive, and biodegradable; (iii) both the biopolymer and its degradation products must be nonantagonistic to the host; (iv) molecular weight, solubility characteristics, glass transition temperature, microstructure, and chemical functionality should allow for proper drug diffusion and release; (v) biosafe and biocompatible; and (vi) when biocompatibility needs to be improved, the biopolymer should be combined with other compounds for a synergistic effect.

needs to be improved, the biopolymer should be combined with other compounds for a synergistic effect. Depending on the mechanism that controls the release of the active agent from the delivery system, the controlled-release modalities may be different. Thus, biopolymer erosion, diffusion, and swelling, followed by diffusion or degradation, may occur [78]. The erosion mechanisms involve: (i) hydrolysis of hydrogels, an important feature for the controlled release of macromolecules; (ii) solubilization of water-insoluble biopolymers by reactions with groups pendant from the polymer covalently bonded atoms; and (iii) cleavage of hydrolytically labile bonds within the biopolymer covalently bonded atoms. The diffusion process occurs when an encapsulated drug or other active agent crosses the outer membrane of the capsule through the biopolymer used for the controlled-release device. In the case of diffusion-controlled systems, the drug delivery system must be stable in the biological environment and must maintain its size and shape through the swelling or degradation [79]. For example, when biopolymers are combined with other bioactive agents, the drug must be able to diffuse through their molecular structure or through pores when it reaches the biological environment. At this stage, it is very important that Depending on the mechanism that controls the release of the active agent from the delivery system, the controlled-release modalities may be different. Thus, biopolymer erosion, diffusion, and swelling, followed by diffusion or degradation, may occur [78]. The erosion mechanisms involve: (i) hydrolysis of hydrogels, an important feature for the controlled release of macromolecules; (ii) solubilization of water-insoluble biopolymers by reactions with groups pendant from the polymer covalently bonded atoms; and (iii) cleavage of hydrolytically labile bonds within the biopolymer covalently bonded atoms. The diffusion process occurs when an encapsulated drug or other active agent crosses the outer membrane of the capsule through the biopolymer used for the controlled-release device. In the case of diffusion-controlled systems, the drug delivery system must be stable in the biological environment and must maintain its size and shape through the swelling or degradation [79]. For example, when biopolymers are combined with other bioactive agents, the drug must be able to diffuse through their molecular structure or through pores when it reaches the biological environment. At this stage, it is very important that there are no changes to the biopolymer itself. Swelling-controlled release devices are those systems that, although dry in the initial phase, will swell when they reach the body and

come into contact with fluids or water. The swelling ability of the biopolymers can be triggered by changing the environmental conditions of the delivery system. This is one of the most important and useful features of the biopolymers because, by changing the pH or temperature, the release of drugs or incorporated active substances can be controlled [80]. Finally, the biodegradation of a biopolymer in the body is a natural process through which the active ingredient is completely eliminated.

Synthetic polymers have long been of interest for use as encapsulating agents of various therapeutic substances. Although they show improved pharmacokinetics compared to small molecule drugs, their accumulation in the body has raised toxicity issues [81]. With the reorientation of the medical industry towards the use of biopolymers, the major issue is the selection of the right compounds based on the need and desired effects. Not all biopolymers are suitable as encapsulating agents for drugs. It is important that they release the active substance to the target area at the right time in a safe manner and without side effects, especially considering that the predominant routes are oral or intravenous administration [82]. The most used biopolymers and which are the focus of this review are those based on polysaccharides, such as sodium alginate, chitosan, agar, starch, and cellulose. They react synergistically with other biopolymers and polymers, have low toxicity and non-immunogenic behavior, and are compatible with tissues and cells. These polysaccharides are stable in vitro and in vivo, and are used in the development of microcapsules, microspheres, or nanocapsules. When tested in vivo, they showed high biocompatibility and biodegradability, facilitating treatment, minimizing side effects, and improving the health condition. Their high solubility is a plus for their use as disintegrants in water-soluble tablets. For example, when used in tablets, the coating of chitosan and starch improved their visual appearance, protected the drug from degradation, and masked the unpleasant taste of the incorporated substance [83]. When used as capsule material, gelatin was replaced with alginate, a vegan version, or with cellulose, for hard capsules. The main biopolymers that are widely used and presented in this review are alginate, chitosan, agar, starch, and cellulose.
