*3.1.1.1 Albumin*

*Microencapsulation - Processes, Technologies and Industrial Applications*

the capsules is designed to serve the desired specific purpose.

site under specific conditions.

materials are highlighted.

**2. Encapsulation techniques**

**3. Polymers as wall materials**

**3.1 Natural polymers**

*Encapsulation techniques.*

Centrifugal extrusion

Fluidized bed technology

Pan coating Spray drying

**Table 1.**

biocompatible in nature.

physical and chemical methods used for encapsulation.

**Physical methods Chemical methods** Air suspension coating Solvent evaporation Coacervation Polymerization

be stabilized by encapsulation. Depending on the applications, the wall material of

Thus, the wall material is the most vital component in any capsule. The selection of appropriate wall material decides the physical and chemical properties of the resultant micro-/nanocapsules. The wall material should have the properties like being inert toward core active ingredients, stabilize the core material, film-forming, pliable and tasteless, non-hygroscopic, moderate viscosity, economical and soluble in an aqueous media or solvent, or melting, the coating may be flexible, brittle, hard, and thin, controlled release at the specific

Understanding the importance of polymers as wall materials, we have attempted to give a review of wall materials used in micro- and nanocapsules for the sustained/controlled delivery of drugs. A detailed account on encapsulation techniques is given. The biodegradable materials employed as wall materials are discussed adequately. The advantages of biodegradable materials including their limitations are covered in the chapter. The release profiles were discussed based on both exogenous and endogenous responsiveness of the wall materials. At the end of the chapter, future prospects and challenges of the wall

Microencapsulation of active compounds can be achieved by physical and chemical methods. Though these techniques are neither purely physical nor purely chemical, they are classified as physical and chemical methods based on the predominant or primary principle involved. In **Table 1**, we have listed commonly used

Natural polymers are broadly classified into protein-based polymers and polysaccharide-based polymers. Albumin and gelatin are the examples of proteinbased polymers. Polysaccharide-based polymers are agarose, alginate, hyaluronic acid, dextran, chitosan, etc. These natural polymers are highly biodegradable and

**4**

Albumin is a biodegradable and water soluble protein and thus plays an important role in the circulating system. It is involved in osmotic pressure regulation, binding, and transport of nutrients to the cells that can be obtained from a variety of sources including egg white, bovine serum, and human serum. It is stable in the pH range of 4–9 and can be heated at 60°C up to 10 h without any deleterious effects [1]. It undergoes degradation by protease enzymes, which helps the microcapsules to release the drugs in the small intestine. It also facilitates the release of therapeutic cargo from nanocapsules inside the endosomes.

### *3.1.1.2 Gelatin*

Gelatin is biodegradable, inexpensive, easily sterilized, non-pyrogenic, nontoxic, non-immunogenic, and easy to be crosslinked or modified chemically. Gelatin has many ionizable groups, such as carboxyl, amino, phenol, guanidine, and imidazole, which are potential sites for conjugation or chemical modifications. Chemical crosslinking agents like glutaraldehyde improves the integrity and performance of the gelatin and provides gelatin with greater stability, shape, and increased circulation time *in vivo* [2]. The degree of crosslinking determines the release of drugs from the gelatin capsules. Thus, gelatin is regarded as a safe excipient approved by the US FDA for pharmaceutical applications.

#### *3.1.2 Polysaccharide-based polymers*

#### *3.1.2.1 Chitosan*

Chitosan, the second most abundant polysaccharide in nature, is a promising biopolymer widely used in biomedical and pharmaceutical fields like wound dressing, tissue engineering and drug delivery. It is produced from chitin which is the structural element found in the exoskeleton of crustaceans like shrimps, lobsters, and crabs. Chitosan has been reported to exhibit many therapeutic properties, such as activation of immune response, cholesterol lowering activity, anti-hypertensive activity, inhibition of growth of microorganism, pain alleviation, and promotion of hemostasis and epidermal cell growth [3]. This is all due to the favorable pharmaceutical properties of chitosan, such as biocompatibility, low production cost, ability to bind some organic compounds, susceptibility to enzymatic hydrolysis, and nontoxicity.

Chitosan is considered as the most important polysaccharide-based polymer owing to its cationic character based on its primary amino groups, which are responsible for its versatile properties, such as mucoadhesion (improves pulmonary drug delivery), controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement [4]. The major drawback is its poor solubility at physiological pH due to partial protonation of the amino groups in the presence of proteolytic enzymes and thereby causing presystemic metabolism of drugs in intestinal and gastric fluids. To overcome these inherent drawbacks, various derivatives of chitosan, such as carboxylated, different conjugates, thiolated and acylated chitosan have been used in drug-delivery systems [3].

Chitosan is produced by the deacetylation of chitin. The degree of deacetylation is related to chitosan's crystallinity and degradation rates. Chitosan's solubility can

also be improved when the primary amino group is protonated at low pH. The viscosity of chitosan solution increases with increasing the concentration of chitosan [5]. These properties and the ease with which it can be modified makes chitosan a versatile and bioactive polymer for its use in encapsulation.

#### *3.1.2.2 Hyaluronic acid*

Hyaluronic acid (HA) is a nonsulfated glycosaminoglycan, comprising a relatively simple linear structure of alternating units of D-glucuronic acid and N-acetyl-D-glucosamine, linked via β-1,3- and β-1,4-glycosidic bonds. Hyaluronic acid is biodegradable, biocompatible, nontoxic, and non-immunogenic glycosaminoglycan distributed widely in connective, epithelial, and neural tissues.

The cluster of differentiation (CD) protein CD44 is the main HA binding receptor. CD44 is involved in the interaction between HA and the surface of specific cells, in cell proliferation, in cellular adhesion processes (aggregation and migration), angiogenesis, in cell survival and endocytosis of HA. CD44 receptor is also overexpressed in many types of tumors and this overexpression is related to tumor invasion and tumor metastasis, which makes HA a promising candidate for intracellular delivery of imaging and anticancer agents exploiting a receptormediated active targeting strategy. HA also interacts with hyaluronan receptor for endocytosis (HARE), lymphatic vessel endothelium receptor-1 (LYVE-1), and intracellular adhesion molecule-1 (ICAM-1), serum-derived hyaluronan-associated protein (SHAP), Brevican and Neurocan (brain and nervous tissue-specific HA and proteoglycan binding proteins), hyaluronan-binding protein 1 (HABP1) and toll-like receptors (TLRs), and all of which have specific functions. This is known as receptor-ligand interaction, which can be exploited to achieve receptor-mediated active targeting strategy [6, 7]. HA has been bioconjugated with anticancer drugs, like paclitaxel, doxorubicin, cisplatin, etc. and anti-inflammatory drugs like methotrexate, dexamethasone, methylprednisolone, etc. to achieve receptor-mediated endocytosis [8]. HA polymer has also been used in the treatment of osteoarthritis, in ocular and plastic surgery, and in tissue engineering.

#### **3.2 Synthetic polymers**

Over the past 5–6 decades, biodegradable polymers have gained tremendous attention due to their growing applications in biomaterials, drug-delivery systems, tissue engineering, and medical devices. Chemists, biologists, physicians, and engineers have collaboratively made significant advancements in these applications. The most commonly used synthetic polymers in micro-/nanocapsules for drug-delivery applications are poly(Ɛ-caprolactone), poly(lactic-co-glycolic acid), and polyethylene glycol.

#### *3.2.1 Poly(Ɛ-caprolactone)*

Poly(Ɛ-caprolactone) (PCL) is a semicrystalline aliphatic polyester with glass transition temperature and melting temperature of about −60 and 60°C, respectively [9]. PCL mixes well with other polymers to form blends that impart good physical and chemical properties to achieve desired properties like swelling, porosity, and stability in different media. Microcapsulation or nanocapsulation with PCL has many advantages like modulation of drug release, control of drug penetration/ permeation into the skin, and improve photochemical stability and pharmacological response. Due to its long degradation times, PCL has found many applications in tissue engineering and prolonged drug release. PCL is approved by the US Food and

**7**

*Encapsulating Wall Materials for Micro-/Nanocapsules DOI: http://dx.doi.org/10.5772/intechopen.82014*

*3.2.2 Poly(lactic-co-glycolic acid)*

imaging, and vaccine immunotherapy.

*3.2.3 Poly(ethylene glycol)*

**4. Sensitive polymers**

endogenous factors.

**4.1 Exogenous factors**

body, such as heat, light, or ultrasound induction.

Drug Administration (FDA) and has found numerous applications in implants and surgical absorbable sutures due to its biocompatibility and slow biodegradability.

Poly(lactic-co-glycolic acid) (PLGA) is the most extensively studied degradable polymer to date. PLGA is an aliphatic polyester and it undergoes hydrolysis in the body to produce biodegradable metabolite monomers such as lactic acid and glycolic acid. During metabolism in the body via the Krebs cycle, carbon dioxide, and water are removed and thereby toxicity is minimized [10]. PLGA is approved by the US FDA for use in drug-delivery systems due to its biodegradability with tissue and cells, drug biocompatibility, suitable biodegradation kinetics, mechanical properties, and ease of processing. Thus, PLGA based microcapsules and nanocapsules are the most viable candidates for drug-delivery systems, anticancer agents, bio-

Polyethylene glycol (PEG) is also the most widely used "stealth" polymer in drug delivery. It is approved by the US FDA and considered to be safe. Coating of nanocapsules with PEG generates a hydration layer due to its hydrophilic nature and forms a steric barrier. This steric hindrance effect helps the nanocapsules to avoid interactions with neighboring capsules and blood components like immunogenic cells [11]. PEG coating on nanocapsules shields it from aggregation, opsonization, and phagocytosis by reticuloendothelial system. The lack of immunogenicity confers PEG-coated nanocapsules with prolonged systemic circulation time which in turn leads to enhance absorption due to enhanced permeation and retention effect. PEGylation has become a mainstay in fabrication of drug-delivery systems

that require high doses of toxic drugs with prolonged duration of action.

The design of polymeric drug-delivery systems has matured to exploit local biochemical changes in pathological states to trigger drug release. In a classical example, organs or tissues with cancer are characterized by a shift in homeostasis which include, but are not limited to, surge in specific enzymatic activity, shift toward acidic pH, reductive or oxidative states, or a buildup of reactive oxygen species. These homeostatic disturbances can be exploited for the development of targeted therapies that can be activated under certain conditions to trigger drug release. Being aware of these intracellular and extracellular changes allows us to design smart polymer microcapsules and nanocapsules. In addition to these homeostatic disturbances, external physical parameters, such as temperature, ultraviolet light, ultrasound, or magnetic energy, can also be used to trigger drug release from polymer capsules. Thus, in this chapter, we have attempted to summarize the effects of adding biologically responsive moieties to the polymer structure in order to achieve more targeted controlled therapeutic outcomes. They are exogenous and

Exogenous stimuli result in manipulation of capsule structure from outside the

Drug Administration (FDA) and has found numerous applications in implants and surgical absorbable sutures due to its biocompatibility and slow biodegradability.
