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The list of drugs and proteins available to cure or at least treat diseases is constantly growing. However, not all drugs can be delivered to a patient directly. Proteins are huge bulky molecules and are often hydrophobic in nature. This can cause huge problems when attempting to deliver a protein around the body. The stability of a protein is a result of a balancing of stabilising and destabilising forces such as van der Waals forces, hydrogen bonding and hydrophobic interactions. Disruption of any of these may cause the protein to lose stability [1]. This reduces, if not destroys, the ability of a protein to carry out its intended function.

Hormones, enzymes, vaccines, antimicrobials and many other bioactive proteins have seen a huge increase in oral delivery in the last number of years. Bioactive proteins can produce a wide range of activities and therefore show great promise for use in supplements and medicine. Lactose intolerance can be treated with the supplementation of lactase which is an enzyme that breaks down lactose to galactose and glucose [2]. Lipase supplementation can aid in the breakdown of lipids in individuals who suffer from pancreatitis [3]. There are however many barriers to oral delivery of proteins.

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Proteins require a specific three-dimensional shape to allow them to work as intended. The stability and specificity of a protein can be altered by many factors such as temperature, pH, enzymes or interaction with metal ions, often rendering a treatment useless [4]. Due to their fragility, proteins have an extremely short half-life. As a protein travels through the body it is constantly being bombarded with enzymes. This is especially true in the gastrointestinal tract (GIT) where an extremely acidic environment alongside a huge amount of protease enzyme makes degradation almost a guarantee [5].

Due to these problems, effective drugs are often not able to efficiently treat diseases. Huge amounts of expensive drugs are wasted this way and patients do not gain any benefit from them. As a result of this, there has been a huge push to develop a method that allows the ability of protein drugs to be maximised. Encapsulation techniques have been developed to help protect proteins and make them infinitely more usable.

Encapsulation involves the drug or protein of interest being caged by synthetic polymers [6]. These polymers are often referred to as being non-covalent supramolecules that are extremely inert and therefore protect the protein from its environment. The need for the polymers to be synthetic is due to the fact that natural polymers vary in purity from one to another. Synthetic polymers offer a degree of control that is not possible with natural polymers. The most common polymers used in encapsulation are polyglycolic acid (PGA), polylactic acid (PLA) and the co-polymer of the two, polylactic-co-glycolide (PLGA). These polymers are extremely biocompatible and show a high resorbability through natural pathways. The rate of release of the proteins can also be controlled by changing the ratio of PLA and PGA [7].

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Encapsulation results in the production of nano or microparticles. The minute size of these molecules allows for deliver to varying areas of the body that could not be reached before by the extremely bulky proteins [8].

Encapsulated proteins have been shown to work far better than normal proteins floating freely in the harsh environment of the human body. Encapsulated proteins are far easier to control and they offer greater bioavailability and bioactivity [9]. The ability to control the release of the protein from the capsule allows for a specific site of delivery to be targeted directly which results in a far greater therapeutic impact. Optimum dosing has been made available and a staggered release increases the efficiency of the protein drug. Encapsulation allows for highly toxic, unstable and insoluble drugs and proteins to be used as therapies in the body [10].

With regards to the target and path of administration, the encapsulation method must be very carefully designed. Therefore, several different forms of encapsulation have been developed to allow for these varying properties.

Figure 1: Methods of nanoparticle preparation (11)

Emulsion evaporation is the most commonly used method of protein encapsulation but both self-emulsifying drug delivery systems (SEDDS) and super critical fluid encapsulation are becoming increasingly more popular. Supercritical fluid encapsulation does not require the use of organic solvents and has therefore been developed as a safer alternative to emulsion evaporation that requires the use of organic solvents. Organic solvents are a risk to the environment and to the human body itself if not used correctly.

Other techniques such as salting out and solvent displacement have also been developed as a quick and easy method of encapsulation however these methods have not been optimised for use as of yet.

Figure 2: Schematic diagram of the salting out process [12].

Figure 3: Schematic diagram of solvent displacement [13].

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Applications of Encapsulated Proteins


Insulin is used to control blood glucose levels and treat patients suffering from diabetes. Insulin is delivery via a subcutaneous injection which is extremely effective but inconvenient and uncomfortable for the patient due to the fact that injections must be taken several times throughout the day [14]. As a result of a demand for an easier way to deliver insulin, oral delivery systems have seen a huge interest. Oral delivery has been very ineffective due to the low bioavailability of insulin and its susceptibility to breaking down in the human GIT [15]. The development of effective methods to oral delivery of insulin has become a very interesting area of research.

A good delivery system for insulin should ensure the protein remains stable, protect the protein from the GIT, release the protein in the small intestine and enhance the permeability of the protein through the epithelial cells.

A recent study showed the ability to successfully encapsulate insulin inside biopolymer microgels made from alginate and chitosan using a gelation emulsifier [16]. A water-in-oil (W/O) emulsion was created by passing an alginate solution through a membrane into an oil. The encapsulated alginate solution was then mixed with a second emulsion of the same oil that contained calcium chloride. Due to diffusion of the calcium ions, cross linked alginate molecules formed as microgels. These microgels were then washed with an organic solvent before being transferred to an aqueous solution of chitosan and insulin. The chitosan was seen to form a shell around the alginate with insulin trapped inside the new formed matrix. This experiment then simulated both gastric conditions and small intestine conditions to shown that the insulin would remain protected in the stomach and be released in the small intestine. Testing was then carried out on diabetic rats and showed that their blood glucose level could be reduced and kept stable for a long period of time after oral administration of the insulin-loaded alginate-chitosan microgels.

Figure 4: Schematic diagram of insulin encapsulation [16].

Digestive enzymes

Similarly to insulin, many individuals suffer from diseases due to the under production of digestive enzymes such as lipase or lactase. These enzymes could be delivered orally to the small intestine to help people who suffer from lactose intolerance or pancreatitis. Enzymes are very sensitive however and may lose their function if they become denatured by the high acidity and protease rich environment of the stomach. Several delivery systems have been developed to help encapsulate enzymes in order to protect them in the stomach and subsequently release them when they reach the small intestine.

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Solid-in-oil-in-water (S/O/W) emulsions have been developed for the delivery of lactase [17]. Firstly, a solid-in-oil phase was formed by adding a spray dried lactase powder to an oil with a lipophilic surfactant (Span 80). This solid-in-oil (S/O) phase was then added to a water phase containing a hydrophilic emulsifier (sodium caseinate). The S/O/W encapsulation was shown to be protected when place in simulated GIT fluids.

An emulsion-evaporation method has been developed to allow hollow micro particles with pH responsive pores to encapsulate, protect and release lactase [18]. An oil phase was first formed by dissolving hydrophobic esters in an organic solvent. The oil phase was then added to an aqueous solution that contained a hydrophilic emulsifier to form an oil-in-water (O/W) phase. This was then centrifuged and washed before the organic solvent was removed by evaporation. The emulsion was then filtered and freeze-dried leaving behind hollow polymer capsules. The capsules were then loaded with lactase by mixing the capsules into an aqueous lactase solution and then placing the mixture in a vacuum oven and switching the oven on and off multiple times. Using various spectroscopy techniques, it was shown that the lactase was protected when placed in simulated gastric juices but release upon being placed in a neutral environment. It was concluded that the release mechanism was the opening of pH sensitive pores upon being placed in a neutral pH.

Figure 5: Model of pH sensitive pores using a whey protein isolate encapsulated in a calcium alginate microgel (19).


Due to the inconvenience of injections, it would be ideal to orally deliver protein-base vaccines. Orally ingested antigens should be taken up by M-cells in the Peyer’s patches of the GIT in order to protect the body from infection [20]. Antigens, however, are poorly absorbed by epithelium cells and are subject to degradation in the GIT often rendering them useless even before reaching the small intestine. Encapsulation methods have been developed to help improve the delivery of antigens to M-cells.

A recent study encapsulated model vaccines within polymer microgels and showed that there was an increase in their biological response when given orally to mice in comparison to the same free vaccine [21].

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