Controlled drug delivery systems have always remained a reliable method for achieving a targeted therapeutic efficiency and minimal side-effects. Yet numerous active molecules cannot be delivered because of the diverse nature of the tissues and cells in the human body. There is still a need to develop an ideal controlled drug delivery system with multiple features like high drug loading capacity, biocompatibility, low toxicity, enhanced stability, reduced side effects, and target–oriented delivery. Advancement in polymer science and nanotechnology has given rise to a variety of targeted drug delivery techniques using different polymers and among these hollow capsules hold a prominent place.  

Synthesis of hollow capsules 

Hollow capsules are easy to fabricate; biocompatible; can load drug molecules of any nature and aid in monitoring the pharmacokinetic drug release. Common methods for the preparation of hollow capsules can be categorised as:  

1. Self-assembly method 
2. Template-assisted method   

1. Self-assembly methods – There are 3 different types of self-assembly methods:  

Solvent displacement self–assembly method – It involves the preparation of a homogenous mixture of a block polymer and an organic solvent which upon addition of water forms hollow capsules by changing the orientation of hydrophilic and hydrophobic segments. The hydrophobic segments orient themselves together to minimise interaction with the aqueous environment and hydrophilic segments diffuse into the water. This orientation results in the formation of bilayer self–sealed vesicles.  

Film-hydration self-assembly method – It includes the addition of water to a preformed thin film of amphiphilic block polymers. By the addition of water, the layer of film swells and detaches from the surface slowing vesicles formation.  

2. Template-assisted method – Layer-by-layer template–assisted method is a multiple-layer deposition of polymer on a colloidal base followed by the dissolution of colloid. This method helps in controlling the thickness of the capsule cell wall during the layer deposition process.  An alternate approach called a single–step polymer approach has been designed which includes the use of cross–linking agents to stabilise the outer single polymer membrane. This technique was introduced to skip multiple steps of layer deposition by using single constituents such as polypeptides and polyelectrolytes.  

Drug loading in hollow capsules  

The drugs can either be pre-loaded into the hollow capsules or post loaded. Pre–loading drugs indicate drug loading before sealing of vesicles.  Pre–loading can be done by either using mesoporous silica or using non-porous templates. Mesoporous silica mediated pre-loading involves the use of mesoporous silica nanoparticles as a template for drug loading due to their larger surface area and adjustable size. Post–loading strategies include the use of pH or ion gradient, emulsion-mediated, and polymer–drug conjugation. pH or ion mediated loading involves the use of the difference in pH between internal and external layers of vesicles to load drugs. The emulsion mediated method involves using an oil phase to dissolve the therapeutic agent and then loading it. Polymer drug conjunction method involves anchoring of drug on the polymer which is then used to make a polymer film. Post loading however suffers from the drawback of low loading capacity and excessive time consumption as compared to pre-loading techniques. 

Drug release from hollow capsules 

The most critical aspect of designing hollow capsules is the ability to trigger drug release at the target site. The release can be achieved by using stimulus–responsive polymeric materials. 

• Thermo-triggered release capsules are a non-invasive technique that releases the drug by external heat stimulation because inflammatory tissues have a temperature higher than other body parts.  
• pH-triggered drug release from hollow capsules is based on the principle of protonation and deprotonation of functional groups such as carboxyls and amines present in the polymer leading to disassembly of carrier capsules and drugs on change of pH.  
• Ultrasound-triggered drug release is another non-invasive and yet deep penetrating technique to trigger drug release. The primary principle of using ultrasound is based on its thermal effect that transmits acoustic energy to the target or oscillation effect which collapses the cavitating bubbles in the capsule wall.  
• Light triggered release uses light–responsive materials such as azobenzene and spiropyran in the capsule wall that undergoes cleavage of chemical bonds to release the drug.    

Takeaway  

Over the past decade, a lot of contribution has been made to develop hollow capsules because of its ability to load various therapeutic agents and easy fabrication. A greener approach to the fabrication of hollow capsules involves reducing the use of harsh chemicals during core removal in template–assisted preparation and the use of lesser steps to make capsules. A shift to the concept of green capsule synthesis approach and developing hollow capsules that can carry both hydrophilic and hydrophobic drugs and release drugs by a combination of stimuli can enhance the efficacy of hollow capsules as an efficient drug delivery system.  

References: 

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3. Itoh, Y., Matsusaki, M., Kida, T., & Akashi, M. (2006). Enzyme-responsive release of encapsulated proteins from biodegradable hollow capsules. Biomacromolecules, 7(10), 2715-2718. 

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6. Caruso, F. (2000). Hollow capsule processing through colloidal templating and self‐assembly. Chemistry–a European journal, 6(3), 413-419. 

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8. Shen, H. J., Shi, H., Ma, K., Xie, M., Tang, L. L., Shen, S., … & Jin, Y. (2013). Polyelectrolyte capsules packaging BSA gels for pH-controlled drug loading and release and their antitumor activity. Acta biomaterialia, 9(4), 6123-6133. 

9. Shchukin, D. G., Gorin, D. A., & Möhwald, H. (2006). Ultrasonically induced opening of polyelectrolyte microcontainers. Langmuir, 22(17), 7400-7404. 

10. Ochs, M., Carregal‐Romero, S., Rejman, J., Braeckmans, K., De Smedt, S. C., & Parak, W. J. (2013). Light‐Addressable Capsules as Caged Compound Matrix for Controlled Triggering of Cytosolic Reactions. Angewandte Chemie International Edition, 52(2), 695-699.