Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Author: Tilda Barliya PhD

Title: Building a DSS: choice of polymers and drugs

Category: Nanotechnology and drug delivery

During the last 40 years, controlled drug delivery has become one of the most challenging and rapidly advancing scientific areas. Delivery systems can offer numerous advantages compared to conventional dosage forms. This coalition of polymeric science and pharmaceutical science led to the innovation in the design and development of drug delivery systems (DDS). Some of the challenges of most drug delivery systems include poor bioavailability, in vivo stability, solubility, intestinal absorption, sustained and targeted delivery to site of action, therapeutic effectiveness, side effects and patient compliance as well as plasma fluctuations of drugs which either fall below the minimum effective concentrations or exceed the safe therapeutic concentrations.

The purpose of these polymers in such system is to increase the delivery effectiveness of drugs to pathological cells by protecting them from degradation in the physiological environment, localize the drug to the desired site and be non-toxic.  (1,3,4 ).

Grund S and colleagues nicely outlined the history of polymer-based drug delivery system, the types of polymers and drug combinations (1).

Classification:

–          Origin (synthetic, natural or both)

–          Chemical nature (polyester, polyanhydride etc)

–          Backbone stability (biodegradable or not)

–          Water solubility (hydrophilic, hydrophobic) and Electrical charges

Although intertwined, delivery systems can be generally grouped as:

–          Biodegradable drug delivery systems

–          Diffusion controlled drug delivery system

–          Responsive drug delivery system (thermo, pH, enzymatic)

These DDS systems among others are differentiated on the basis of the mechanism controlling the release of the drug from the polymers (1,2).

Biodegradable polymers disintegrate into biocompatible compounds when exposed to chemicals (like water), enzymes or microbial which leaves the incorporated drug behind.  The drug molecule present in the DDS is released due to the process of erosion. Moreover, the degradation of the polymers involves breakdown of polymers and reduction by the Kreb’s cycle to carbon dioxide and water.  Furthermore, biodegradable polymers can be manipulated by the addition of functional/liable groups such as: esters, amine, urea, anhydride, carbonates etc to the backbone.  Here are some examples to the most common biodegradable polymers; polyesters, polyacrylic acids,  polyanhydride, polyurea etc

Diffusion controlled-polymer systems involve the dispersion of the therapeutic molecule within the polymer shell. The sustained release of the drug from this system is driven by diffusion through the pores or between the polymer chains. Drug: Progestasert (intra-uterine), Nicoderm (transdermal)

Responsive drug delivery systems release the drug in a more controlled manner which can be stimulated by the surrounding such as temperature, solvent, pH and/or concentration. Poly (N-isopropylacrylamide) is a well known example for a thermo-responsive polymer. Poly (ethylene glycol), poly lactic acid etc are known to be used for their thermogelling system.  Drug: Atridox.

 A different way to approach drug delivery system is:

–          Temporal controlled

–          Distribution controlled

In temporal control DDS, the aim is to deliver the drug a specific time during the treatment and controlled release over extended duration is highly beneficial for drugs that are rapidly metabolized and eliminated from the body after administration (2)

in distribution controlled DDS, the aim is to the deliver the drug to a specific site in the body.  This delivery system is highly beneficial when natural distribution encounter body cells and cause major side effects that prohibit further treatment ( i.e chemotherapy) or when natural distribution can’t be facilitated using the regular systemic system (i.e passing the BBB and reaching brain tumors)

The choice of drugs imposed various restrictions on the type of the delivery system employed.

For example, a drug that is to be released over an extended period in a patient’s stomach where the pH is acidic and environmental conditions fluctuate widely will require a controlled release system very different from that of a drug that is to be delivered in a pulsatile manner within the blood system.

It is also very important to understand the fate of the polymer after the drug has been released, such as polymers that naturally excreted from the body (kidneys), removed after the drug release (patch or and insert) or extract through the GI track, are acceptable in medical application.

Four physicochemical properties of polymers can affect the opsonisation process and determine the degree of RES clearance (1):

• Charge
• Molecular size
• Shape
• Hydrophobicity/lipophilicity

In summary

Polymer science has become the motor for the development of new drug delivery systems in the past decades and requires an increasingly intensive cooperation between chemists, technologists and biologists.

“Over the years, especially induced by the introduction of micro- and nanosized carriers, they have changed their profile to parenteral drug applications and are now capable of offering advanced, more sophisticated and multifunctional approaches such as stealth effects and drug targeting for medicines. Combination therapy applying multiple types of drugs concurrently with one single drug delivery system will lead to more effective therapeutics and a more convenient application for the patients”

Novel, tailored polymers with more complicated and complex structures and functions may influence many related scientific and regulatory fields. However, several questions regarding regulatory approval of polymer-based carriers are still pending, and the establishment of new guidelines and policies especially adapted to nanosized polymer materials and their unique properties is still in the beginning. New criteria to determine identity, purity, and stability of the materials during manufacturing and storage have to be
defined and confirmed by new validated analytical methods.

References

1. Grund S, Bauer M and Fischer D.   Polymers in drug delivery-State of the art and future trends. Advanced Engineering Materials 2011, 13(3); B61-B87. http://onlinelibrary.wiley.com/doi/10.1002/adem.201080088/abstract
2. Unrich K.E, Cannizzaro S.N and Langer R.S.  Polymeric systems for controlled Drug release. Chem. Rev. 1999, 99; 3181−3198. http://www.qmc.ufsc.br/qmcweb/artigos/dor/bonus/Polymeric%20Systems%20for%20Controlled%20Drug%20Release.pdf
3. Mody V.V. Introduction ro polymeric drug delivery. Internet journal of medical update 2010; 5(2): 1-2 http://www.akspublication.com/Editorial_Jul2010_.pdf
4. Muhammad T, Nur Z, Piletska E.V, Yimit O and Piletsky S.A.Rational design of molecularly imprinted polymer: the choice of cross-linker.  Analyst.  2012 Jun 7;137(11):2623-8. Epub 2012 Apr 26. http://pubs.rsc.org/en/content/articlelanding/2012/AN/C2AN35228
5. Torchilin VA. Polymeric Immunomicelles: Carriers of Choice for Targeted Delivery of Water-Insoluble Pharmaceuticals. Drug Delivery Tech 2004: 4(2). http://www.drugdeliverytech.com/ME2/dirmod.asp?sid=&nm=&type=Publishing&mod=Publications%3A%3AArticle&mid=8F3A7027421841978F18BE895F87F791&tier=4&id=5F2B931260F14B7786C80C84E46AEC1
6. William B. Liechty W.B, David R. Kryscio D.R, Brandon V. Slaughter B.V and Peppas N.A. Polymers for Drug Delivery Systems. Annual Review of Chemical and Biomolecular Engineering 2010 1: 149-173. http://www.annualreviews.org/doi/abs/10.1146/annurev-chembioeng-073009-100847.
7. Chen Y and Liu L. Modern methods for delivery of drugs across the blood–brain barrier. Adv Drug Deliv Rev 2012: 64(7); 640-665. http://www.sciencedirect.com/science/article/pii/S0169409X11002900.
8. Kaparissides C, Alexandridou S, Kotti K and Chaitidou S. Recent Advances in Novel Drug Delivery Systems. Journal on nanotechnology online. March 2006. http://www.azonano.com/article.aspx?ArticleID=1538

Key words: polymers, drug delivery system, materials, nanotechnology