CHAPTER ONE

1.0  INTRODUCTION AND LITERATURE REVIEW

1.1 DRUG DELIVERY

The method or process of administering or delivering an active pharmaceutical compound through one of the common routes in order to attain a therapeutic effect in man or animals is known as drug delivery. There are various routes in which drugs can be delivered to the target specie. In humans it could be oral, nasal, pulmonary or parenteral with the nasal and pulmonary routes gaining more importance in recent times. For this purpose, a number of drug delivery systems have been formulated and are being investigated for nasal and pulmonary routes. Some of these systems are liposomes, proliposomes, microspheres, gels, prodrugs, among others (Tiwari G et al.,2016).

Polymer drug conjugate is designed so that the drug is delivered in a controlled manner with the release from the conjugate occurring over a defined time interval.

A controlled release drug delivery system should be able to maintain optimum therapeutic drug concentration in the blood. It should be able to enhance the activity duration for short half-life drugs as well as eliminate side effects, frequent dosing and drug wastage. To achieve these, the chemical and physical properties of the drug, the route of administration, the nature of the delivery vehicle, the mechanism of drug release as well as other factors would have to be considered.

1.1.1 ADVANTAGES OF DRUG DELIVERY SYSTEMS (Coelho J.F et al.,2010)

       i.            The duration of action of the drug being delivered is prolonged when using drug delivery systems.

     ii.            The bioavailability of the drug is increased.

  iii.            Drug loss and deterioriation is highly reduced.

  iv.            Minimal side effects is associated with drug delivery systems.

     v.            The frequency of dosing and administration of the drug is reduced.

  vi.            Fluctuations in plasma drug concentration is greatly minimized.

1. It enhances patient compliance and drug use.

1.1.2 DISADVANTAGES OF DRUG DELIVERY SYSTEMS(Coelho J.F et al.,2010)

For everything that has an advantage, there is always a disadvantage. The disadvantages of DDS includes;

       i.            Risk of formulation materials being toxic.

     ii.            The degradation products may be harmful.

  iii.            Some forms of DDS may involve surgical intervention either on application or removal of the system.

  iv.            DDS devices may be uncomfortable to patients in the cause of usage.

     v.            High cost of products.

1.1.3 Mechanisms for Drug Delivery

Mechanisms of drug release from a given polymer matrix can be explained using three main processes or systems;

A. Diffusion of the drug from the polymer ( This is known as diffusion-controlled

system).

B. Drug release through polymer swelling (Swelling-controlled system).

C. Drug release due to degradation of polymer matrix and erosion (erosion-controlled system). One common thing among these three systems is Diffusion. Diffusion occurs in all the three mechanisms. Diffusion takes place when a drug or other active agent penetrates the polymer that forms the delivery device.

A. Diffusion-controlled system;

The diffusion controlled system comprises of the reservoir and the matrix system. In the reservoir system, the polymer used encircles the core containing the drug molecule thereby acting as an envelope, meanwhile, in the matrix system, the drug is homogenously dispersed in the polymer matrix. However, the membrane of the polymer surrounding the core should be paid attention to with regards to the resistance. This is because a rupture of the membrane would cause an abrupt drug release (Brannon-Peppas L.,2009).

1)    Reservoir Systems.  The resevcrvoir system is one of the most widely used polymeric systems. Here, the drug is enveloped by the polymeric membrane through which it must diffuse to release the drug into circulation thereby controlling its rate of delivery. There are some factors which can affect diffusion of the drug throughout the polymer such as presence and effects of excipients, porosity and functionality of the polymer, etc (Martı´n del Valle E.M et al.,2009).

2)    Matrix Devices. Matrix system and devices consists of drug distributed throughout a polymer matrix. These devices are readily used in controlling drug release this is due to the fact that there is no risk of overdosing which can occur as a result of membrane rupture that can be experienced in reservoir devices and also its ease of manufacture. A matrix device is produced either by compression of a drug and polymer mixture, by dissolution, or by melting. In this system, the of the drug from the device relies on the extent to which the drug is soluble in the polymer matrix (Andersson, M. L et al.,2002). The release through diffusion can either occur through the polymer pores or through movement between polymer chains.

B. Swelling-Controlled Systems;

Swelling controlled release systems consists of a polymeric crosslinked chain which has a high affinity for water and has the ability to absorb a large volume of water without dissolving immediately till it gets to the point beyond which it can no longer swell. These systems are designed such that the active therapeutic agent contained in the drug delivery system is not released until it is placed in the desired environment. Initially, the delivery system is dry then when it gets into the body, it tends to suck up water or other body fluids then increases (Nam, K et al.,2004). As the polymer swells, the solvent absorbed increases in volume, this enables the drug to diffuse through the swollen matrix into the surrounding environment. This takes place by diffusion as the drug moves out at a velocity dependent on the fluid content of the polymer matrix (Coelho, J.F et al.,2010). Hydrogels are the basis for most materials used in swelling controlled release systems in which the polymers can suck up as much water as possible without dissolving when in contact with body fluids or water. The polymers are able to do so despite the properties of the solvent as a result of the fact that they are cross-linked systems. The drug loading content isregulated by thecomposition and can be evaluatedfrom the level of  swelling  in the solvent. The physical properties of a drug, its loading level and its desired release kinetics must be taken in to consideration when formulating a hydrogel matrix for the drug carrier. The hydrogels have the ability to suck up and retain a large volume of fluid and may contain about 60-90% of fluid and only 10-40% of polymer (Abraham, S et al.,2005). Some polymers are sensitive to changes in the environment and they are known as environmentally sensitive. The environmental change may involve change in pH, temperature or ionic strength. In most cases, the structural changes are reversible and can occur again in the case of another change in the environment. In summary, drug can be released from a swelling controlled system only when the polymer swells and the drug diffuses into the environment. The polymers which are sensitive to pH changes would swell at a high pH and shrink at a lower pH. These kinds of materials are suitable for delivery into the oral route in which the polymer only swells to release the drug at the upper region of the small intestine which has a high ph value (S. Kiil, S et al.,2003).

C. Polymer Degradation and Erosion; Unlike the systems above, the mechanism of drug release here involves degradation. The polymers of great concern with regards to this mechanism are the biodegradable polymers. Natural biological processes in the body bring about a breakdown of biodegradable polymers when taken into the body. In this mechanism, there is no need to remove the drug delivery system from the body after the active therapeutic ingredient has been released. Hydrolysis of the polymer chains into harmless and much smaller compounds is one of the ways in which most biodegradable polymers degrade. In some others such as the polyanhydrides and polyorthoesters, it's only at the surface of the Polymer that degradation occurs. This results in a release rate which is proportional to the surface area of the drug delivery system (Sharma K.,2011). With regard to biodegradable polymers ,we must understand that degradation is a chemical process, while erosion is a physical phenomenon which depends on dissolution and diffusion (Tom J.W et Al.,1991). Erosion can occur depending on the chemical structure of the Polymer either by surface or bulk erosion. Surface erosion occurs when the erosion rate is greater than the rate at which water penetrates the polymer bulk while bulk erosion occurs when the bulk of the rate at which water penetrates the polymer matrix is greater than the rate of erosion. Most biodegrade polymers in drug delivery undergo bulk erosion