Overview On Drug Delivery with Emphasis On Polymeric Implants


1. Introduction
2. Ideal Polymer
3. Biologically Degradable Polymers
4. Controlled Release Mechanisms
5. Commercial Applications

6. Protein and Peptide Delivery By Maria Alonso, Spain
7. Colloidal Drug Delivery
8. Pro-Drugs

Till early 1970, drugs were delivered to the human body exclusively via oral and intravenous means. These modes of delivering drugs, though still the most common ones have various disadvantages associated with them such as: 1. High doses of drug cannot be injected into the body at one time. 2. Intravenous delivery leads to high concentration of drug into the blood stream and can create toxic side effects. 3. Only a very small percentage of the injected drug reaches the affected area in the body and hence multiple injections are often required for effective treatment.

In 1970, Yolles and coworkers reported the use of Lactic acid based polymers for drug delivery. Since then a lot of effort has gone into developing new methods of drug delivery which can overcome all the above mentioned problems. Some of the recently developed modes of drug delivery are summarized below:

1. Transdermal drug delivery

As the name suggests, transdermal drug delivery involves the delivery of drugs through the skin pores. The commonly used mechanism of drug delivery in this case is diffusion. However the skin pore size limits the use of this technique to small drugs. Hence various techniques such as Iontophoresis (which uses an electrical gradient as a driving force for the delivery of the drug) and Sonication (which uses ultrasound techniques to increase the pore size) are being investigated.

2. Pulmonary drug delivery

Pulmonary drug delivery mainly includes aerosol based systems wherein drug delivery is carried out using nasal sprays.

3. Polymeric implants

Polymeric drug delivery is the most widely studied area of drug delivery in the recent past. A polymeric implant which consists of the drug imbedded in a polymer matrix is surgically planted into the body (in the affected area). The drug is then released directly into the affected site via diffusion or surface erosion.

This report presents an overview on the use of polymers (natural and synthetic) in the area of drug delivery.

The "ideal" polymer for drug delivery

Various synthetic as well as natural polymers have been examined in drug delivery applications. If the polymer matrix does not degrade inside the body, then it has to be surgoically removed after it is depleted of the drug. Hence to avoid the costs as well as risks associated with multiple surgeries, the polymer used should be biologically degradable. Thus for a polymer to be used as a drug delivery matrix, it has to satisfy the following criteria:

1. It has to be biocompatible and degradable (i.e. it should degrade in vivo to smaller fragments which can then be excreted from the body).

2. The degradation products should be nontoxic and should not create an inflammatory response.

3. Degradation should occur within a reasonable period of time as required by the application.

Biologically Degradable Polymers

Biologically degradable polymers can be loosely defined as that class of polymers which degrade to smaller fragments due to chemicals present inside the body. Thus two types of degradable polymers can be included under this definition, viz. biodegradable polymers and bioabsorbable polymers. Biodegradation in the strictest terms is defined as enzymatically promoted degradation (Swift 1993). Hence biodegradable polymers are the ones which degrade to smaller fragments by enzymes present in the body. Bioabsorbable polymers on the other hand are those which degrade in the presence of other chemicals in the body (generally this class refers to hydrolitically less stable polymers).

(1) Natural Polymers
Natural polymers are always biodegradable. Examples of this are collagen, cellulose and
chitosan. Various studies have been reported in which natural polymers have been tested as drug delivery matrices. For example, collagen have been tested for the delivery of various protein based drugs.

(2) Modified Natural Polymers
One problem with natural polymers is that they often take longer time to degrade. This problem can be overcome by adding polar functionalities to the polymers. The polar groups are more labile and hence they can enhance the degradability of the polymers. Various functional groups can also be added on to the polymers to change their physical and chemical characteristics to suit a particular application. Polymer modification can be carried out in two ways:

(1) Chemical modification

The polymer structure can be modified by reacting with highly reactive chemicals. Examples of chemical modification include crosslinking of gelatin using formaldehyde, crosslinking of chitosan using glutaraldehyde and chemical modification of cellulose to give cellulose acetate.

(2) Enzymatic modification

While chemical modification of natural polymers involve harsh reaction conditions, polymers have also been shown to be modified under mild conditions using appropriate enzymes. Examples of this type include the modification of lignin using horseradish peroxidase and modification of chitosan using tyrosinase (Chaubal et al., 1996; Dordick, 1995).

In both the cases, the nature and extent of modification is extremely important. Excessively modified natural polymers may not be easily degradable. Also the pendant groups added to the polymer may lead to toxic degradation products.

(3) Synthetic Polymers

Various synthetic polymers have been examined for their degradability and their applications in drug delivery. Extensive reviews on the use of synthetic polymers in drug delivery are available in the literature (Langer, 1993; Heller, 1990; Peppas, 1991). Some of the polymers examined for use in drug delivery applications include:

(1) Polyanhydrides (Tamada and Langer, 1992)
(2) Polyesters (Heller, 1990)
(3) Polyurethanes (Dahiyat et al., 1993)
(4) Polyphosphoesters (Kadiyala et al., 1996)
(5) Polyphosphazenes (Crommen et al., 1992)

Based on the available literature, the following rules of thumb can be used to assess the biodegradability of synthetic polymers (Swift, 1993; Tayashi, 1994):
1. Hydrophilic polymers are more likely to be degradable than hydrophobic polymers.
2. Polymers with heteroatoms in backbone > polymers with C-C backbones
3. Amorphous polymers > crystalline polymers
4. Higher the molecular weight, lower is the rate of degradation.
5. Synthetic step-growth or condensation polymers are generally biodegradable
to atleast a certain extent.

Controlled release mechanisms involved in drug delivery systems

An ideal controlled release mechanism for a device is the one which exhibits a zero order drug release. i.e. the release of drug is independent of time. However as the drug levels inside the device deplete, the rate of release also goes down. Thus most drug delivery devices often show two phases of drug release: An initial phase (which may or maynot be linear) and a second phase which relates to the rapid depletion of the drug from the device. A well designed drug delivery device would show a zero order release in its "initial" phase.
Depending on the mode of delivery (transdermal, pulmonary or polymeric), the mechanisms involved in the controlled release of the drug from the device may vary. For example, transdermal delivery involves diffusion of the drug through the skin. This diffusion can be enhanced using external driving forces such as electrical gradients or ultrasonic techniques. Polymeric implants involve either one or a combination of the following three mechanisms:
2. Bioerosion
3. Osmosis

Out of these three mechanisms, diffusion of the drug through the polymer matrix almost always occurs to a certain extent. For devices employing diffusion and/or osmosis, parameters such as size of the drug molecules, porosity of the polymer matrix (total void volume available), degree of crosslinking and swelling characteristics of the polymer play an important role during the design of the drug delivery device. On the other hand bioeroding systems include polymers which have active ingredients attached to them via labile bonds in which case the reactivity of the linkage becomes important, or surface eroding polymers wherein hydrophobicity of the polymer as well as the lability of the interchain linkages govern the controlled release characteristics.

Commercial applications of drug delivery systems

Drug delivery applications are spurring interests not only in the laboratories but also in the commercial market. Sevaral drug delivery based products have been recently approved by FDA and several others are in the pipeline. The
Alza Corporation (Electro-transdermal; Transcutaneoues systems)
2. Elan Corporation plc

Pulmonary systems
1. Dura Pharmaceuticals Inc.
2. Aradigm Corp.

Polymeric Implants
1. Guilford Pharmaceuticals
2. Atrix Laboratories
3. Alza Corporation
4. DepoTech Corporation

Change Update.. A review on Pro-drug type Delivery Systems has been
added (5/15/97). Suggestions and comments are welcome at chaubal@engr.umbc.edu
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