As an increasing number of people are becoming aware of the side effects of smoking tobacco and the detrimental health effects associated with this act, nicotine replacement therapy has now become a multi billon dollar industry. There is a lot of activity in research and development in the field of controlled drug delivery. Chemical Engineers play a crucial role in the development of controlled and programmed drug delivery as it employs the knowledge of mass transport and diffusion, a familiar domain. This has led the pharmaceutical industry to propose many radical, innovative techniques to deliver nicotine at a controlled, safe rate to curb the withdrawal symptoms of nicotine addiction. For years the tobacco industry has made fatal attempts to promote a safer cigarette, but the advancements of drug delivery science has led to a long term nicotine maintenance market with safer, efficient products designed to withdraw people away form a deadly addiction. There are huge financial rewards as well as clear benefits to all society. Thanks to the advancements in polymer science, engineers are able to employ the use of these materials to create a sophisticated nicotine patch with precise control of the release of the drug into the body.

The main parts of the patch are the reservoir, the rate controlling membrane, an occlusive backing and an adhesive layer. In diffusion controlled reactions the driving force for diffusion is the concentration gradient across the delivery device, which can be a reservoir or matrix system.(10) The reservoir, in which the nicotine is held, is completely encapsulated by a rate controlling membrane which is microporous. Usually the rate controlling membrane is surrounded by an occlusive or airtight backing on one side and microporous layer of adhesive on the other side which attaches to the skin. The nicotine is dispersed throughout the polymer in the matrix and as the drug concentration decreases the distance the drug has to travel to the membrane increases through the matrix. Therefore, the rate decreases over time and this is the reason why you have to replace the nicotine patch daily. Delivery would be constant if one kept the nicotine at a saturated level.

There are many challenges associated with delivering nicotine into the body. Smokers tend to administer consistent amounts of nicotine throughout the day depending on when they feel the withdrawal symptoms. Nicotine’s effects on the body are dose dependant, when there are trace amounts stimulation occurs and when there are large amounts a depressed reaction can occur. Large doses can also cause respiratory failure and nausea. Release of nicotine into the blood stream at a controlled rate is needed or an overdose can occur. Nicotine has also a high toxicity. It is a natural alkaloid, which is made up of a tertiary amine composed of a pyridine and pyrrolidine ring. Nicotine is a weak base with a pH around 8. At this pH it can readily cross cell membranes and absorbed rapidly through the skin. Since nicotine is an irritant and a high dosage occurs at a small area of skin a reaction can occur. Design of the right adhesive contacting the skin that can provide the benefits of staying on the skin for an extended period of time and by controlling unwanted skin reactions is imperative.(7) Here is the structure of nicotine:

As we see there are many challenges associated with delivering nicotine into the body. One of the most important reasons for using polymers is that it can achieve these certain functions of releasing nicotine at a controlled rate throughout the day. It is important to maintain a therapeutic range of concentration into the bloodstream and it is desirable to maintain this level of drug concentration for an extended period of time. Therefore it is important that the correct polymer is used in the nicotine patch. Polymers have an enormous range of compositions that can be classified into three major states: a crystalline solid, an amorphous hard glass, or an amorphous rubber, which can be plasticised by a suitable lower molecular weight liquid. The diffusion coefficients will generally increase as one passes from a glass to a rubber. Therefore, the more amorphous the polymer, the greater the rate of release of nicotine into the body. The manufacturer must decide the rate at which the nicotine should be released into the body and choose the correct polymer and state. As the free volume or volume fraction increases or density of the polymer decreases, microscopic, molecular size holes increases. This must be available for the nicotine to diffuse through. The transition from a glass to a rubber or solvent-swollen polymer can change the rate of diffusion by as much as ten decades to microseconds depending on the molecular weight of the diffusate. The diffusion coefficient clearly depends on the polymer selected for use. Since we now have a wide variety of polymers to use, we can now select which polymer will be best for our system. The percent of the release is given by

(Ms/Mo)= -4[(D/Pi)(T)]1/2

Where Ms=change in amount of diffusate, Mo=amount of diffusate at initial time, D=the diffusion coefficient and T= thickness of slab

It can easily be seen that the variation of the thickness provides a further control factor in the design of our system. Rate controlling films or membranes can be from a few microns to millimeters, which can change the time control. Most polymeric materials are hydrophobic and water soluble drugs often have a low solubility. The mechanism of transport or the permeability can be represented as a product of the solubility and diffusivity.(11) So we can now see that there are two important parameters the material or polymer and the thickness of the membrane. Using these two control factors the resistance to diffusion can be varied. As polymer synthesis and processing has become more advanced picking the right polymer and controlling the thickness of it’s membrane has assisted the field of drug delivery and pharmokinetics.(8)

The basis or challenge in choosing the correct polymer for adhesion between the skin and the nicotine patch is its ability to be totally permeable to nicotine. Most transdermal drug delivery systems employ the use of both natural rubber and silicon as a base. Polybutadiene seems to be the best and most logical choice to fulfill this role. Polybutadiene, also used in tires, belts, hoses, gaskets, and seals, is an amorphous polymer that has a very low glass transition temperature of about –106 degrees C. Therefore, it will remain amorphous and not become brittle at temperatures occurring in every day life. This is of course necessary because if polybutadiene becomes brittle, and more crystalline it will not only not work well as an adhesive, but also would not allow nicotine molecules through as easily.

Polybutadiene is a diene polymer, or a polymer made from a monomer containing two carbon-carbon double bonds.(1) (see figure) Polybutadiene is formed by Ziegler-Natta polymerization. Ziegler-Natta polymerization is a form of coordination polymerization useful because it allows one to manufacture polymers of specific tacticity.(2)

Another member of the nicotine patch is the rate-controlling membrane. Being, probably the most important, it controls the rate at which the nicotine is released into the blood stream. As was stated above, this is accomplished by choosing a polymer and state of that polymer, which has a certain diffusion coefficient suitable for the proper release of nicotine into the body. It is also important not to allow the polymer in with the nicotine is held in suspension to diffuse through. High-density polyethylene (HDPE) is the polymer most commonly used as the rate controlling membrane in nicotine patches. HDPE has a very simple structure. It is simply a long, highly crystalline, linear chain of carbon atoms with no branching. (see figure) (3) The linear conformation allows for strength, stiffness, resistance to cracking and permeability. Its high degree of permeability is to due the fact that HDPE has no branching and therefore less chain entanglements allowing nicotine to pass through more easily. (4) It has a melting temperature of 137 degrees C and a glass transition temperature ranging from –130 to –80 degrees C. HDPE usually has a molecular weight ranging from 200,000 and 500,000, but it is possible to obtain molecular weights of three to six million. HDPE is also made by Ziegler-Natta polymerization, again in order to obtain this specific tacticity. (3) High-density polyethylene is one of the most used polymers today. Over eight billion pounds are manufactured per year. Other common uses for HDPE include uses in, blow-molded bottles, house wares, and toys. (4)

The polymer in which the nicotine is held in suspension is, Ethylene vinyl acetate copolymer (EVA). EVA also has a high annual production of approximately one billion. It is most commonly used in meat, poultry and frozen food packaging. As the concentration of EVA increases there are decreases in crystallinity, glass transition and crystalline melting temperatures, and a chemical resistance coupled with increases in optical clarity, impact and stress cracking resistance, flexibility and adhesion to a variety of substrates.(4) The fact that crystallinity decreases as the concentration increases, means that, the more nicotine diffused, the more amorphous EVA will become and it will gradually become easier for the nicotine to diffuse through the reservoir. This will allow for virtually all the nicotine to be used, thus assuring nothing will be wasted. Also, allowing for a constant rate of diffusion.

The occlusive backing on the patch is made from pigmented polyester. This backing must be airtight, or impermeable, not allowing any air in the reservoir or allowing any polymer or nicotine out. Polyester’s have hydrocarbon backbones that contain ester linkages. (see figure) The ester groups in the polyester chain are polar, with the carbonyl oxygen atom having a somewhat negative charge and the carbonyl carbon atom having a somewhat positive charge. The positive and negative charges of the different ester groups are attracted to each other. This allows the ester groups of nearby chains to line up with each other in crystalline form, therefore making them strong fibers ideal for use in the nicotine patch. Plus its fairly cheap.

Polyester is manufactured using a step-growth reaction. It is normal to start off with a compound called dimethyl terphthalate and react it with ethylene glycol. Which yields bis-(2-hydroxyethyl)terephthalate and methanol. The methanol, however, can be separated simply by heating the reaction to around 210 degrees C. The reaction is called transesterification. Then the bis-(2-hydroxyethyl) terephthalate is heated to 270 degrees C to give poly(ethylene terphthalate) and ethylene glycol as a byproduct, which can be used again in the transesterification process. (6)

There are several patches from different manufacturers which all differ by nicotine content per system, method, and the pattern of release. All the devices are similar in that they use five layers; a protective layer, contact adhesive, internal membrane, drug reservoir, and impermeable backing. The patches all vary in size and shape but they are all designed to release the nicotine at a controlled rate. The challenge of all the competitors is to differentiate their products to both the doctors and the public.(11) Nicoderm has a discrete membrane and Nicotrol has the membrane attached to the adhesive layer. Prostep has the nicotine stored in a gel matrix. We only touched on a few examples of polymer design, but certain companies like Prostep are trying other techniques such as hydrogels which cross-links water-soluble polymers and uses a product membrane that is highly swollen with water and in which the water soluble drugs will have a much higher solubility and will permit a high flux.(8) There is a battle for the share of the committed quitters who number around 10 million. Each course costs approximately 350 dollars.

Nicotine transdermal drug delivery is the most widely used pharmacological approach to aid smoking cessation. The designs of these systems have been also used as models to use for therapy for ulcerative colitis, Alzheimers disease, Parkinsons disease, and hormonal replacement such as testosterone and estrogen. This past half century has led to the developments in the pharmaceutical industry which has done so much for our health. From painkillers to antibiotics there has been a huge growth in the use of drugs. Microbiologists and organic chemists have developed numerous drugs to treat an array of symptoms. The challenge now is to deliver the drugs at desirable rates to eliminate undesirable side effects. Instant delivery of drugs results in peaks and troughs of plasma levels and inadequate concentrations of the drug in the bloodstream. Controlled drug delivery leads to an improved therapy. There are innovative areas of controlled drug delivery. Biodegradable implants which is absorbed harmlessly by your body for extended treatments has exploded due to the interest in genetic engineering. Targeted delivery is another area which allows a drug to locate a particular body site where it is needed for a specific physiological effect. Potential side effects are decreased and a smaller concentration of a drug is needed. Treatment of tumours has employed targeted delivery. Chemical engineers and polymer science have an important role in developing these drug delivery technologies to treat a myriad of diseases and addictions.