Figure (a) Drug level in the blood with traditional drug dosing, and (b) drug level in the blood with controlled drug delivery system5.
POLYMER AS DRUG CARRIER AND CONTROLLER
Abstract
This paper will discuss a recently popularized drug delivery system, where polymer substances act as carriers as well as controllers in the amount of drug release into the body. Three areas of application are covered in this paper. These are microencapsulation, transdermal, and implanted reservoir drug delivery. Basic mechanisms, including the advantages and also the disadvantages, will also be described.
Introduction
We can view the human body as a reactor, in which biological, mechanical, electrical and chemical activities are involved. The key to running these networks ideally in order to maintain a healthy condition is balance. A simple example of how our body keeps itself in harmony is the feedback mechanism that occurs during blood sugar regulation. Based on this idea, drug delivery systems for the human body should also follow the concept of balance, in terms of the interaction between the drugs and the body system. There are two scenarios that can describe drug-body system interactions when the two are not in harmony. First, medicines can be harmful to other non-targeted parts of the body, or enzymes and other chemical substances in the body can assimilate the drug and cause toxin production. Second, the body system can ‘digest’ drugs before they are useful for a cure if administered orally.
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Figure (a) Drug level in the blood with traditional drug dosing, and (b) drug level in the blood with controlled drug delivery system5. |
Traditional drug delivery, although not complicated in practice, hardly includes the idea of balance combined with effectiveness. As an example, to medicate a tumor graft in a certain area of the body, a chemotherapeutic drug is administered by injection in most cases. This way, the drug will be unnecessarily distributed through the entire body as the blood will not limit drug delivery only to the targeted area, causing the effectiveness of the drug towards the tumor to be decreased, and raising the potential for harm to be done to other areas of the body. In addition to this, because the drug concentration from the first supply is not optimal when it arrives in the targeted area, a second injection must follow soon after. Another important drawback of traditional dosing is that drug concentrations cannot be increased because it is imperative to prevent a severe damaging effect to other body parts. These disadvantages can be summarized as a ‘hill and valley’ effect. Lastly, humans may also cause additional error if a dosage is delayed or missed.
Research has been done to better drug delivery into the human system, to increase its effectiveness, and adjoining to that, to reduce drug cost. Sustained release mechanism with polymers as a type of carrier is one possible solution. Some descriptions and the advantages of this type of system in general are:
1. Drug effectiveness is increased.
The sustained drug delivery system involves delivering the drug directly to the targeted area; optimum doses for that specific location can be administered without causing a toxic effect to other parts of the body. This controlled drug delivery system also allows medicine to spend more time in the body due to the slow release of the drug particles over a long duration. Combining these two functions eliminates the ‘hill and valley’ effect in traditional drug delivery.
Instead of increasing the drug concentration in the body by local inputs, such as by injection or by drugs that have to be taken orally within a specific time interval, the sustained drug delivery system provides constant drug release. Not only is this an ideal way of medication, but also by this method, patients do not have to be responsible for taking medication. It is clear that this will eliminate human error.
The controlled drug delivery system allows medicine to achieve optimal level in a specific location alone. As a result of this effectiveness, more drugs do not have to be applied to get the same result, as in the case of traditional drug delivery system. This way, consumers do not have to spend more money in order to get the same result.
The disadvantages of this system are due to the fact that it is more difficult to manufacture, because a carrier has be to designed in specific manner to be able to provide the time-controlled release mechanism. In addition, polymeric carriers should also be selected carefully so that they are human-system ‘friendly.’
What is polymeric drug delivery?
There has been a large development in controlled drug delivery using polymeric carriers in recent years. Drugs are embedded in a polymeric matrix so that they may be protected from reactions by enzymes and body chemical substances that can destroy the drug chemistry before it reaches the targeted areas. The polymeric matrix also functions as a time controller in the concentration of active ingredient release. Some characteristics that can describe the ideal polymer for drug delivery use are: first, for some purposes, it is important to have a degradable polymer. This means that the polymer matrix should degrade into smaller fragments over a period of time, which then can be excreted from the body. Second, the degradation products of the polymer should contain non-toxic material for the body. Finally, an ideal mechanism for release of the drugs by this polymer matrix should be at a constant rate.
There are two definitions of a degradable polymer. The first, biodegradable, can be described as a polymeric matrix that is degradable by enzymes. The second, bioabsorbable, can be described as a polymer that is degradable by other chemicals in the body. There are three types of degradable polymers suitable for coating active ingredients for drug delivery.
Polymer matrices derived from natural polymers are always biodegradable. For example, these include collagen, cellulose and chitosan.
Here, the natural polymers are modified in order to suit certain applications. The reason for the alteration is due to the fact that sometimes polymers take longer to degrade within the body. Therefore, for example, adding polar functionality to make the polymer chain more labile can enhance degradability.
This type of polymer is still under examination for use in drug delivery systems.
Some materials that are plausible for use are polyesters, polyurethane, and polyanhydrides.
Polymer Chemistry
This section is devoted to describe biodegradability factors of synthetic polymers. Synthetic polymers offer advantages due to the facts that compare to natural polymers, they can be engineered to give a wider range of properties, and also can give more predictable uniformity. Engineering polymers that have hydrolytically unstable linkages in the backbone can achieve biodegradation of synthetic polymers.
In general, factors which affects degradation mechanism3.
There are two types of biodegradations in drug delivery, bulk degradation and surface erosion. They both undergo two phases:
Bulk degradation occurs when the rate of the first phase is faster than the second one to occur. When the opposite occurs, surface-eroding mechanism is known.
Unfortunately, for drugs that are hydrolytically unstable, a polymer that absorbs water may be contraindicated. Therefore researches have been done to focus on polymers that degrade with surface erosion rather than by bulk degradation.
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Another important feature in the morphology of polymers used for drug delivery is glass transition temperature (Tg). There are two principal classes:
In general, low Tg translates to high drug permeability into the polymer matrix, which may retard drug release to the environment. In addition, drug molecules do not diffuse through crystalline phase of a polymer. Therefore, good polymer matrix to encapsulate drugs requires Tg much greater than 37(C and/or low crystallinity.
The following section presents and overviews of some synthetic biodegradable polymers.
Polyanhydrides have been synthesized via the dehydration of diacid molecules. Degradation time can be adjusted according to the degree of hydrophobicity of the monomer. The material degrade primarily by surface erosion, possess good in vivo compatibility. An example of a product, which uses this material, is Gliadel, designed to deliver chemotherapeutic drug.
The data below are based on 1,3-bis-p-carboxyphenoxypropane (CPP) and Sebatic Acid (SA) with several compositions.
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0:100 |
22:78 |
46:54 |
100:0 |
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Tg ° C |
60 |
47 |
101 |
96 |
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Crystallinity |
66 |
35 |
14.2 |
61.4 |
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Structure of poly(SA-HAD anhydride)3 |
Polyorthoesters are hydrophobic, with hydrolytic linkages that are acid sensitive but stable to base. This type of polymer degrades by surface erosion, degradation rate can be controlled by adding acidic or basic excipients.
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Structure of poly(orthoester)3 |
Glycolide monomer is synthesized from dimerization of glycolic acid. Polymerization mechanism is by ring opening, which results in high molecular weight materials with approximately 1-3% residual monomer. PGA is highly crystalline (45-55%), therefore PGA needs to be copolymerized with another type of polymer before it can be useful for drug encapsulation. Melting point is also high (220-225(C).
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Tg ° C |
MW > 20,000 |
45 |
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MW = 50,000 |
36 |
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Synthesis of polyglycolide3 |
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Tg ° C |
50-57 |
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c |
0.1-0.3 |
Copolymer of glycolide with both l-lactide and dl-lactide has been developed for drug delivery applications, in order to disrupt the crystallinity. It is important to note that there is no linear relationship between copolymer composition with degradation properties.
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Structure of poly(lactide-co-glycolide)3 |
In summary, factors that accelerate polymer degradation are 4:
Polymer as a carrier has many qualities that can help improve controlled drug delivery systems. Based on these characteristics of polymers, our discussion will continue to their three areas of application: microencapsulation, transdermal administration, and implanted reservoir drug delivery.
I. Microencapsulation
Microencapsulation is a technique that surrounds drug particles in polymer matrices. The system’s outer layer, which consists of an organic polymer, is designed to control drug release at a desired level and only release drugs to the specific areas in the body. This way, active ingredients will not leak out to other areas before they reach their target.
How does a drug vesicle only deliver drugs to a targeted area?
A brief explanation of the previous question is the following: the polymer matrix is combined with bioactive agents, which can act as ‘sensors’ to some physicochemical conditions, including enzyme substrate, temperature, pH and ionic strength. This will allow the drug to diffuse through the pores or macromolecular structure of the polymer only upon introduction into the desired biological environment.
Controlled release mechanism
There are two pathways to designing a polymer matrix to allow it to release its active ingredients. First is the reservoir system, and second is the matrix-swelling controlled-release system.
In this type of design, drugs are stored in a polymer matrix, and will be released when in contact with the target areas. As drug release continues, its rate normally decreases with time, since the active ingredients have a progressively longer distance to travel and therefore require a longer diffusion time in order to be release. To have a constant drug release rate, a film or membrane that functions as rate-controlling material is placed on the outer side of the polymer (see figure below).
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Microencapsulation without membrane, drug release decreases with time5. |
Microencapsulation with membrane, constant drug release with time5. |
The main principal of this system is to design a polymer matrix capable of absorbing water or other fluids for the purpose of swelling. Drug is normally incorporated in hydrogel polymer in the glassy (dry state). The polymeric chains network will then swell when introduced in aquaeaous media. A parameter, which is used to describe the interaction of polymer chains with solvent, is c (chi) parameter. c parameter is denoted to have the value of < 0.5 when swelling occurs. The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network and into the external environment (see figure below).
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Drug particles are released because of the swollen polymer matrix4. |
Bio-erodible system
Essentially, biodegradability of the polymer matrix is an important factor for determining the effectiveness of polymers for this purpose. In general, drug microencapsulation utilizing bio-erodible polymer coatings allows the body to metabolize the polymer system into lactic acid and glycolic acid, which will break down further into carbon dioxide and water. These two inorganic products can then be released through the normal metabolic pathway. Factors affecting this, as well as possible materials for the purpose of biodegradation are listed above.
Many of the following materials are designed for this purpose, for example:
II. Transdermal Drug Delivery
The second application of controlled drug delivery is via the skin. Known as transdermal drug delivery or TDD, administration of drugs this way leads to several advantages over the other methods of delivery and their effects on the human system. Polymers have proven to be an integral part of the design of these systems, because of the properties they exhibit and the purposes they can serve.
Transdermal delivery of drugs was first initiated in the early eighties, when scopolamine patches were introduced for the treatment of motion sickness. Since that time, various other drugs serving a variety of other functions have been administered in this fashion, including nitroglycerine, nicotine, estradiol and isosorbide nitrate. The reason for such rapid advances in this area has been the motivation to exploit the range of advantageous properties of TDD systems.
Polymers have been a major part in the design, development and improvement of TDD procedures. There are two basic designs that allow the utilization of polymers within these systems. One incorporates a reservoir, while the other demonstrates a monolithic design.
Reservoir Design
The reservoir system design consists of four layers: an adhesive which allows for bonding to the skin, a control membrane which is comprised of the polymer material, a reservoir which contains the drug, and a water-resistant backing which prevents contamination into or convection out of the device (see figure below). The drug needs to diffuse through the polymer membrane and adhesive in order to allow absorption into the skin. The polymer design here results in a uniform amount of drug delivery from the device, which is less than the saturation limit of the skin. Based upon this model, the polymer materials used to compose the membrane can be varied according to the drug to be used, how much of the drug is to be dispensed, and the intended duration of transdermal delivery. An example of this capacity for design is the following. It would be optimal to develop a membrane that would allow the small particles of the drug through with a small enough resistance to allow transportation through the skin into the circulatory system. In addition, a large enough resistance is needed so that the drug is not dumped into the human system all at once. Therefore, a polymer whose structure does not demonstrate a particularly random configuration would be best, as this gives less particle control than a polymer with a more dense and structured configuration. Basically, it is necessary to encourage maximum control by selecting a proper polymer substance for membrane formation. In addition to this, it is also essential to consider a potential reaction between the drug and the polymer membrane. Obviously, polymer substances should be chosen so as to eliminate membrane degradation by the drug or alteration of the drug properties by the polymers. The duration intended for transdermal delivery is a third consideration, and can be accomplished by selection of polymer membrane material with the appropriate strength to withstand a certain length of proposed wear and diffusion.
(fromRef. 5)
Monolithic Design
The monolithic design also relies on polymer properties in a similar manner, but opposes the reservoir design in the fact that the polymer material used here results in a rate of drug delivery that is dependent on the skin’s capability to absorb drug molecules rather than the actual device. Consisting of three instead of four layers, the monolithic design has one level of adhesion, one of polymer and a third of waterproof backing. Polymers here are prepared into a matrix that serves to contain the drug, and the drug diffuses through the polymer matrix up to the point of skin saturation, giving a non-uniform rate of absorption. In addition, decreasing the amount of drug saturation below the skin’s saturation limit causes a decrease in the rate of delivery by larger molecules. The polymer considerations in this design are similar to those considered previously in terms of inertness and wear of the polymer, but differ with respect to the intention of control. Whereas the reservoir TDD design focused on highly-structured, dense polymeric material to control the rate of drug delivery, the monolithic design relies on the skin for this control, making it less imperative to gauge the exact spacing of the polymer with respect to the drug particles. Essentially, the polymer here serves more as a casing for the drug rather than a means of policing its delivery, so it is necessary to ensure that the drug is capable of diffusing through the membrane without the added concern of its rate management.
The primary advantage of TDD is the fact that it is non-invasive. A patient choosing to participate in this type of drug delivery does not have to endure any needles or even worry about swallowing a pill. The drug is absorbed into the skin and dispensation of the drug is achieved. Because of this, it is also very easy to terminate drug administration in the event of adverse effects, as it is only necessary to remove the device in order to conclude treatment.
In addition to this advantage, it is also more possible for maintenance of drug-plasma level when a patch or other device is consistently delivering a regular amount of a drug
at all times, as opposed to a peak-valley effect sometimes experienced when other
processes of drug delivery are used. This also means that an overall lower dosage of the
drug is required, as it is no longer as difficult to maintain a high level of drug-plasma.
A final advantage of TDD systems involves what is referred to as a "first-pass effect." A first-pass effect occurs when digestive and liver enzymes deactivate drugs that are administered orally. Because skin diffusion eliminates the need for a drug to pass through the digestive system, this negative effect is eliminated with TDD.
Aside from these advantages, it is also worth acknowledging the disadvantages to TDD systems. Among these are the fact that there are few drugs that have proven capable of diffusing through human skin. The specific properties required for this are many, and in short, few drugs meet these requirements, such as small drug-molecular size. Also, it is difficult at times to determine the sensitivities of different types of skin on the human body, and how these sensitivities vary from person to person. Therefore, the potential for irritation is problematic.
The need for exceptional polymer design and control is evident in the development and continuing exploration of TDD systems. Whether the polymers are responsible for the rate of delivery or simply polymer housing within a device, they are equally integral and valid to the drug delivery system’s overall performance.
Some polymers that are often selected because of their physical properties are:
Poly(methyl methacrylate) for physical strength ⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪⨪ĀĀ℀_. The main purposes of these implants are to deliver drugs into the blood stream at a control rate of transmission, and to reduce the threat of infection since they are completely subcutaneous. Although some products of implant drug deliveries are already available in the market, implantation is still in a developing stage. In this paper, three examples of application are discussed. First is a non-biodegradable reservoir for contraceptive drug delivery, second is a biodegradable reservoir system.
Non-biodegradable Reservoir
Non-biodegradable polymer for drug delivery is sometimes used. A good example that incorporates this system is a contraceptive drug delivery system such as Norplant.
Norplant is an implant birth control system that has been developed to take the place of methods such as oral or injectable contraceptives. The drug carrier is made of a non-degradable polymer, called silastic, which is designed to carry levonorgestrel, a type of contraceptive hormone used to keep the ovaries from releasing eggs and also to thicken cervical mucus and keep sperm from fertilizing eggs. Some descriptions of Norplant are:
There are some advantages and disadvantages to using this type of implant as opposed to the traditional forms of contraception. Some advantages are: first, the patients are spared from the anxiety of remembering to take pills every day, and its effectiveness is increased to 99%. Secondly, the patients can avoid the repeating injection that can potentially lead to infection. Third, in specific to this type of drug delivery system, polymer matrices are non-degradable, and therefore it can last for a long period without worrying to replace the implant frequently, which also reduces some removal surgery expenses. Lastly, because this type of delivery system is invisible, it does not hinder everyday life.
On the other hand, some disadvantages come from the active ingredients instead of the polymer carrier. Some recorded disadvantages are irregular bleeding, menstrual changes, headache, weight changes and acne. Health risks can also come for overweight women, women who smoke, and also women with diabetic or heart problems.
Biodegradable Reservoir
In many cases, biodegradable polymers are used for sustained drug delivery, where drugs are encased in a reservoir made of biodegradable polymer. The drug is gradually released as the polymer breaks down. The Gliadel system for treating brain cancer is an example of this drug delivery type. Giadel contains a chemotherapeutic drug called carmustine stored in a white polymeric disk. This system can be described by the following characteristics:
Another application using reservoir system might involve an implantable polymer containing reservoirs of insulin and glucose oxidase.
Advantages of this system are: the drug stays in the system for a longer period and therefore increases effectiveness, regular injection of active agents is not needed, and drugs can target only specific areas instead of the entire body. The disadvantage is the fact that this system is limited by the amount of medication the polymer matrix can hold, although this limitation could be overcome by replenishing the reservoir through injection or implanting a fresh system. In addition, some polymers have been reported to have the capability of adsorbing some body fluids, therefore infection and some side effects are expected.
Although many thorough research studies are still being done for implantable drug delivery systems, there are many applications in the medical field that can incorporate the use of this system. Not only does designing the ideal mechanism of control release systems play a big role in determining the applicability of this system, but choosing suitable polymers is important as well.
Some polymers that are often used for implantable delivery system are:
Conclusion
In conclusion, three major ways to use polymers in drug-delivery systems are discussed in this paper. The main goal of designing a sustained release dug delivery system is to increase drug effectiveness, which can be reached if delivery is done at constant concentration for a longer period. Secondly is to reduce human error, which often occurs in traditional drug delivery. Lastly, relating to increasing drug effectiveness is to reduce cost. Engineering and selecting polymer material is very essential. Polymer matrix has to be engineered so that it can perform the desired task in delivering drug particles at constant rate at certain concentration. Selecting good polymer materials come into play when polymer is designed to biodegrade as well as to be biocompatible.
References:
1. http://www.accesscom.com/~frakoeps/Ocular.htm
2. http://www.aclu.org/issues/reproduct/norplant.html
3. http://www.devicelink.com/mpb/archive/98/03/002.html
