Controlled Drug Delivery Systems: Principles, Types, and Polymers, Lecture notes of Biopharmaceutics and Pharmacokinetics

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PTE 404

CONTROLLED RUG DELIVERY

SYSTEMS

BY

DR. O.J. OLAYEMI

CONTROLLED DRUG DELIVERY SYSTEM

Introduction A drug is usually administered in combination with other excipients to make a dosage form which is suitable for the patient. The appropriate introduction or administration of drugs into the body through various routes is known as drug delivery. The means of drug administration has changed drastically over the years and more changes maybe anticipated in the future as a means of adequately meeting the needs of the patient. Drug delivery systems basically control the rate at which a drug is released in the body and/or the location where it is released. These systems are divided into the conventional systems which include peroral, parenteral, among others and the controlled systems which include sustained, extended, pulsated, targeted delivery systems. There are various means of delivering drugs into the body; these include: a) Oral route This is the safest, easiest, relatively cheap and most convenient way of drug administration but it has some disadvantages. There could be inactivation of the drug by the gastrointestinal tract (GIT) enzymes, poor bioavailability with poorly soluble drugs e.g griseofulvin and also delayed absorption or action of some drugs when administered orally. Extensive metabolism (first-pass effect) of certain drugs like propranolol may occur when administered via this route. It is also not a suitable route for unconscious patients or those suffering from nausea and vomiting. b) Parenteral route The use of this route is dependent on the physicochemical characteristics of the drug, the required therapeutic effect and the urgency or seriousness of the disease condition. This type of administration allows for immediate drug action, is suitable for unconscious patients and for patients who may be suffering from conditions like diarrhoea and vomiting. It is however costly with chances of pain and sepsis and in some cases death.

which is of great advantage but certain setbacks limit their use and effectiveness. They are saddled with some setbacks including drug degradation or loss, reduced bioavailability, increase in drug accumulation at some sites in the body or fluctuations in the drug plasma concentrations leading to under or over-medication and also increase in emergence of adverse effects. Such variations in plasma drug concentrations are accompanied by adverse effects; in addition, increased dosing frequency becomes cumbersome leading to loss of compliance and therapeutic ineffectiveness. However, modification of this immediate release systems can bring about better positive outcomes. Controlled drug delivery systems (CDDS) are those devices or mechanisms that controls the way a drug can be delivered to the body. Although the development of modified systems has spanned over about 35 years, scientists have used various names to identify them and this has led to some controversies about the actual nomenclature of these systems. Controlled drug delivery systems are those which allow drug release only after a specified time or over a long period of time or to a specific site in the body. They are fabricated to alter the time and proportion of drug released such an optimal amount is available at the required site continuously released through a time frame. An ideal modified delivery system must release the drug at a predetermined rate, dissolve in the GIT, be absorbed and available at a concentration sufficient to cause therapeutic effect. These systems include sustained, prolonged, delayed, extended or targeted action delivery. Generally, these systems provide certain benefits which include: i) Reduction in fluctuations of the drug plasma levels experienced with conventional drug delivery; this provides a steady plasma level over a prolonged time. Maintaining steady plasma

state improves the tolerance of those drugs with a narrow therapeutic index and reduces their side effects. ii) Increased efficacy of the drug iii) Allows for site or targeted delivery of drugs iv) These systems provide convenience of dosing thus improving patient compliance. v) They provide increased safety margin of high potency drugs. vi) Lower doses of drugs can be utilized which reduces the overall cost of therapy vii) Greater flexibility in dosage form design viii) Overall reduction in hospitalization period Commercial / Industrial Advantages ix. Illustration of innovative/technological leadership x. Product life-cycle extension xi. Product differentiation xii. Market expansion xiii. Patent extension Controlled delivery systems have certain drawbacks which include; i) Tend to give poor in-vitro/in-vivo correlations ii) Possibility of decrease in systemic availability of the drug iii) Delay in onset of drug action iv) Possibility of dose dumping in the case of a poor formulation strategy v) Increased potential for first pass metabolism vi) Possibility of less accurate dose adjustment in some cases vii) Cost per unit dose is higher when compared with conventional doses

Advantages of sustained release systems These include positive outcomes of clinical interest and those of commercial gains. Clinical advantages of sustained drug delivery systems are those that are linked to the benefits the patient enjoys from their use and they include; i. Reduction in the undulating plasma concentration levels experienced with of conventional systems while also ensuring constant drug plasma concentration. This guarantees that the drug is readily available in the system to elicit its required activity. ii. Shorter dosing frequencies which reduces toxicity as a result of overdose iii. Decreased local and systemic adverse effects which are experienced as a result of increased dosing frequency iv. Improvement in patient compliance as a result of reduced number of times the drug is administered and its associated untoward effects. v. Increased margin of safety for highly potent drugs vi. Creates shorter duration for the treatment of diseases vii. Averts night-time dosing viii. Reduction in overall cost of therapy. The commercial benefits of these systems include those attributed to the producers and the delivery products themselves; i. These systems show the extent of technological advancements which is required globally ii. They provide means of product identification and differentiation

iii. It ensures that the life-cycle of the delivery product is extended which also leads to its availability in the market iv. They provide opportunities for increasing patent filing and re-patenting without the rigors of discovery/development of novel drug moieties Disadvantages of sustained release systems These are associated with the development and application of these systems and they include i. Poor in vitro – in vivo correlation ii. It restricts adjustments of doses which would normally be possible with administration of varying drug concentrations as in conventional systems iii. It does not provide the option for immediate change or termination of drugs in the course of therapy in cases of toxicity or hypersensitivity iv. Higher possibility of dose dumping than with conventional systems v. Manufacturing of sustained release systems requires sophisticated equipment and processes and these increase the cost of manufacturing. vi. Modification in the rate of drug absorption may affect drug efficiency vii. Kinetics of drug release varies across the sustained release systems. The principle behind the sustained release system is to achieve zero-order drug release; this describes that drug is released at a constant rate over a period of time. Here, once the plasma steady state is achieved, drug concentration remains constant as long as absorption continues. Although zero order release is desirable, there are certain factors that influences the /outcome of these delivery systems.

problem and in addition, drug release from this system may be affected by food, gastro intestinal transit time and pH. Reservoir diffusion-controlled systems These entails enclosure of a drug in a hydrophobic polymer (membrane) and its distribution across the membrane. The drug moves through the membrane into the fluid surrounding the matrix particles, more of the drug is then diffused to the polymer membrane surface and then into the surrounding fluid. One of the advantages of this system is that it makes achieving zero order drug release possible and the extent to which this can be accomplished is dependent on the type and concentration of the polymer that is used in these formulations. However, this type of system is expensive to develop, poses huge toxicity threat when withdrawal due to system failure is not possible, in addition it is also not suitable for the delivery of compounds with high molecular weights. Matrix diffusion-controlled systems This involves uniform distribution of a drug in a polymer (hydrophilic or hydrophobic) matrix. Here the rate of drug release is influenced by the extent to which the drug can diffuse out of the matrix. The drug can be incorporated into a hydrophobic matrix and when placed in a medium, penetration of the fluid causes the drug to diffuse out into the surrounding fluid. These hydrophobic diffusion matrix systems make use of polymers like the acrylates, ethyl cellulose and fatty acids in some cases. Although utilization of insoluble polymers here helps to keep the integrity of the formulation during the process of drug release, it is also necessary that these formulations have some soluble ingredients in them which would serve as channels for drug release.

When the drug is dispersed in a hydrophilic polymer material, the rate of drug release is then dependent on the type and concentration of polymer included in the formulation. The rate at which the polymer absorbs aqueous fluids, forms gelatinous layer on the surface of the formulation would ultimately affect the extent and degree of drug release. Penetration of fluid into the intermolecular spaces of the polymer, would lead to polymer relaxation, weakening the polymer chains and create a path for the incorporated drug to rapidly diffuse out of the matrix. However, as the polymer swells and forms thicker gelatinous layer, the ease with which the fluid penetrates the matrix decreases and the path length for drug transportation increases thus influencing the rate of drug release.

2. DISSOLUTION CONTROLLED RELEASE SYSTEMS These systems are easier to develop particularly if the API is soluble and has rapid dissolution rate making it possible to incorporate the drug into an insoluble polymer carrier with slower dissolution rate or coat. The drug is formulated with such polymers in order to modify the rate of drug release. Dissolution and diffusion often times work hand in hand and where this occurs, the rate of drug diffusion from the surface to the surrounding medium becomes the rate limiting step. Dissolution controlled release system can be categorized into two: Matrix dissolution-controlled systems In this system, the drug is incorporated into a matrix formulation containing a release-modifying polymer and once the formulation comes in contact with an aqueous medium, the polymer swells, forms a gelatinous layer. This controls the dissolution of the soluble drug in the formulation and influences the rate at which the drug is being released into the surrounding medium.

5. PH-DEPENDENT RELEASE SYSTEMS

Most drugs are weak acids or weak bases and their release from the sustained release formulations is dependent of pH of the release medium. The rate of release however can be influenced by incorporating buffering agents like salts of citric acid, phosphoric acid or tartaric acid which would help create constant rate of drug release.

6. DENSITY-RELATED CONTROLLED SYSTEMS Altering the density of formulations is another technique of achieving sustained release effect. The high density approach involves the development of formulations whose densities are greater than that of the GIT contents while the low density approach involves formulations with apparent densities less than that of the GIT contents. These systems sustain drug release and improve bioavailability of the drug by increasing the contact time of the formulations in the GIT; the high density formulations would sink in the GIT while low density formulations would float and remain in the GIT. The efficacy of this strategy however is dependent on GIT motility. FACTORS AFFECTING THE FORMULATION OF SUSTAINED RELEASE DRUG DELIVERY SYSTEMS The design of sustained release systems is governed by features like the route of administration, disease treated, duration of therapy and the properties of the drug. All these impact on the rate of drug release and invariably influences the formulation design and effect on patient compliance. Some properties that affect the formulation of sustained delivery systems are hereby discussed below;

1. Diffusivity and molecular size Drugs are transported across various membranes in order to elicit their activity, in addition to the biological membranes that they must traverse, they are expected to diffuse out of the polymeric membranes which control their release. Diffusivity is the ability of a drug to disperse out of a polymer and is influenced by the molecular size and shape of the drug and/or on the size and shape of the polymeric membrane that houses the drug. High molecular weight drugs diffuse slowly through the polymeric membrane and expectedly display slow release kinetics via diffusion. 2. Aqueous solubility and Ionization Absorption of an aqueous soluble drug is controlled by its dissolution rate which foretells the amount of the drug in solution, it is also controlled by the propensity of the drug to penetrate/permeate the tissues. Therefore, sustained delivery systems that rely on dissolution and diffusion are solely dependent the solubility of the drug in aqueous medium. Unionized drug forms are advantageous when drug permeation and absorption is required however, their solubility in aqueous fluids decrease when left in their unionized forms. Drugs with low solubility have limited dissolution in the release medium, have inherent slow release and sustained effects. However, highly soluble drugs have fast dissolution rates as such sustaining their release is often a challenge. 3. Partition coefficient Drugs must transverse the biological membrane before they can elicit their therapeutic effect, it is therefore important to know the partition coefficient of drugs. Lipophilic drugs with high partition coefficient will have fast permeation through lipophilic membranes whereas those with

Drugs with high tendency to bind to plasma protein like Albumin, get retained in the vascular spaces and their ability to get dissociated influences drug distribution in the extravascular spaces. Drug-protein complexes serve as drug reservoirs since plasma proteins are not eliminated but re- circulated thereby sustaining drug release. Extensive protein binding would lead to long elimination half-life which precludes their formulation into sustained release systems. Some drugs could also bind to biopolymers in the GIT and influence the rate of drug delivery as well as release.

8. Polymer hydration It is important to consider the type of polymer being used in formulation as the rate and extent of its hydration could be a rate determining step to drug release. The ability of the polymer to imbibe fluid (dissolution medium), hydrate, swell and rupture/erode is associated with its capability to form strong or weak polymer chain linkages. The strength of the polymer chains determine the integrity of the formulation and the rate of drug release from such formulations. For example, high molecular weight hydroxyl propyl methyl cellulose (HPMC) and Methocel K, with low methoxy content, hydrate rapidly and thus explains their rationale for use in modified delivery systems. DELAYED DRUG RELEASE SYSTEMS These systems allow for portions or complete drug release at a later time or at other times other than immediately after administration. This delivery protects the drug from degradation or inactivation in the stomach and reduces the side effects that may be associated with drug release in the upper part of the GIT while also targeting the drug to specific parts of the GIT.

Targeted drug delivery connotes that a drug is transported to an exact location (tissue, cell or organ) in the body or selectively delivered to a site in the body. The ability of these systems to transport drugs to specific locations in the body in sufficient concentration without affecting the surrounding tissues or organs is a very welcomed development in the drug delivery technologies. Drugs that are unstable, have low solubility, poor absorption, short half-life, and low site specificity are the ideal for targeted drug delivery. The principle of developing a successful targeted delivery system is based on its ability to preserve the drug within the system, protect the drug from being degraded by the GIT environment during transit, and target the drug to the site where it would be released for therapeutic action. Targeted drug delivery systems must be biocompatible, nontoxic and stable, they must ensure only minimal drug loss during transit so that an effective concentration is delivered to the site of action. Drug distribution should only be to target sites at predictable drug release rates. In addition, they must be reasonably easy and cost-effective so that they can be relatively affordable. The challenge however is that development of targeted drug delivery systems that can specifically aim at a particular cell/tissue without affecting other healthy cells/tissues is almost impracticable. Furthermore, the existence of different barriers can hinder drug delivery to some sites for example, the tight junctions in the colon could restrict drug transport across the mucosa and prevent or reduce drug availability at the required site. These challenges nonetheless can be overcome via development of applicable approaches, tweaking of physicochemical characteristics of the drug and carrier system to allow for effective targeting. For the purpose of this lecture, our discussion will be centered on colon delivery as a means of targeted drug delivery system.

Targeting of drugs to the colon has grown over the past two decades, particularly in treatment of local diseases that affect the colon such as Crohn’s disease, ulcerative colitis, cancer of the colon etc. Various approaches that ensure the drug reaches the colon, is therapeutically effective at the site and with minimal toxicity have been postulated. These include pH-dependent, pressure- dependent, time-dependent and enzymatically-controlled approach.

1. pH-Dependent approach This approach utilizes the different pH in the upper and lower parts of GI tract to effectively target drugs to the colon. The pH of the colon is often lower than that of the small intestine due to the presence of short chain fatty acids and it is this fall in pH that is exploited to target drugs to the colon using pH-dependent polymers. The strategy here is to coat the drugs with pH sensitive or enteric polymers that have relatively high threshold to withstand the different pH of the GIT; such polymers are generally insoluble at low pH but become increasingly soluble as the pH increases. The knowledge of these polymers and their solubility in different pH environments has made formulations that can effectively resist drug release in the acidic environments of the GIT possible. Polymer-coating is a simple, relatively easy strategy employing the single-unit or multi- particulate approach to ensure that the drug remains intact in the formulation until it arrives at the colon. Single-unit formulations are those coated with just one enteric polymer whose solubility is pH dependent. Multi-particulate systems involve utilization of two polymers where one is pH dependent and the other is not or where the two polymers have different pH-dependent solubility profiles. The rate of drug release from the formulation is influenced by the type and

concentration of polymer as well as the thickness of the polymer coat. Most commonly used pH- dependent coating polymers are methacrylic acid copolymers (Eudragit®), hydroxypropylmethylcellulose, polyvinyl acetate phthalate, cellulose acetate phthalate etc.

2. Time-dependent approach This approach is based upon the theory that the lag time in the GIT corresponds to the time it takes a dosage form to arrive at the colon; this strategy uses the concept of the GIT transit time. Time-controlled systems are useful for synchronous delivery of a drug at pre-selected times so that drug activity is observed only when needed or at the predetermined site. Of particular interest is their use in the therapy of diseases which depend on circadian rhythms. Effects of variation in gastric transit time can be minimized by developing formulations that can retain their integrity during GI transit until arrival at the proximal part of the small intestine or at the beginning of the colon where the drug will be released. Hydrophilic, hydrophobic or enteric polymers which swell, diffuse or employ both mechanisms for drug release can be used in formulation of time-dependent systems and the rate of drug release is dependent on the type, concentration and thickness of the polymer coat where applicable. 3. Pressure-controlled approach The GI pressure is another mechanism that is utilized to initiate drug release in the colon. The digestive processes within the GIT involve contractile activity of the stomach and peristaltic movements for propulsion of intestinal contents; these muscular contractions generate pressure which is responsible for grinding and propulsion of the intestinal contents. In the large intestine, however, contents are moved from one part to the next by mass peristalsis. The luminal pressure resulting from the peristaltic motion is higher in the colon than in the small intestine due to viscosity differences of the luminal contents. This change in viscosity leads to increase in