Chronopharmacokinetics Classification Essay


The Biological Basis of Addiction. Although tobacco products contain several thousand chemicals, nicotine is considered to be the principal constituent in tobacco that leads to the persistent use of tobacco products (U.S. DHHS, 1988). However, other yet unknown constituents in tobacco may also have a role in the maintaining the use of tobacco. For example, smokers experience a reduction of monoamine oxidase (MAO) activity in the brain (Berlin et al., 1995) as a result of some constituent in smoke (Fowler et al., 1996); inhibition of MAO may result in antidepressant activity (Oxenkrug, 1999) and contribute to the high prevalence in smoking among individuals with depressive disorders. Physical addiction to nicotine is associated with euphoriant and other psychoactive effects, the development of tolerance, and the experience of withdrawal symptoms when the tobacco product is no longer used (U.S. DHHS, 1988). In addition, the rate of absorption and therefore the speed of delivery of nicotine to the brain also play a significant role in the addictive potential of nicotine (Henningfield and Keenan, 1993). These factors contribute to the reinforcing effects or persistent use of nicotine and also may be responsible for day-to-day regulation of nicotine levels in tobacco users.

Psychoactive and reinforcing effects from nicotine are the result of the release of a number of neurotransmitters and hormones (Benowitz, 1999; U.S. DHHS, 1988; Watkins et al., 2000). This cascade of events is associated with mood modulation, cognitive and motor performance enhancements, and weight reduction. These effects may contribute to the initiation and maintenance of tobacco use. Chronic administration of nicotine can lead to neuroadaptation. One of the effects of neuroadaptation is the development of tolerance. Adaptation occurs so that the brain can maintain a state of homeostasis despite an increased release of neurotransmitters. This process includes receptor inactivation and desensitization and an increase or upregulation in receptor number (Benowitz, 1999). The extent of these changes could vary depending on the receptor subtype and site (Watkins et al., 2000). Tolerance may lead to individuals' using more of the tobacco product or switching to higher nicotine-containing products.

Neuroadaptation may subsequently lead to withdrawal symptoms when the tobacco user is no longer exposed to the product. Withdrawal symptoms include negative affect (e.g., irritability, frustration or anger, anxiety, dysphoric or depressed mood), restlessness, difficulty in concentrating, insomnia, decreased heart rate, and increased appetite or weight (APA, 1994). These symptoms occur among regular users of cigarettes and smokeless tobacco (Hughes and Hatsukami, 1992). They are less pronounced with nicotine gum use, but this distinction blurs with prolonged use of the gum (Hughes et al., 1986b; West and Russell, 1985). Approximately 49% of self-quitting smokers and 87% of tobacco cessation program attendees meet Diagnostic and Statistical Manual of Mental Disorders (DSM) IIIR (APA, 1987, 1994) criteria for nicotine withdrawal syndrome (Hughes and Hatsukami, 1992). These withdrawal symptoms peak during the first week of abstinence and return to baseline levels by four weeks (Hughes et al., 1990a). The intensity of these symptoms is further reduced over the course of time. The only exception to this pattern is increased weight. Weight may continue to increase over six months, and a reduction may not be seen at all or only after several months of abstinence (Hughes et al., 1990a).

A major determinant of whether nicotine is likely to be addictive is the amount and speed of nicotine delivery. The route of delivery also determines the pattern of nicotine delivery (as discussed earlier). For example, each puff of a cigarette delivers a bolus dose of nicotine, resulting in a rapid peak, which then falls to a trough level. The time between these bolus doses allows for resensitization of brain nAchRs, so that each delivery can remain reinforcing (Benowitz, 1999). In addition, this route of administration allows the delivery of a greater number or frequency of reinforcements. Other delivery routes result in a slow and persistent absorption of nicotine. Subjective effects, the desire to use more of a drug, and the actual self-administration of a drug are functions of absorption rate (Henningfield and Keenan, 1993). Therefore, whereas cigarettes have high abuse potential, nicotine patches have lower abuse potential.

It is also important to note that addiction to nicotine is not just a biological phenomenon, but also one in which learning or conditioning has taken place. Nicotine self-administration comes under the control of stimuli that have been associated with smoking or tobacco use. These stimuli can precipitate a strong desire for nicotine, withdrawal symptoms, or drug effects. Exposure to these stimuli may lead to the same biological effect on neural substrates as observed from the direct actions of the drug (Childress et al., 1999). Furthermore, stimuli associated with tobacco use, such as the sensory aspects of smoking, can become reinforcing as well; that is, they become secondary reinforcers. In addition a tobacco user develops expectancies regarding the use and effects of the substance, leading to a psychological reliance on the drug.

The susceptibility to nicotine addiction is thus a result of both the biological effects of the drug and learning history. In addition, environmental factors (e.g., access to tobacco, restrictions on tobacco, social modeling) and genetic or organismic factors (e.g., rate of nicotine metabolism, psychiatric disorders, personality factors) may play a significant role. Specific populations might be more vulnerable to nicotine addiction. Genetic twin studies have shown heritability estimates that range from 28 to 84%, with a mean estimate of 53% (Hughes, 1986). Genetic heritability has been associated with the onset as well as the persistence of smoking (Heath et al., 1998, 1999). Examples of what is inherited may be differences in sensitivity to nicotine (Pomerleau, 1995), the rate of nicotine metabolism (Tyndale et al., 1999), or other mechanisms such as genetic polymorphisms in the dopamine transporter and subtypes of dopamine receptors (Lerman et al., 1999; Shields et al., 1998). In addition, individuals with comorbid disorders tend to have a high prevalence of smoking. For example, high prevalence of smoking is found in individuals with depressive disorders, schizophrenia, and alcohol or drug abuse disorders (Breslau, 1995; Hughes et al., 1986a). The mechanisms responsible for susceptibility to smoking may differ across disorders. The nicotine-associated release of neurotransmitters is similar to those found with antidepressants and may be responsible for the association between smoking and depression and for the recurrence of depressive disorders after smoking cessation. Furthermore, studies have shown a genetic linkage between smoking and depression (Kendler et al., 1993), and observations have been made that depression can predate smoking or smoking predate depression (Breslau et al., 1993, 1998). For individuals with schizophrenia, the sensory gating effects of nicotine via the α7 nicotinic receptor may provide some symptomatic relief (Dalack et al., 1998; Freedman et al., 1997). A genetic link also seems to exist for alcohol and nicotine addiction (Hughes, 1986), along with commonality in the release of dopamine across all drugs leading perhaps to increased sensitivity to the reinforcing effects of drugs or the potential for substitution. Furthermore, nicotine can be used to offset the aversive effects of drug use (Benowitz, 1999).

Assessment of Addiction. Various measures and methods have been developed to measure dependence on a drug and its abuse or addiction potential (see Table 9–1). These measures and methods are important in examining harm reduction products since addiction to a drug is one of the determining factors associated with its harmful consequences. The addictive potential of a drug can be determined by examining the number of individuals, within the general population and among those exposed to the drug, who are regular users of the drug or are considered dependent on a drug, using specific criteria. Determination of the abuse potential of nicotine replacement agents has also relied on examining whether users of the product escalate their use over time or continue its use beyond a recommended period. However, deciphering whether this persistent medication use is a result of the desire to prevent relapse to cigarettes or an addiction to the product can be difficult. The “addictiveness” of a drug can also be determined by the extent to which relapse occurs among those individuals who have tried to stop using it. In addition, various animal and human laboratory methods have been developed to assess the abuse liability of a drug, including measurement of psychoactive or stimulus effects and determination of whether a drug is a reinforcer (positive or negative) leading to preference for a drug or drug self-administration (Bozarth, 1987; Balster, 1991; U.S. DHHS, 1988).

According to Food and Drug Administration (FDA) guidelines, abuse liability is determined by two primary factors (see deWit and Zacny, 1995). One is the likelihood of repeated use, which is determined by the drug's psychoactive, positive reinforcing effects and the extent to which it can relieve withdrawal symptoms as a result of chronic use. Repeated use may also be determined by the degree of unpleasant effects associated with drug use. The second factor is the incidence of adverse short- and long-term consequences as a result of use. Drugs with a greater number of adverse consequences are thought to be more likely to have abuse liability than those with fewer adverse effects.

Measures and Surveys of Dependence. Surveys and instruments have been used to assess the amount and frequency of use (e.g., daily use, regular use) and whether an individual is dependent on a drug based on specific diagnostic criteria. These measurement tools have been used to determine the extent to which dependence occurs within a general population and among those who have been exposed to or have experimented with the drug. In addition, these diagnostic tools for dependence have been used to determine whether dependence on nicotine is a dose-related phenomenon. Both DSM-IIIR and DSMIV (APA, 1987,1994) and the World Health Organization (WHO) International Diagnostic Code-10 (IDC-10) (WHO, 1991) are the commonly used criteria to assess for nicotine dependence. According to the DSM and the IDC-10, substance dependence, including nicotine, results in several behavioral and cognitive characteristics and physiological manifestations (see Table 9–2). The primary criteria for dependence based on these definitions include a strong desire to take the drug for periods longer than intended, problems controlling its use, use despite negative consequences or having a higher priority than other activities or obligations, tolerance, and physical withdrawal (APA, 1994; WHO, 1991). Not all criteria have to be met, nor is any one criteria critical to satisfy a diagnosis of dependence. In the 1988 Surgeon General's report The Health Consequences of Smoking: Nicotine Addiction, the primary criteria for drug dependence included (1) highly controlled or compulsive use of a drug, (2) psychoactive effects from the drug, and (3) drug-reinforced behavior. Additional criteria, similar to those listed in DSM-IV and IDC, were also included. The number or type of symptoms experienced varies across different drugs of abuse. The major difference between nicotine and some other drugs of abuse is the lack of intoxication in regular tobacco users that results in behavioral and cognitive disruption (U.S. DHHS, 1988). However, this makes nicotine no less an agent of addiction or dependence than other drugs (Stolerman and Jarvis, 1995). In fact, many cigarette smokers exhibit at least as many indicators of dependence as other drug users and abusers (CDC, 1995b; U.S. DHHS, 1988). Assessment of nicotine dependence using these criteria can be made by a number of diagnostic structured instruments including the Composite International Diagnostic Interview-Substance Abuse Module, the National Institute of Mental Health-Diagnostic Interview Schedule (NIMH-DIS), and the NIMH-DIS for children (see Colby et al., 2000, for review).

Other methods have been used to assess addiction or dependence on nicotine or tobacco products. For example, population surveys such as the National Household Survey on Drug Abuse (NHSDA) assess for symptoms of tobacco dependence and include such items as how many current tobacco users (1) reported daily use of the product, (2) have tried to cut down, (3) were unable to cut down or quit or experienced difficulty quitting, (4) felt a need for more tobacco for the same effect, (5) felt dependent, or (6) felt sick or experienced withdrawal symptoms when stopping smoking and met at least one or more of these indicators (CDC, 1995a, b; CDC, 1994). Researchers have used meeting a specified number of these symptoms as proxy measures for the DSM-IV criteria for substance dependence. In some assessments, individual items, such as experiencing withdrawal symptoms or difficulty quitting have been of particular focus as indicators of dependence (CDC, 1994, 1995a, b).

Other reports assessing nicotine dependence determine the number of smokers who meet criteria for high level nicotine dependence according to the Fagerström Tolerance Questionnaire (FTQ; Fagerström, 1978; Fagerström and Schneider, 1989) or the revised version, the Fagerström Test for Nicotine Dependence (FTND) (Heatherton et al., 1991). Several adolescent versions have also been developed (Prokhorov et al., 1996, 1998; Rojas et al., 1998). Although this scale is continuous, a cut-off score of 6–7 or higher has been used to separate low and high level of dependence.

Based on the measures of dependence described above, the percentage of cigarette users that report dependence on their tobacco product varies according to the population examined (e.g., total populations, daily smokers, ever smokers, and so forth) and the definition of dependence used. According to the NHSDA, a population survey of noninstitutionalized civilians 12 years and older, the proportion of respondents who reported experiencing at least one indicator of dependence was 75.2% among those individuals who used cigarettes one or more times during the 30 days preceding the survey and 90.9% among daily users (reporting daily use for≥ 2 consecutive weeks during the 12 months preceding the survey) (CDC, 1995b). In another study, the estimated prevalence of dependence according to the DSM-IIIR criteria (APA, 1987) among Americans 15–54 years old sampled for the National Comorbidity Survey was about 24.1% (Anthony et al., 1994). The lifetime prevalence of dependence among middle-aged male ever smokers in Japan was 42, 26, and 32% according to IDC-10, DSM-IIR, and DSM-IV criteria, respectively (Kawakami et al., 1998). In another study, very high rates were observed with 90% of a general sample of middle-aged male smokers meeting DSM-III criteria for dependence (Hughes et al., 1987). Kandel and associates (1997) used the indicators listed in the NHSDA (see above) including items assessing for frequency and quantity of use and problems related to use in order to diagnose nicotine dependence. The criteria for diagnosis were based on the DSM-IV method in which smokers must experience three or more of seven indicators of dependence. The findings showed that while 8.6% of the general population 12 years and older met criteria for nicotine dependence, 28% of those who had used tobacco products in the past year experienced nicotine dependence. A few studies have also been conducted with adolescents. The study conducted by Kandel and associates (1997) using the NHSDA examined the prevalence of nicotine dependence by age. They observed that about 19.9% of adolescents who smoked any cigarette met criteria for nicotine dependence, compared to rates ranging from 26.4 to 32.7% among smokers between the ages of 18 and 49 years and 23.7% among those 50 and older. In a study conducted in New Zealand, about 20% of a general sample of 18-year-olds were dependent on tobacco and more than half (56.4%) of the sample who smoked daily met DSM-IIIR criteria for nicotine dependence.

In another survey that used the FTQ with a score of 7 or more (indicative of a high level of dependence, not dependence per se), only 19% of Japanese male ever-smokers age 35 and older met this criteria (Kawakami et al., 1998), but 36% of U.S. males did (Hughes et al., 1987). Among adolescent smokers, the prevalence of high level of dependence according to the FTND or FTQ has also been wide-ranging. Many of the studies assessed prevalence of high level of dependence in special populations of adolescents. The highest percentage of adolescents with a score of 7 or more on the FTQ was observed among a heavy-smoking group who participated in a nicotine patch trial, with an observed rate of 68% (Smith et al., 1996). The lowest rate was 20% using a modified FTQ with a cutoff score of 7 or higher, which was observed in vocational technical high school student smokers (Prokhorov et al., 1996). This proportion was lower than the 50% rate that the investigators observed among adult smokers.

An indicator of the addiction potential of a drug is the development of daily or regular use or dependence among those who have been exposed to it. There is strong evidence to show that a significant number who are exposed to cigarettes may become daily smokers or dependent on them. Among high school students participating in the 1997 Youth Risk Behavior Survey (YRBS), of the 70.2% who tried cigarette smoking, 35.8% went on to smoke daily. This rate of escalation from trying cigarette smoking to regular use of tobacco is similar to the 33–50% observed in other studies (U.S. DHHS, 1994). The development of dependence among those who tried tobacco products is similarly high. In one population-based study of adult smokers, about 31.9% of those who tried tobacco became dependent on it based on the DSM-III criteria (Anthony et al., 1994). In another study of young adults aged 21–30, of the 74% who had smoked tobacco at least once, 27% developed DSM-IIIR criteria for tobacco dependence (Breslau et al., 1993). Similar data are not available for smokeless tobacco users. Existing data are limited to the number of individuals who report having used smokeless tobacco in the past month versus the number who report lifetime use of smokeless tobacco; this method of calculation represents about 18% for smokeless tobacco users. This figure is compared to 37% for cigarette smokers using a similar method of calculation (U.S. DHHS, 2000).

Relapse rates among those who tried to quit have been considered another indicator of dependence on or addiction to a drug. Relapse is high among a general population of smokers who have tried to quit smoking, with only 2.5% being able to sustain abstinence for a year (CDC, 1994). One study showed that among self-quitters, about two-thirds reported smoking within two days postquit (Hughes et al., 1992). The rate of relapse among a population of smokers who have undergone clinical treatment tends to be about 75%, with a significant number of these relapses occurring within the first few weeks. These rates and patterns of relapse are similar to those observed with smokeless tobacco (Hatsukami and Severson, 1999) and other drugs of abuse (Hunt and Matarazzo, 1973; Maddux and Desmond, 1986; Wallace, 1989). High rates of relapse are also observed among youth that smoke. Based on results from the YRBS, among high school students who smoked daily, 72.9% had ever tried to quit smoking and only 13.5% were former smokers (CDC, 1998).

Most research on the dependence on nicotine replacement products has examined the persistence of use or escalation of use over time. No data are available on the prevalence of daily use in the general population or on dependence on these products according to diagnostic criteria for dependence or FTND scores. The rate of persistent use of nicotine replacement products among smokers enrolled in clinical trials who were assigned these products is much lower than the rate of persistent use of cigarettes, ranging from 9% for nicotine gum to 18% for nicotine nasal spray (Hughes, 1998). With nicotine nasal spray the rates of persistent use are higher, and there is evidence to show that a small number escalate the amount of use over time (deWit and Zacny, 1995). In general, addiction to these products is significantly less than addiction to cigarettes due to the relatively slow absorption of nicotine, the side effects that sometimes results from use, and the cost per unit of purchase.

In summary, research shows that nicotine delivered via cigarettes and smokeless tobacco is likely to lead to a high prevalence of use and dependence. One third to one-half of individuals who experiment with cigarette products are likely to become regular users and dependent on them. No data are available on the initiation of nicotine replacement product use among tobacco-naïve individuals or rates of diagnosable dependence, although these rates are likely to be low (Shiffman et al., 1998). The number of new NRT users among those attempting to quit was approximately 10% per year prior to over-the-counter (OTC) nicotine replacement products and 26% per year after OTC availability (Shiffman et al., 1998). Therefore, increased availability has led to increased use of these products among smokers, however, the rate of use still remains quite low. Furthermore, among smokers who use nicotine replacement products, persistent use tends to be low. Future research endeavors should concentrate on developing uniform methods and measures for assessing nicotine dependence so comparisons can be made across products and studies. The present measures are limited to assessing the extent of dependence and limited by being designed to diagnose other drugs of abuse and not specifically to diagnose nicotine dependence. In addition, as new products evolve, rates of initiation, regular use or persistent use and dependence, or progression to dependence as a result of experimentation should be assessed.

Models of Addiction. Several methods have been developed using clinical and animal models to determine the addiction potential or abuse liability of a drug. These include models of self-administration, drug discrimination, and conditioned drug placement. Models to examine withdrawal have also been developed. For humans, subjective responses to drugs can also be determined, although these responses may not necessarily be associated with actual drug-taking behavior.

When a drug is reinforcing, it is more likely to be self-administered or preferred compared to a control drug that has no abuse potential. The subject is exposed to a drug, typically, at varying doses and then required to choose between this particular drug and a control drug or an alternative reinforcer (e.g., sucrose for animals, money for humans), or between different doses of the drug.

  • In self-administration models, the animal is required to perform a particular maneuver, such as lever pressing, to obtain the drug, which is typically administered intravenously. This lever pressing could be based on a fixed ratio (a specific number of responses are required prior to drug delivery), a progressive ratio (more responses are required after each drug delivery), or an interval schedule (a certain time interval is necessary before drug delivery), or a combination of these. Scheduled reinforcement in response to environmental stimuli associated with drug administration are called second-order schedules (Goldberg et al., 1981). Drugs can be made available for a fixed amount of time or throughout the day. Drugs that are reinforcing prompt the subject to work more or pay a higher cost for them than for the control; reinforcing drugs also lead to a greater persistent responding for them even when they are no longer available (Henningfield et al., 1991). Typically the dose-response curve is U-shaped (Risner and Goldberg, 1983; Rose and Corrigall, 1997) with low and high doses resulting in reduced drug self-administration. Low doses may produce limited or undetectable effects and high doses may produce adverse effects.

  • Drug discrimination models involve training the subject to discriminate the stimulus properties of drug A from drug B. A third drug may be introduced, and the animal or human subject is asked to decide whether the drug is more like drug A or drug B (Bigelow and Preston, 1989; Preston, 1991). Subjects can also be trained to discriminate among several sets of drugs or different doses of a drug. This model allows determination of the mechanism of action of a drug. For example, if one wanted to determine whether an opioid has µ agonist or κ agonist activity, an experiment can be developed in which the subject is trained to discriminate between drugs that are known to have each of these activities. After this period of training, the drug in question is introduced and the subject has to indicate whether the drug is more like drug A (e.g., a µ agonist) or drug B (a κ agonist). This model can be also used to determine whether a drug has the stimulus properties of a particular pharmacological class of drugs that are abused. A similar method is used in a drug preference procedure, in which subjects are exposed to drug A and drug B, and are required to self-administer each of these drugs during separate experimental sessions. After the drug exposure or sampling period, subjects are then asked to choose between drugs A and B, to determine their preference for one drug or another (de Wit, 1991). Drug A or B can be two different doses of a drug, different types of drugs, or an active and placebo drug.

  • The conditioned place preference model also is used to determine the abuse liability of a drug. Animals are trained that the drug is available only in a particular place (e.g., a specific chamber). Then a determination is made of how frequently the animal is willing to go to this place. If it is chosen significantly more frequently than the other place which is associated with a control drug or no drug administration, the experimental drug may have abuse potential (Bozarth, 1987).

  • Drug withdrawal models have typically involved observing signs and symptoms during a period of abstinence after repeated administration of a drug (U.S. DHHS, 1988; Hughes et al., 1990; Malin et al., 1992). These withdrawal symptoms can be precipitated by antagonist drugs or allowed to occur naturally. Although the occurrence of withdrawal signs and symptoms does not necessarily indicate that that the drug will be abused, it may be one indicator of the potential for abuse.

  • Finally, among humans, subjective responses to drugs can be determined (Jasinski and Henningfield, 1989; Fischman and Foltin, 1991; Jaffe and Jaffe, 1989). Subjects can be asked to indicate the intensity of experiencing different subjective effects, such as the degree of euphoria, liking of a drug, “high,” desire for a drug, or “head rush.” Comparisons can be made across different drugs and across doses within a particular drug. Subjects can also be asked to rate the effects of a drug using various standardized measures that have been developed to assess a drug profile (e.g., stimulant-like effects, depressant effects) such as the Addiction Research Inventory (Haertzen et al., 1963).

Self-administration paradigms have been used to demonstrate that a wide range of species (monkeys, mice, dogs, and rats) exhibit preference for administering nicotine over a control vehicle (Henningfield and Goldberg, 1983; RCP, 2000; Rose and Corrigall, 1997; Swedberg et al., 1990; U.S. DHHS, 1988). Studies have shown that these animals are willing to lever-press several hundred times in order to receive an injection of nicotine (Goldberg et al., 1981; Risner and Goldberg, 1983). However, unlike other drugs such as cocaine, the range of environmental conditions under which nicotine serves as a reinforcer is more restricted (Henningfield and Goldberg, 1983). In laboratory studies, human smokers have also been found to lever-press for intravenous doses of nicotine (Henningfield and Goldberg, 1983) as well as to self-administer greater number of doses of nicotine nasal spray (Perkins et al., 1997) and nicotine gum (Hughes et al., 1990b) compared to the respective placebo conditions. Clinical trials for the nicotine spray (Sutherland et al., 1992) and gum (Hughes et al., 1991) have also observed greater self-administration of active compared to placebo doses. Most human studies, however, have focused on assessing smoking behavior, looking at various indices of exposure, including number of cigarettes, number of puffs, puff volume, puff duration, inhalation duration, and intercigarette interval as well as biochemical indices of exposure such as cotinine or nicotine concentrations. Smoking behavior has been examined in response to changes in dose of cigarettes, preloading with nicotine or administering nicotinic antagonists and other drugs that may affect the reinforcing effects of nicotine (U.S. DHHS, 1988). Self-administration of nicotine is dose related in both humans and animals, although there is lesser dose-dependency than other drugs in animals, and the curve is somewhat flat for humans (Corrigall, 1999). Nonetheless, reduced nicotine self-administration in humans is observed with nicotine preloading and compensation with changing nicotine doses in cigarettes. Speed of nicotine delivery also plays a role in the extent to which nicotine is self-administered. Rapid bolus injections of nicotine result in greater self-administration than a slow infusion (Wakasa et al., 1995). Self-administration can be blocked by mecamylamine, a nonspecific nAchR antagonist or by dopamine receptor antagonists (see earlier discussion of the biological basis of addiction). Self-administration can be facilitated not only by the dosing characteristics of cigarettes or nicotine but also by the sensory characteristics of cigarettes (Henningfield and Goldberg, 1983; Rose and Corrigall, 1997).

Smokers tend to report dose-related subjective effects such as drug liking, drug strength, head rush, and feeling dizzy or aroused as a result of inhaled, buccal (smokeless tobacco), intravenous, or nasal spray nicotine administration (Fant et al., 1999; Henningfield et al., 1985; Jones et al., 1999; Perkins et al., 1994a, 1994b). Smokers who have a history of drug dependence exhibit a similar dose-related increase in “liking” and other subjective responses for intravenously administered nicotine as observed for cocaine, amphetamine, morphine, pentobarbitol, and heroin (Jasinski et al., 1984; Jones et al., 1999; Keenan et al., 1994). Findings from another study also revealed that intravenous nicotine was misidentified as cocaine or amphetamine by the study participants who had histories of drug use (Henningfield et al., 1985; Jones et al., 1999). Subjective responses to nicotine gum, patch, spray and inhaler have been less pronounced than responses to cigarettes or intravenous nicotine (deWit and Zacny, 1995; Henningfield and Keenan, 1993; Schuh et al., 1997).

The occurrence of withdrawal symptoms after cessation of continuous nicotine infusion in rodents has been demonstrated (Malin et al., 1992). In humans, withdrawal symptoms upon cigarette smoking cessation has also been well established (Hughes et al., 1990a). However, fewer studies have been conducted with other tobacco products or nicotine replacement agents. Cessation of smokeless tobacco use generally produces less intense withdrawal symptoms than cessation of cigarette smoking (Hatsukami et al., 1987; Keenan et al., 1989). However, in a population of smokeless tobacco users enrolled in clinical trials, the severity and number of withdrawal symptoms from smokeless tobacco were comparable to those experienced by cigarette smokers who were trying to quit (Hatsukami et al., 2000). Nicotine gum withdrawal symptoms also tend to be significantly less intense in number and severity than cigarette withdrawal symptoms (Hatsukami et al., 1991, 1993, 1995), and higher doses of gum produce greater withdrawal than lower doses of gum (Hatsukami et al., 1991). On the other hand, among those who have used the product for a prolonged period, nicotine gum may be comparable to cigarettes in the number of withdrawal symptoms experienced (Hughes et al., 1986b; West and Russell, 1985).

In summary, various laboratory studies have observed that nicotine is self-administered, produces psychoactive effects, and produces withdrawal symptoms. The route of delivery can determine the extent to which nicotine-containing products can produce these effects and lead to addiction, with cigarettes showing the highest potential for addiction.

Future studies on new products should routinely measure the abuse potential of a drug by using the various methods that have been described. Furthermore, these paradigms could be considered to test medications focused at reducing frequency of tobaccco use.


1.1 Introduction
1.2 Historical viewpoints of controlled release drug delivery
1.3 Sustained release drug delivery system
1.3.1 Concept of sustained release drug delivery system
1.3.2 Rationale of sustained release drug delivery system
1.3.3 Oral sustained release drug delivery system
1.3.4 Advantages of sustained release dosage forms
1.3.5 Disadvantages of sustained release dosage forms
1.3.6 Drugs unsuitable for sustained release dosage forms
1.3.7 Factors affecting sustained release dosage forms Physicochemical properties of the drug affecting sustained release dosage forms Biological properties of the drug affecting sustained release dosage forms
1.3.8 Formulation methods used to prepare sustained release dosage forms Particle size modification Matrix system Coating system Beads and sphere Enteric coated beads in capsule Mixed release granules Repeated action tablets Erosion core with initial dose Erosion core only Ion exchange resin Complexation Microencapsulation The osmotic tablet Gel forming hydrocolloids Environmentally responsive system
1.3.9 Methods and mechanisms of sustaining drug action Diffusional systems Dissolution controlled system Water penetration controlled system Chemically controlled systems Hydrogels Ion exchange resins
1.3.10 Technical sophistication based classification of sustained release drug delivery
1.4 Matrix devices
1.4.1 Polymers used in matrix devices
1.4.2 Properties of an ideal polymer
1.4.3 Classification of polymers Matrix devices with insoluble inert polymer Matrix devices with insoluble erodible polymer Matrix devices with hydrophilic polymer Matrix devices with hydrogel polymer
1.4.4 Use of excipients in matrix devices
1.4.5 Release mechanisms from matrices
1.4.6 Mathematical models of release mechanics from matrices Release from soluble retardants Release from insoluble retardants Drug release of low solubility in eluting media Exponential model Geometric dependence of diffusion exponent (n) and variation of n values with mechanism of diffusion
1.5 Thesis topic
1.5.1 Rationale
1.5.2 Active component
1.5.3 Physico-chemical properties of Nitroglycerin
1.5.4 Mechanism of action
1.5.5 Therapeutic use
1.5.6 Therapeutic dose
1.5.7 Contraindications
1.5.8 Pharmacokinetics
1.5.9 Pharmacology and toxicology Mode of action Interactions Nitrate tolerance
1.5.10 Clinical effects Acute poisoning Chronic poisoning
1.5.11 Management of clinical effects
1.5.12 Decontamination

2. Materials and methods
2.1 Materials
2.2. Drug profile
2.3. Excipients profile
2.3.1 Methocel Nomenclature Chemistry Degree of substitution Properties of Methocel K15M CR and Methocel K100LV CR
2.3.2 Profile of colloidal Silicon Dioxide (Aerosil 200)
2.3.3 Profile of Magnesium Stearate
2.4 Methods of study
2.4.1 Preparation of matrix tablet
2.4.2 Formulation of Nitroglycerin matrix tablet (F-1 – F-9)
2.5 Characterization of Nitroglycerin matrix tablets
2.5.1 Evaluation of physical properties of formulation granules Bulk density Compressibility index Total porosity Pharmacology and toxicology Moisture content Flow properties Assay
2.5.2 Evaluation of physical properties of matrix tablet Weight variation test Hardness Friability Surface area Moisture content
2.5.3 Chemical assay of Nitroglycerin in matrix tablets Uniformity of content of active Nitroglycerin Assay of Nitroglycerin after preparation of tablets Assay of Nitroglycerin after 1 Month at 40°C + 75%RH
2.5.4 In-vitro release studies of Nitroglycerin matrix tablet In-vitro dissolution medium In-vitro dissolution studies of the tablet matrix
2.5.5 In-vitro release kinetic models Zero order equation First order equation Higuchi square root law Korsmeyer-Peppas model Hixson-Crowell cube root law
2.5.6 Successive fractional dissolution time

3. Results and discussion
3.1 Evaluation of physical properties of Nitroglycerin granules
3.2 Evaluation of physical properties of Nitroglycerin tablets
3.3 Assay of Nitroglycerin matrix tablet
3.3.1 Uniformity of content of active Nitroglycerin
3.3.2 Assay of Nitroglycerin in the matrix tablet
3.3.3 Assay of Nitroglycerin after 1 Month at 40°C+75%RH in the matrix tablet
3.4 In-vitro dissolution and kinetic studies of Nitroglycerin matrix tablet in formulations (F–1 to F–9)
3.4.1 Effect of Methocel K15M CR (25%,20%,15%) and Methocel K100LV CR (15%,10%,5%) on release pattern of Nitroglycerin Matrix tablet Zero order plot First order plot Higuchi plot Korsmeyer-Peppas plot Hixson-Crowell plot
3.4.2 Interpretation of release rate constant and R-square values for different release kinetics of (F–1 to F–9)
3.4.3 The best fitted model and mechanism of drug release from the matrix tablet of Nitroglycerin
3.4.4 Successive fractional dissolution time
3.5 Discussion about formulations (F–1 to F–9)

4 Conclusion

5 Bibliography


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I have great pleasure to acknowledge with sincere appreciation and a deep sense of gratitude to reverend teacher and supervisor Dr. Abu Shara Shamsur Rouf, Professor, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh, for his hearty co-operation, keen interest, excellent laboratory technical support and constant guidance to this work and also for his continuous constructive suggestions during the preparation of the manuscript of the thesis.

I am also highly obliged to all the honorable teachers of Department of Pharmaceutical Technology, University of Dhaka for their kind cooperation.

I also express my heartfelt felicitation to ACI Pharmaceutical Limited, for endless support with instruments, reagents and other accessories.

I extend my sincerest thanks especially to Mr. A. K. Lutful Kabir, Assistant Professor, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, and Ms. Sharifa Sultana, Lecturer, Department of Pharmacy, Daffodil International University Dhaka, Bangladesh, for their continuous suggestions and help during this work and the preparation of the manuscript of the project.

I also extend my sincerest thanks to all my friends, classmates, and senior brothers & sisters and well-wishers especially Shimul Halder, Shahidul Islam, Mizanur Rahman, Anwar Chowdhury, Abdullah Al Masud, Helal and Saiful.


The aim of the present studies was to develop and characterize 2.6 mg sustained release matrix tablets of Nitroglycerin. Tablets were prepared by direct compression method. Methocel K15M CR and Methocel K100LV CR polymers were used as rate retarding agents in nine formulations (F-1 to F-9). The granules were evaluated for angle of repose (26.78±0.01 to 29.25±0.030), loose bulk density (0.423±0.06 to 0.447±0.01gm/ml), tapped bulk density (0.516±0.02 to 0.544±0.04 gm/ml), Carr’s index (14.203±0.03 to 20.857±0.04%), Hausner ratio (1.166±0.01 to 1.264±0.03), moisture content (2.8879 to 3.4502%), total porosity (13.58±0.01 to 17.65±0.06%) and assay (2.593 to 2.721 mg/tablet). The tablets were subjected to diameter (8.0 mm), thickness (3.84±0.02 to 4.30±0.01 mm), assay (2.57 to 2.65 mg/tablet), uniformity of content (2.59±0.02 to 2.68± 0.02 mg/tablet), assay after 1Month at 40°C+75%RH (2.57±0.03 to 2.64±0.03 mg/tablet), hardness (8.0±0.06 to 8.9±0.06 kp), friability (0.11 to 0.49%) and in vitro dissolution studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with pharmacopoeial specifications for tested parameters. The in vitro dissolution study was carried out for 8 hour using USP-2009 Apparatus-I (Rotating basket method) in distilled water as the dissolution medium. The release mechanisms were explored and explained by Zero order, First order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell equations. Nine formulations were prepared by using three variable ratio of two polymers; Methocel K15M CR (25%, 20%, and 15%) and Methocel K100LV CR (15%, 10%, and 5%) where all the formulations (F-1 to F-9) contained 0.5% colloidal silicon dioxide and 1% magnesium stearate. Among these nine formulations, six formulations; F-2 (Methocel K15M CR: Methocel K100LV CR = 25% : 10%), F-3 (Methocel K15M CR : Methocel K100LV CR = 25% : 5%), F-4 (Methocel K15M CR : Methocel K100LV CR = 20% : 15%) F-5 (Methocel K15M CR: Methocel K100LV CR = 20% : 10%), F-6 (Methocel K15M CR : Methocel K100LV CR = 20% : 5%) and F-7 (Methocel K15M CR : Methocel K100LV CR = 15% : 15%) met the official specification of release profile. It was also found that the type and the amount of polymers significantly affect the time required for 50% (T50% or MDT) of drug release, release rate constant and diffusion exponent. Higher the MDT value indicates a higher drug retaining capacity of the polymers and vice-versa. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism of all proposed formulations followed anomalous type or non-Fickian transport (n>0.43 and n<0.85). These studies explored both of the optimum concentration and effect of polymers on Nitroglycerin release pattern from the tablet matrix for 8 hour period.


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1.1. Introduction

A drug is a chemical substance used in the diagnosis, treatment or prevention of a disease and it should be recognized or defined by the U.S. Food, Drug, and Cosmetic Act ( Drugs are rarely administered as pure chemical substances alone rather these are almost always given as formulated preparations or medicines. These can vary from relatively simple solutions to complex drug delivery systems through the use of appropriate excipients in the formulations.

The principal object of dosage form design is to achieve a predictable therapeutic response to a drug included in a formulation which is capable of large scale manufacture with reproducible product quality. To ensure product quality, numerous features are required-

- Chemical and physical stability
- Uniformity of dose of drug
- Suitable preservation against microbial contamination
- Acceptability to user including both prescriber and patient
- Suitable packaging and labeling.

Before a drug substance can be successfully formulated into a dosage form many factor must be considered. These can be broadly grouped into three categories:

1. Biopharmaceutical considerations, including absorption, distribution, metabolism and excretion of drug;
2. Drug factor, such as the physical and chemical properties of the drug substance;
3. Therapeutic considerations, including consideration of the clinical indication to be treated and patient factor.

Table 1.1.: Dosage forms available for different administration routes

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The oral route of drug delivery is typically considered the preferred and most patient-convenient means of drug administration. In order to achieve prolong and effective action by oral route, sustained release dosage formulations are commonly used for maintaining therapeutic action of a drug for a specific time period. This type of dosage form can be defined as “the drug delivery system that is designed to release a drug at a predetermined rate by maintaining a constant plasma drug level for a specific period of time with minimum side effect by continuously releasing the active ingredient(s) after the administration of a single dose”.

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Figure 1.1: Pathways a drug may take following the administration of a dosage form by different route.

Most conventional dosage forms function merely to place a drug at the site of administration and pay no regard to the regulation of release and absorption or the duration and targeting of drug in the body. So, now-a-days one of the most active areas of research and development in drug delivery involves “controlled release” products rather than develop new drug entities at higher cost; as some drug therapies already on the market can be improved simply by controlling the rate at which they enter the blood stream as shown scheme-1

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Kr = rate constant for drug release, Ka = rate constant for drug absorption & Ke = rate constant for drug elimination.

Figure 1.2: Model for (a) Conventional Dosage form and (b) Sustained Release Dosage form Scheme -1 represents the model for conventional (a) & sustained release (b) oral drug movement in the body. The Kr & Ka values will be smaller for SR than conventional dosage form.

Oral sustained release dosage form by direct compression technique is a very modern and common approach in the pharmaceutical arena due to relatively ease, cost effective and faster production compared with other compression techniques. This technique also avoids hydrolytic or oxidative reaction occurred during processing of dosage forms.

After the administration of a dosage form, sustained or controlled drug delivery occurs while the active agent embedded with polymer(s) that may be natural or semi synthetic or synthetic in nature. The polymer is judiciously combined with a drug or other active ingredients in such a way that the active agent is released from the material in a redesigned fashion. The main target is that the active agent must be released at constant rate over a stipulated period of time. In most cases, the purpose of controlling or sustaining the drug delivery is to achieve more effective therapeutic action with eliminating the potential for both under and overdosing.

It is possible to formulate a sustain release dosage form in several techniques. But in the development studies of sustained release formulation, several new techniques, and approaches are also proving their acceptability and feasibility. Among the systems, matrix tablet has attracted much attention due its technological simplicity in comparison with other controlled release systems developed to achieve the sustained action.

In this study, direct compression method has been applied for preparation of tablet matrix that is most advanced technology ever discovered. It involves simple blending of all the ingredients along with the active agent used in the formulation and then underwent direct compression. It requires fewer unit operations, less machinery, reduced number of personnel and reduced processing time, increased product stability and faster production rate.

In general, the goal of a sustain release dosage form is to maintain therapeutic blood or tissue levels of the drug for an extended period. This is usually accomplished by attempting to obtain zero-order release from the dosage form. Zero-order release constitutes the drug release from the dosage form that is independent of the amount of drug in the delivery system (i.e. a constant release rate). This is usually achieved by incorporating one or more polymers with the active agent. But sustain release system generally do not attain this type of release and usually try to mimic zero-order release by providing drug in a slow first order fashion (i.e. concentration dependent).

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Figure 1.3: Drug level verses time profile showing differences between (a) traditional drug dosing and (b) sustained delivery dosing.

Depending on the route of administration, conventional dosage forms i.e. solution, suspension, capsule, tablet, cream, gel, ointment, suppository etc. produce effective drug concentration in blood vs. time for a short period of time. The short duration of action of the conventional dosage forms is due to their failure to control the delivery of the active agent. If any attempt is made to maintain drug blood level in the therapeutic range for longer periods increasing the dose, toxic effects of the drug may be produced at any time. An alternative is to administer the drug repetitively using a constant dosing interval as in multiple dosing therapies. In this case, effective drug blood level depends on both the dose and the dosing interval. There are some potential problems inherent to this multiple dose therapy. Primarily, if the dosing interval is not appropriate for the biological half-life of the drug, large peaks and valleys in the drug blood level may result within the therapeutic window. Secondly the blood level of the drug may not be reached within the therapeutic range at required time that is very important for certain disease states. Finally, the patient noncompliance with the multiple dosing regimens can result in the failure of the approach.

In recent years considerable attention has been focused on the development of new drug delivery systems. Recognition of the possibility of re-patenting success drugs by applying the concepts and techniques of controlled release drug delivery systems, coupled with the increasing expense in bringing new drug entities to market, has encouraged the development of new drug delivery systems. Therapeutic efficacy & safety of drugs administered by conventional methods can be improved by more precise, spatial, and temporal placement within the body, thereby reducing both the size and number of doses.

1.2. Historical viewpoints of controlled release drug delivery

The first sustained release dosage form was marketed in the United States in 1952 by Smith Kline & French under the trade name ‘Dexadrin Spansule’. The Spansule provided a novel form of drug delivery and was a major therapeutic breakthrough. It quickly released the required initial dose and then slowly and gradually released many extremely small doses to maintain a therapeutic level lasting from 10 to 12 hours, providing all-day or all-night therapy with one dose. The goal behind the development of oral controlled-release formulations at that time was the achievement of a constant release rate of the entrapped drug. On the basis of that concept, the zero-order osmotic delivery used in Procardia XL became one of the top 10 best-selling medicines in the past century (Das and Das, 2003).

In 1968, Alejandro Zaffaroni founded ALZA (ALZA Corporation, our Technologies, June 2004), now owned by Johnson and Johnson, with the aim of creating controlled drug delivery systems whose release rate of drug could be controlled with precision, independent of the release environment. The formation of ALZA marked the beginning of the modern era of drug delivery technology (Robinson, 1987). And Elan Corporation was founded in 1969 “with a vision: to approach the challenge of drug delivery from an entirely new angle - that of controlled absorption of a drug to provide longer duration of drug effect”.

Two major disease groups that have had an important bearing on the evolving nature of controlled drug delivery:

1. Diabetes - fluctuations in insulin/glucose minimized [sustained drug release]
2. Cancer - target abnormal cells [localized / targeted drug release]

From an economic point of view, the development of novel delivery systems can potentially prove profitable for a modest investment (in terms of acquiring market share). In Time magazine of Jan. 13th this year, Charles P. Wallace in 2003 wrote: "R and D costs as a percentage of drug-company sales were 12% in 1970, 15% in 1990, and 20% today". According to Visiongain, revenues of pharma products that utilize advanced drug delivery technology were estimated at US$38 billion in 2002. The growth of this market is expected to continue at an average rate of 28% over the next 5 years, significantly higher than the pace of the overall pharmaceutical industry (Corporate Fact Sheet, Q2 2005,

Recently Controlled drug delivery industries have made certain standard innovation in drug delivery technology. Ms. Callanan commented, “Definitely a key for large pharma companies is to use novel approaches to extend the patent life of their products or, even if they don’t extend the patent life, to add something new to the compound to get marketing advantage. Things like fast-melt technology, extended release compounds, all those areas, those types of technologies; in the next few years they will be exploited to their fullest extent by large Pharmaceutical companies all over the world.”

Consider PROCISETM ( is a programmable solid oral drug delivery system customized to the required release specification for a particular drug. The technology work on a unique patented tablet design and formulation. The PROCISETM system consists of a slow dissolving core with a cylindrical core in the middle. The surface of the core, excluding the peripheral edge, is covered with a very slow dissolving (slower than the active core) inert coating material. Dissolution of the core and drug release is therefore restricted to the peripheral edge. As the dissolution progresses over time, the core diameter decreases but the height of the cylindrical releasing surface increases thereby maintaining a constant surface area and thus constant release.

The popularity and importance of these dosage forms can be appreciated from the fact that for the first time in 1985 the official compendia adopted the use of the term “Modified Release” to identify these dosage forms as being different from the conventional dosage forms (USP XXI). The USP defines modified release dosage forms as “One for which the drug – release characteristics of time – course and /or location are chosen to accomplish therapeutic convenience not offered by conventional dosage forms.”

The majority of oral drug delivery systems are matrix-based. In such systems, the tablet is in the form of a compressed compact that contains an active ingredient, a lubricant, an excipient and a filler or binder. Erosion, diffusion, and swelling of the matrix are the various methods through which the systems control drug delivery. The polymer properties invariably play an important role in the release pattern of the drug. If the polymer is predominantly hydrophilic, the swelling process chiefly controls the drug release. The swellable matrices are monolithic systems prepared by compressing a powdered mixture of a hydrophilic polymer and drug. The success of these drug delivery systems is attributed to the established tablet manufacturing technology (Hogan, 1989). Thus hydrophilic matrices are an interesting option when developing an oral sustained-release formulation. They can be used for controlled release of both water-soluble and water-insoluble drugs. Release of drugs from such matrices can be controlled through their physical properties, the correct choice of gelling agent and setting up the conditions for fabrication (Vezquez et al., 1992).

The development of controlled release formulation continues to be a big success for the pharmaceutical industry. The success of any technology relies on the ease of its manufacturing process and its reproducibility of desirable biopharmaceutical properties. The market for oral controlled drug delivery alone is expected to grow at 9% or more every year through 2007 (Das and Das, 2003). The future of controlled – release products are promising especially in the areas of Chronopharmacokinetic systems and Mucoadhesive delivery (Amidon et al., 2000).

1.3. Sustained release drug delivery system

Sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful at maintaining constant drug levels in the blood or target tissue, it is considered as a controlled-release system. If it is unsuccessful at this, but nevertheless the duration of action over that achieved by conventional delivery, it is considered a prolonged-release system.

1.3.1. Concept of sustained release drug delivery system

Most conventional drug products, such as tablets and capsules, are formulated to release the active drug immediately to obtain rapid and complete systematic absorption of the drug. In recent years, various modified drug products have been developed to release drug products are designed for different routes of administration based on the physicochemical, pharmacological, and pharmacokinetic properties of the drug. Sustained release, sustained action, prolonged action, controlled release, extended action, time release, depot, and respiratory dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. In the case of injectable dosage forms; this period may vary from days to months. In the case of orally administered forms, however, this period is measured in hours and critically depends on the residence time of the dosage form in the GI tract (Ballard, 1978).

A more finite explanation of these types of medication has been provided by Nelson (1961) and Parrot (1963). They indicated that a sustained release or sustained action product provides an initial sufficient amount drug to cause a rapid onset of desired therapeutic response, and an additional amount of drug that maintains the response at the initial level for a desired number of hours beyond the activity resulting from conventional dose; the initial desired therapeutic response is maintained because the rate of release of the desired therapeutic concentration is equal to the rate at which the drug is eliminated or inactivated.

1.3.2. Rationale of sustained release drug delivery system

Depending on the route of administration, a conventional dosage form of the drug, e.g., a solution, suspension, capsule, tablet, etc., produce a drug blood level versus time profile which does not maintain within the therapeutic range for extended periods of time. The short duration of action is due to the inability of conventional dosage forms to control temporal delivery. If any attempt is made to maintain drug blood levels in the therapeutic range for longer periods, for example, by increasing the dose of an intravenous injection, toxic levels may be produced at early times. This obviously is undesirable and the approach therefore is unsuitable. An alternative approach is to administer the drug repetitively using a constant dosing interval as in multiple-dose therapy. In this case the drug blood level reached and the time required to reach that level depend on the dose and the dosing interval. There are several potential problems inherent in multiple-dose therapy. Firstly, if the dosing interval is not appropriate for the biological half-life of the drug, large `peaks’, and `valleys' in the drug blood level may result. For example, drug with short half-life may require frequent dosing to maintain constant therapeutic levels. Secondly, the drug blood level may not be within the therapeutic range at sufficiently early times, an important consideration for certain disease states. Thirdly, patient noncompliance with the multiple dose regimens can result in failure of this approach.

In general, controlled delivery attempts to:

1. Sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a saw-tooth kinetic pattern,
2. Localize drug action by spatial placement of a controlled release system (usually rate-controlled) adjacent to or in the diseased tissue or organ,
3. Target drug action by using carriers or chemical derivatization to deliver drug to a particular "target" cell type.

Sustained release dosage forms include those dosage forms in which the drug-release characteristics are different from the conventional dosage form to saw-tooth pattern of drug delivery (Except continuous IV perfusion) & results in increase adverse effects, decrease therapeutic effect & poor patient compliance (Madan, 1985)

In recent years considerable attention has been focused on the development of new drug delivery systems by applying the concepts and techniques of controlled release drug delivery. An appropriately designed sustained release drug delivery system can be a major advance toward solving the problems facing continuously in case of conventional dosage form, thereby reducing both the size and number of doses. It is for this reason that the science and technology responsible for the development of sustained release pharmaceuticals have been and continue to be the focus of a great deal of attention in both industrial and academic laboratories. The first such dosage form was marketed in the United States in 1952 by Smith Kline & French under the trade name Dexadrin spanules. At present more than 50 major manufactures produce about 200 special delivery products, representing nearly five percent of the pharmaceutical market (Madan, 1990).

1.3.3. Oral sustained release drug delivery system

The goal of sustained release drug delivery system is to supply the optimal concentration of a drug for a longer time than conventional system allows. For example, in case of immediate release tablet dosage form, medicine is ingested at intervals of specified time. When a tablet is taken, systemic drug concentration raises rapidly and then falls. After the ingestion of second tablet, the concentration of the active agent in the bloodstream again raises and then again falls. In this way, the cycle continues. The problem with this scenario is that optimal concentration cannot be maintained within the therapeutic window and the peaks may cross the toxic level. Also, human error may cause additional difficulties if a dose is delayed or missed. Sustained release systems directly combat these problems associated with the "Hill and Valley" phenomenon described above.

Oral sustained release drug delivery is a drug delivery system given by oral route that provides the continuous delivery of drug(s) to the systemic circulation at predictable and reproducible kinetics for a predetermined time period throughout the course of GI transit.

In the exploration of oral sustained release drug administration three potential changes are encountered. These are:

- Development of drug delivery system
- Modulation of gastrointestinal transit time
- Minimization of hepatic first pass elimination

In vitro drug release data, drug release profiles should be generated by a well-designed, reproducible in vitro testing method, such as the dissolution test for solid dosage forms.

The key elements for in vitro release are:

- Reproducibility of the method
- Proper choice of medium
- Maintenance of perfect sink conditions
- Good control of solution hydrodynamics

Controlled release dosage form is also known as­-

- Sustained release dosage form
- Prolonged release dosage form
- Delayed release dosage form
- Timed-release dosage form
- Retarded release dosage form
- Extended action dosage form
- Depot dosage form
- Repeat action dosage form
- Repository dosage form

1.3.4. Advantages of sustained release dosage forms

- Sustained release dosage forms maintain the therapeutic and prophylactic effect for longer period of time than can be obtained by immediate release single medication.
- For patient compliance as they reduce the number and frequency of doses administered.
- They reduce the total amount of drug needed to obtain the desired therapeutic response, thus maximize availability with a minimum dose.
- They reduce the incidence and intensity of both local and systematic adverse effects in sensitive patients caused by excessively high peak blood levels of drugs that may result from the administration of conventional dosage forms, thus safety margin of high potency drug can be increased.
- They reduce the possibility of the patients defaulting from treatment by forgetting to take his/her medication.
- They eliminate the inconvenience of night-time administration of drug.
- They reduce the necessity of nursing-staff in hospitals.
- Better control of drug absorption can be attained by sustained dosage forms.
- They reduce or eliminate “peak” and “valley” effects and thus maintain an even blood level of drug concentration in the body.
- In case of conventional dosage form of antibiotic during valley effect, the microorganisms may grow resistance against drug. But in case of sustained release dosage forms there is no chance of this, because they do not create peak and valley effect.

1.3.5. Disadvantages of sustained release dosage forms

- Sustained release dosage forms do not permit prompt termination of therapy when this is not desired or required.
- The physician has less flexibility in adjusting dosage regimens.
- They are comparatively more expensive than medication in conventional dosage form design.
- They are prepared on the basis of average rate of release and elimination. So, there may be drug accumulation.
- The sustained release dosage form contains the equivalent of two or more conventional dosage forms. Therefore, the failure of the sustained release dosage form might lead to dose dumping. Dose dumping may be defined as the release of more than the usual fraction of drug, or as the release of drug at a greater rate than the customary amount of drug per dosage interval, such that potentially adverse plasma levels may be reached.
- They produce a high concentration of drug at some specific sites along the GIT. This may cause local irritation to the GI mucosa.
- Effective drug release period is influenced by GI residence time.

1.3.6. Drugs unsuitable for sustained release dosage forms

- Drugs whose precision of dosage id important; e.g. Anticoagulants and Cardiac glycosides.
- Drugs having long biological half-life (>12 hrs); e.g. Diazepam, Phenytoin.
- Drugs whose absorption from the gastrointestinal tract is impaired or erratic; e.g. Riboflavin, Ferrous salts.
- Drugs having short biological half-life (<1hr); e.g. Penicillin G, Furosemide.
- Drugs whose large doses are required; e.g. Sulfonamides.
- Drugs with low therapeutic indices; e.g. Phenobarbital, Digitoxin.
- Drugs having no clear advantages for sustained release formulation e.g. Griseofulvin.

1.3.7. Factors affecting sustained release dosage forms:

Table 1.2: Factors affecting sustained release dosage forms

illustration not visible in this excerpt Physicochemical properties of the drug affecting sustained release dosage forms:

a) Dose size:

If an oral product has a dose size greater than 0.5gm it is a poor candidate for sustained release system, Since addition of sustaining dose and possibly the sustaining mechanism will, in most cases generates a substantial volume product that unacceptably large.

b) Aqueous solubility of the drug:

Most of drugs are weak acids or bases, since the unchanged form of a drug preferentially permeates across lipid membranes drugs aqueous solubility will generally be decreased by conversion to an unchanged form for drugs with low water solubility will be difficult to incorporate into sustained release mechanism. The lower limit on solubility for such product has been reported 0.1mg/ml. drugs with great water solubility are equally difficult to incorporate in to sustained release system. pH dependent solubility, particularly in the physiological pH range, would be another problem because of the variation in pH throughout the GI tract and hence variation in dissolution rate

c) Stability of the drug:

Orally administered drugs can be subject to both acid base hydrolysis and enzymatic degradation. Degradation will proceed at the reduced rate for drugs in the solid state, for drugs that are unstable in stomach; systems that prolong delivery ever the entire course of transit in GI tract are beneficial. Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered form a sustaining dosage from. This is because more drug is delivered in small intestine and hence subject to degradation.

d) Partition coefficient of the drug:

Partition coefficient is generally defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase. Accordingly compounds with relatively high partition coefficient are predominantly lipid soluble and consequently have very law aqueous solubility. Compounds with very law partition coefficients will have difficulty in penetrating membranes resulting poor bioavailability.

d) pKa value of the drug :

The relationship between pKa of compound and absorptive environment. Presenting drug in an unchanged form is adventitious for drug permeation but solubility decrease as the drug is in unchanged form.

e) Protein binding:

It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re-circulated and not eliminated, drug Protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug binding occurs.

Extensive binding to plasma proteins will be evidenced by a long half-life of elimination for drugs and such drugs generally most require a sustained release dosage form. However drugs that exhibit high degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drug delivery.The presence of hydrophobic moiety on drug molecule also increases the binding potential.

f) Molecular size and diffusivity:

The ability of drug to diffuse through membranes it’s so called diffusivity & diffusion coefficient is function of molecular size (or molecular weight).

Generally, values of diffusion coefficient for intermediate molecular weight drugs, through flexible polymer range from 10-8 to 10-9 cm2/sec. with values on the order of 10-8 being most common for drugs with molecular weight greater than 500, the diffusion coefficientin many polymers frequently are so small that they are difficult to quantify i.e. less than 16-12 cm2/sec.Thus high molecular weight drugs and/or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane.

g) Protein binding:

It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Since blood proteins are for the most part re-circulated and not eliminated, drug Protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug binding occurs.

Extensive binding to plasma proteins will be evidenced by a long half-life of elimination for drugs and such drugs generally most require a sustained release dosage form. However drugs that exhibit high degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drug delivery.The presence of hydrophobic moiety on drug molecule also increases the binding potential. Biological properties of the drug affecting sustained release dosage forms:

a) Biological half-life of the drug:

The usual goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To action this, drug must enter in the circulation of approximately the same rate of which it is eliminated. The elimination rate is quantitatively described by half-life (t1/2). Therapeutic compounds with short half-lives are excellent candidates for sustained release preparations. Since this can reduce dosing frequency. In general drugs with half-lives shorter than 3hrs are poor candidates of sustained release dosage forms of dose size will increase as well as compounds with long half-lives, more than 8 hrs. are also not used in sustained release forms because their effect is already sustained.

b) Absorption characteristics of the drug:

The rate, extent, and uniformity of absorption of a drug are important factors when considered its formulation into a sustained release system. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption. Rapid rate of absorption of drug, relative to its release is essential if the system is to be successful. It we assume that transit time of drugmust in the absorptive areas of the GI tract is about 8-12 hrs. The maximum half-life for absorption should be approximately 3-4 hrs. Otherwise device will pass out of potential absorption regions before drug release is complete.

c) Distribution characteristics of the drug:

The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending on time course of drug disposition. For design of sustained/ controlled release products, one must have information of disposition of drug.

d) Metabolism characteristics of the drug:

Drugs that are significantly metabolized before absorption, either in lumen or the tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions less total drug is presented to the enzymatic. Process device a specific period, allowing more complete conversion of the drug to its metabolite.6

e) Duration of action of the drug:

The biological half-life and hence the duration of action of a drug obviously plays a major role in considering a drug for sustained-release systems. Drugs with short half-lives and high doses impose a constraint because of the dose size needed and those with long half-lives are inherently sustained.

f) Margin of safety of the drug:

Drug with a narrow therapeutic range require precise control over the blood levels of drug, placing a constraint on sustained-release dosage forms.

1.3.8. Formulation methods used to prepare sustained release dosage form:

It includes:

- Particle size modification
- Matrix system
- Coating system
- Beads & spheres
- Enteric-coated beads in capsule
- Repeat action tablet
- Mix release granules
- Erosion core with initial dose
- Erosion core only
- Ion exchange resin
- Complexion
- Micro encapsulation
- The osmotic tablet
- Gel forming hydrocolloids
- Environmentally responsive system Particle size modification

The solubilization of a drug is directly related to the surface exposed to the solvent. The purpose of increasing particle size is to decrease the surface area of the particle thus to decrease the release of the drug from the dosage form. Matrix system

The matrix system is defined as uniform dispersion of drug in a solid which is less soluble than the drug in the depot fluid and which is the continuous internal phase of dispersion, effectively inhibits the passage of drug from the matrix to the depot fluid. Release is controlled by a combination of several physical factors, which include permeation of the matrix, by water, leaching and erosion of matrix materials, number of porous channels etc. It is one of the of the less complicated approaches in the manufacture of sustained release dosage forms which consists of a drug dispersed in a polymer the polymer plays the role of a matrix.

Several workers have also reported that the rate of drug release from the matrix system is affected by-

- Drug solubility
- The compression force applied
- pH of the dissolution fluid
- Shape
- External agitation
- Mass of the drug
- Porosity of the matrix Coating system

Coating with a material that retards penetration of the depot fluid may control the rate of availability of drug from the dosage form. Drug release rate depends upon the physicochemical nature of the coating material. The dosage form itself or the individual particles may be coated. Beads & sphere

The beads and spheres of drug are coated with a material that differs in thickness from bead to bead, determining the time at which the drug will be released. Release is controlled by using waxes that erode with time, chemicals that dissolved at a particular pH or compound the release the drug by diffusion through their pores. A number of materials are reportedly useful for such coatings including mixtures of bees wax or carnauba wax with glyceryl monostearate, stearic acid, palmitic acid, glyceryl myristate, cholesterol, such higher fatty alcohols, & esters of fatty acids of high molecular weight. Enteric coated beads in capsule

This strategy incorporated drug into beads or spheres of uniform size and uniformly coated with a suitable enteric coating material. Thus the rate of drug release depends on stomach emptying rate of the beads. Since there will be large number of beads, their stomach emptying rate will be randomized, the overall pattern approaching normal distribution to eliminate the "all or none" affect associated with enteric coated tablet, and capsules. The total release pattern approaches a constant value, providing sustained and continuous release of drug. Mixed release granules

This method uses granules as use in the preparation of compressed tablet. Two sets of granules are used. One set, which carries the immediate-release component of the drag, is prepared in the usual manner. The second set contains drug that is either coated with slowly digestible or poorly soluble materials or mixed with dissolution retarding additives. Hydrogenated vegetable oils, a number of waxes, fatty acids, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, mixtures of some of these glyceryl esters and bees wax or higher fatty alcohol & higher fatty acids used either singly or as mixture, have all been used in the preparation of such granules. Repeated action tablets

Repeated action tablet contains an individual dose which is released fairly soon after administration, and second or third doses are subsequently released at intermittent intervals. Erosion core with initial dose

In this method the sustaining component is formulated as a non-disintegrating tablet that essentially maintains its geometric its ape throughout the gastrointestinal tract. The drug in this component is usually incorporated into a tablet with insoluble materials such as high-molecular weight fats & waxes.

The principle of sustained drug release from the non-disintegrating tablet is based on the fact that the dissolution, rate of the drug from such tablet is directly proportional to the product of the drug's solubility & the tablet surface area. Erosion core only

Many drugs do not require an initial dose when the primary purpose is to maintain a therapeutic consideration once therapy has been initiated. In such cases it may be more appropriate to formulate the dosage form to contain only the sustained-release component. Ion-exchange resin

The phenomenon of ion exchange presents a useful method of sustaining action control. Ion-exchange resins are water-insoluble cross linked polymers containing salt forming groups in repealing positions on the polymer chain. Drug molecules are attached to the anionic or cationic group of ion-exchange resin and due to attachment drugs release is regarded.

The ion-exchange method involves the administration of a dosage form containing salts of drugs complexes with an ion-exchange resin that exchanges the drug for ions as it passes through the gastrointestinal tract. Complexation

The preparation of complexes or salts of active drugs that are slightly soluble in the gastrointestinal fluid is the strategy used in this method of producing sustained-release product. Microencapsulation

Microencapsulation is a means of relatively thin coating to small particles of solids or droplets of liquids and dispersion. Drugs from many pharmacological classes have been micro encapsulated in particular analgesic, antibiotics, antihistamines, cardiovascular agents, iron salts, tranquilizers, and vitamins. There are many reports in the literature regarding the reasons of micro encapsulation of drugs and related chemicals. The osmotic tablet

The oral osmotic tablet is also a relatively recent addition to sustained-release tablet technology. This device consists of a core tablet & a semi permeable coating with a hole, produced by a laser beam, through which the drug exists. The product operates on the principle of osmotic pressure, which develops us gastrointestinal fluids permeate the semi permeable membrane & reach the core. These fluids dissolve the drug contained in the core & the osmotic pressure forces (or pumps) the drug solution out of the delivery orifice. Gel forming hydrocolloids

Roche's recent produce 'Valueless' is based on this new technology. Capsules are filled with a dry mixture of drug & hydrocolloids. Upon dissolution of the capsule shell, the gastric fluids swell. The outermost hydrocolloid forms a gelatinous mass which acts as a barrier, preventing further penetration of gastric fluids. Initially, only the outer portion forms a gel & the center remains dry. The gelatinous erodes, exposing the next inner portion of hydrocolloid to the gastric fluid, with subsequent formation of a new barrier layer. The process continuously releases the drug as each gelatinous layer continues to erode & a new layer forms. The gelatinous mass formed on contact with gastric fluid has a low density & therefore its gastric transit time is prolonged. Environmentally responsive system

It is as also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. Swelling-controlled release systems are initially dry and, when placed in the body will absorb water or other body fluids and swell. The swelling increases the aqueous solvent content within the foundation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. Examples of these types of devices are shown in Figures 1.3 and 1.4 for reservoir and matrix systems, respectively. Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and at equilibrium, typically comprise 60-90% fluid and only 10-30% polymer.

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Figure 1.4: Drug deliveries from (a) reservoir and (b) matrix swelling-controlled release system

One of the most remarkable, and useful, features of a polymer's swelling ability manifests itself when that swelling can be triggered by a change in the environment surrounding the delivery system. Upon the polymer, the environmental change can involve pH, temperature, or ionic strength, and the system can either shrink or swell upon a change in any of these environmental factors. A number of these environmentally sensitive or "intelligent" hydrogel materials are listed in Table 1.2. For most of these polymers, the structural changes are reversible and repeatable upon additional changes in the external environment. The diagrams in Figure 1.4 illustrate the basic changes in structure of these sensitive systems. Once again, for this type of system, the drug release is accomplished only when the polymer swells. Because many of the potentially most useful pH-sensitive polymers swell at high pH values and collapse at low pH values, the triggered drug delivery occurs upon an increase in the pH of the environment. Such materials are idea for systems such as oral delivery, in which the drug is not released at low pH values in the stomach but rather at high pH values in the upper small intestine.

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Figure 1.5: Drug delivery from environmentally sensitive release system

1.3.9. Methods and mechanisms of sustaining drug action:

- Diffusional systems
- Reservoir devices
- Matrix devices
- Dissolution controlled systems
- Encapsulation
- Matrix
- Water penetration controlled systems
- Osmotically controlled
- Swelling controlled
- Chemically controlled systems
- Bioerodible systems
- Drug covalently linked with polymer
- Hydrogels
- Chemically controlled
- Swelling controlled
- Diffusion controlled
- Environment responsive
- Ion-exchange resins
- Cationic exchange
- Anionic exchange Diffusional systems

Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert water insoluble membrane barrier.

There are basically two types of diffusion devices.

(I) Reservoir devices
(II) Matrix devices

- Reservoir Devices:

Reservoir devices are those in which a core of drug is surrounded by polymeric membrane. The nature of membrane determines the rate of release of drug from the system.

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Figure 1.6: Polymeric membrane controls the release of drug from the device

The process of diffusion is generally described by a series of equations governed by Fick’s first law of diffusion.

J = - D (dc/dx) --------------------------(1)


J= Flux of drug across the membrane given in unit of amount / area-time

D = Diffusion coefficient of drug in membrane in units of area / time. This is a reflection of the drug molecule’s ability to diffuse through the solvent and is dependent on molecular size and charge.

dc/dx = Rate of change in concentration c relative to a distance x in themembrane.

The law states that amount of drug passing across a unit area, is proportional to the concentration difference across that plane.


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