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  IN THIS Article
 ::  1. bioavailability
 ::  2. drug-delivery...
 ::  Conclusions
 ::  Acknowledgments
 ::  References

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Year : 1992  |  Volume : 38  |  Issue : 3  |  Page : 130-4

Bio-availability and drug delivery systems: clinical perspective.

Hindustan Ciba-Geigy Limited, Bombay, Maharashtra.

Correspondence Address:
A D Bhatt
Hindustan Ciba-Geigy Limited, Bombay, Maharashtra.

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Source of Support: None, Conflict of Interest: None

PMID: 0001303414

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Keywords: Biological Availability, Chemistry, Pharmaceutical, Drug Delivery Systems, Human, Intestinal Absorption,

How to cite this article:
Bhatt A D, Vaidya A B. Bio-availability and drug delivery systems: clinical perspective. J Postgrad Med 1992;38:130

How to cite this URL:
Bhatt A D, Vaidya A B. Bio-availability and drug delivery systems: clinical perspective. J Postgrad Med [serial online] 1992 [cited 2023 May 30];38:130. Available from:

From disparate origins the interest in medicinal value of synthetic compounds, elucidation of the mechanism of action by experiments in animals and man and understanding of pathophysiological basis of disease-clinical pharmacology has emerged as a discipline. Amongst the many aspects of clinical pharmacology, pharmacokinetics did attract attention disproportionate to its importance because of the ability to make precise measurements of drug concentrations in biological fluids using refined methodology[1]. The plethora of articles on new techniques and measurements of drugs in different body fluids and different populations have led to what is called “pharmacokinetisation” of the discipline. The perspective of a clinical pharmacologist, whose opinions and conclusions should be of critical importance to prescribers and regulatory agencies[2] is more often biased towards metabolism of drugs or on quantitative aspects and development of biomathematical models[3]. The stress on basic science has led to an increasing gap between rational therapeutics and vast pharmacological knowledge. In such a situation, a clinician has to develop his/her own perspective of the pharmacokinetic process and its newer applications to drug delivery systems[4]. As opposed to the pharmaceutics and pharmacokinetics, the clinician's perspective is usually oriented to understanding and improving the patient's overall response to a drug[3]. The article will discuss the issues of bioavailability and drug delivery systems from a clinical perspective.

  ::   1. bioavailability Top

Although the concept of bioavailability was initially introduced by Oser et al in 1945, its problem has only recently been recognised and discussed, as a result of controversies involving chloramphenicol, digoxin and phenytoin[4],[5],[6]. A change in formulation caused decreased bioavailability of digoxin in Britain[5] and phenytoin intoxication in Australia[6]. In 1966, FDA found that of 4000 formulations available in USA, more than 300 were ineffective[4]. The availability of over 45,000 formulations of 5,000 drugs in India[7], the recent interest in cheap generic formulations[8],[9] and availability of special long acting formulations[4],[5],[6],[7],[8],[9],[10] have made it imperative for the physician to consider and understand the influence of bioavailability on the therapeutic decisions.

Bioavailability is defined as the fraction of a dose reaching the systemic circulation as unchanged drug following administration by any route other than intravenous[11]. The term absolute bioavailability means that the bioavailability of a given dose forms is compared with the intravenous form. However, in practice, it is often only possible to compare two other forms, e.g. two tablets of different salts. This provides data referred to as relative bioavailability[3]. When the bioavailability of different preparations, salts or forms of a drug are compared at the same molar dose under similar experimental conditions and are found to be same the drugs are said to be bioequivalent. Some of the clinically important aspects are discussed below.

Bio-analytic considerations: The correct evaluation of bioavailability can only be achieved if accurate analytic data are obtained. Significant error may be introduced into pharmacokinetic data evaluation and interpretation if an imprecise or inaccurate method is employed. Careful scrutiny of the drug stability, assay sensitivity, selectivity, recovery, linearity, precision and accuracy is necessary for proper interpretation of data[12]. Newer methods e.g. high performance liquid chromatography (HPLC) are preferred over older s pectro photometry, as the former are more specific and sensitive. However, even among the recent methods, there could be variations affecting estimation. In uremic patients, some interference has been reported in phenytoin estimation with the EMIT technique, probably as a result of accumulation of phenytoin metabolites[13]. An improper blood collection can result in spuriously low plasma propranolol concentrations[14]. These issues might appear trivial to a physician. Inadequate quality control of laboratories is a common and worldwide phenomenon[15]. Unless the collection, transport and analysis of drug samples are done properly, clinical interpretation of bioavailability is likely to be faulty.

Assessment of bioavailability: Several approaches have been used to assess bioavailability[5]. Area under the concentration time curve (AUC) is generally employed to judge completeness of absorption. Quantitation of rate of absorption which is important for drugs like analgesics or drugs used in psychopharmacology[16] is measured by peak plasma concentration (Cmax) and time to peak concentration (Tmax). Estimation of rate of absorption requires frequent plasma sampling till a peak is reached. Higher values of Cmax coincident with lower values of Tmax generally indicate rapid absorption. For chronically administered drugs e.g. digoxin, the emphasis is on completions, rather than rate of absorption[5]. Besides, for chronically administered drug steady state plasma concentration (Css) is the clinically most relevant value[5]. However, steady state data can be obtained only through relatively expensive and long studies[5],[9]. For these reasons, single dose bioavailability studies are performed most commonly and provide useful data if there is good correlation between 5 single dose and chronic dosage studies, e.g. digoxin.

Factors affecting bioavailability: Bioavailability of a drug may be affected by many factors, the most important of which are formulation and physiochemical characteristics of drug[3]. A change of excepient led to an outbreak of phenytoin toxicity due to increased bioavailability. Differences in bioavailability of carbamazepine brands are reported[17] and a change of brand with good bioavailability to one with uncertain bioavailability can precipitate seizures in a controlled epileptic[18]. In-vitro dissolution data may not always predict how the drug will behave in humans[3]. Hence, it is necessary to have comparative bioavailability of conventional as well as sustained release formulations, e.g. theophylline[19]. The size and shape of tablets can influence esophageal transit[20]. The tablets when taken in supine position are known to get stuck in lower oesophagus[20].

Drug absorption can be influenced by a variety of gastrointestinal conditions[11]. Rapid intestinal transit due to diarrhoea (common problem in India) may inhibit drug absorption. Pregnancy has occurred after the use of oral contraceptives during a period of diarrhoea[11]. Metoclopramide, which accelerates gastric emptying, has been shown to increase rate of absorption of aspirin, levodopa, lithium and tetracycline[11]. In contrast, propantheline decreases the absorption rate of many drugs[11]. The changes in bioavailability after food may not be of clinical relevance when therapeutic effect is unaffected. e.g. sulphadiazine[21]. For drugs like chloroquine, increased bioavailability with food can improve compliance, by reducing gastric side-effects[22]. As food can also reduce or delay absorption[3],[11],[23] proper instructions regarding spacing of dose in relation to food are necessary for drugs like rifampicin, isoniazid. Temporal variations in drug absorption have been shown for benzodiazepines, e.g. triazolam[24].

Bioavailability of nitroglycerine and propranolol is affected by hepatic first pass and is likely to increase in liver dysfunction[23]. Giving nitroglycerine sublingually avoids the problems; however, the buccal absorption will be impaired if the mucosa is dry due to concomitant administration of imipramine or an anticholinergic.

In addition to these factors, changing absorption, bioavailability, especially at steady state will be affected by factors influencing distribution, metabolism and excretion. The list of such interacting host and external factors is vast[3],[25]. Genetic factors, variations in vascular, cardiorenal, hepatic or endocrine disorders can affect bioavailability and bioequivalence[9]. One or more such factors may need to be considered while assessing bioavailability in individual patient.

Bioavailability and therapeutic relevance: The relationship between bio-availability/bioequivalence and therapeutic effect is of vital importance to a clinician. The concentration at site of action-tissue receptors is most relevant to pharmacodynamics than the plasma concentration. A lipophilic drug like metoprolol is shown to be better distributed in ischaemic myocardium (site of action, of animals than atenolol and is also found to attenuate or delay the developing ischaemic process[26]. This would be difficult to establish if only plasma concentration - effect relationship is looked at. Tissues obtained during surgery e.g. tonsillectomy can be used for estimation of drug levels and extrapolating/establishing relationship to therapeutic situations[27]. For certain drugs, e.g. anticonvulsants, theophylline therapeutic plasma levels have been established and these will be useful in assessing therapeutic relevance of bioavailability problems. However, it should be remembered that these therapeutic concentrations might differ for different therapeutic effects, e.g. beta blockade vs. antihypertensive effect of propranolol[15]. Even for long acting preparations pharmacokinetic-dynamic correlation should be established[14].

With the availability of multiple formulations of a single drug, a change of formulation to a conventional or long acting is a common phenomenon at the prescriber, the patient or the chemist level. The regulatory agencies demand a comparison of in-vitro dissolution data and in-vivo bioavailability between a generic and a standard reference brand. The agencies accept a + 20% difference in rate and extent of absorption and consider the two drugs bioequivalent[8]. However, the question of paramount concern to physician is whether bioequivalents are therapeutic equivalents[2],[9],[28]. In 1988, a company manufacturing carbamazepine recalled more than 50 million tablets when they failed dissolution test after a change in bulk ingredient, leading to therapeutic failure[28]. Similar therapeutic problems are also reported for phenytoin, digoxin, aspirin, phenyl butazoi ne, levodopa and thyroid[29]. Koeh-Weser claims that there is no evidence to adopt any fixed figure from 10 to 50% as indicative of bioequivalence; he suggests consideration of inter-and intra-individual variations, therapeutic and toxic dose- response curves, therapeutic index, elimination kinetics, dosage schedule and disease being treated in judging therapeutic inequivalence[30]. An arbitrary rule of 20% deviation applied to furosemide could produce a variation of 64 mg in a patient receiving 160 mg In other words; the daily dose can vary from 138 mg to 192 mg. In other words the daily dose can vary from 128 mg to 192 mg among generics and could still be within the allowable range[9]. Moreover, the dose variation could be remarkable when a brand which is -20% compared to reference drug is changed to another one with +20% next time. These issues have led to opposition of mandatory generic substitution in USA[9].

For a practicing clinician, it is safer to remember the importance of therapeutic inequivalence especially in "critical patients" (very old, very young, suffering from multiple disease, on multiple drugs) "critical diseases" (intercurrent illness in chronic disorders, e.g. epilepsy) and "critical drugs"[9]. (narrow therapeutic index. e.g. phenytoin).

  ::   2. drug-delivery systems Top

Modern pharmacologic research began at the end of the 19th century. Since then the pharmaceutical industry has made enormous efforts to synthesise new drugs and relatively modest efforts to utilise available technology to improve drug administration[4]. However, the new drug development has not remained productive because of increasing stringent government regulations, fierce competition from companies involved in research on similar drugs and increasing cost of research and development[10]. This dilemma has called for shift in emphasis from constant search for new drugs in traditional random, hit-or-miss way, to make clinically established drugs do their therapeutic best[10]. It has been the pioneering contribution of Zaffaroni and his colleagues[31] to recognise this need and to develop the concept of programmed or rate-controlled drug administration called "therapeutic systems."

Potential benefits: Controlled release drug administration means not only prolonged duration of drug delivery as in sustained release, but also implies predictability and reproducibility of drug release kinetics[10]. A good drug delivery system is expected to provide efficient delivery to target tissue, steady therapeutic concentrations and minimising exposure to nontarget tissue. It is also possible to reduce the dose or frequency and to improve compliance[10]. The systems can enhance the therapeutic ratio and regimens of many existing agents that would not be useful in conventional dosage forms because of their toxicity or short half-lives[4]. In this manner, a drug treatment is achieved whose criteria are better efficacy, selectivity and safety[4].

Structure and mechanism: The therapeutic efficacy of a drug, under clinical conditions, is not simply a function of its intrinsic pharmacologic activity. Of equal importance is the path the drug molecules take in ytting from site of administration to site of action[10]. The bioavailability of pharmacologically active substance to the site of absorption and from there to the availability at target site of drug action, are important determinants. To maintain optimum bioavailability over a prescribed period of treatment, it is important that the fraction of drug dose released from a controlled release product should be sufficiently large to make up for the amount of active drug metabolished and/or excreted from the body during the same period of time[10].

A therapeutic system consists of four componentsdrug, drug delivery module, platform and therapeutic program[4]. A drug with a short half-life is usually selected, so that the time course of plasmalbody fluid concentration is closely related to the amount of drug released. When a therapeutic programme system is removed from body, the concentration of a drug in plasma and tissues falls rapidly from a therapeutically active to an inactive level[4]. The drug delivery module is responsible for releasing the drug according to a predetermined therapeutic programme. All the elements of a therapeutic system are integrated into the platform to form the functional unit, which comes into contact with body. The platform must be reliable and safe and easy for doctor and patient to use. The platform must not interfere with the patient's activities to interact with or affect the drug[4].

In contrast to conventional dosage forms where only the drug content is mentioned, the therapeutic programme in a therapeutic system is well defined and expressed as the rate of release of one or several medicines per time unit and for the total period of drug release. For example, Ocular Therapeutic System Pilocarpine for glaucoma has a functional span of 7 days and contains total of 5.0 mg pilocarpine, 20 mcg of which is given off per hour; in 7 days total of 3.4 mg of the drug is released.

Characteristically, all conventional dosage forms, except continuous iv infusion, release drugs largely according to the first-order kinetics. This produces alternating high and low concentrations and the optimal therapeutic level is only briefly present. In contrast, the therapeutic systems may release the drug at a constant rate (zero order) or at a predictably constant declining rate (first order) for a certain time period. The result is isonemic condition, Le a uniform concentration of drug in plasma and tissue[4].

Type of therapeutic system: Therapeutic systems are available for systemic use and local use. For systemic use, infusion pumps, transdermal systems, oral and rectal systems have been designed. Infusion pumps are promising for administering anticoagulants, antibiotics for chronic kidney disease, as well as for cytostatic therapy for various malignancies[4]. The most widely used have been transdermal therapeutic systems[32], scopolamine for motion sickness[33], nitroglycerin for angina pectoris[34], clonidine for hypertension[35] and estrogen for menopausal syndrome [32]. The oral systems-Oral Osmotic Therapeutic System (OROS) are available for metoprolol for hypertension, indomethacin for rheumatism and acetazolamide for glaucoma[4]. The systems for local use are ocusert-pilocarpine ophthalmic system for glaucoma[4],[10] and progestasert uterine system for contraception[4],[10] etc.

Pharmacokinetics and pharmacodynamics: It is a popular practice use in-vitro or computer assisted to models for determining optimal performance characteristics for a drug system's rate of release[36]. There is however little or no correlation in most cases between in-vitro dissolution rates and drug behaviour in humans[36]. Known drug entities when formulated in a new pharmaceutical dosage form may have a different bioavailability and pharmacodynamic effect than the reference product. The first test for a new drug delivery system is the blood level data of active drug and its metabolites found after administration of simple doses of the new formulation to human volunteers[36].

In order to have a good in vitro-in vivo correlation, the in vitro test must adequately simulate the biologic milieu; such in vitro conditions can be described as bioanalogues. Development of any successful therapeutic system requires extensive pharmacokinetic studies and investigations of bio-availability[37], Comparative bio-availability of similar formulations e.g transdermal nitroglycerine of four different types[37] is also necessary. The relationship between pharmacodynamic activity and plasma level over the entire duration of release of active drug has also to be established[34]. This should also be followed by efficacy studies to confirm the expected benefits of improved efficacy, long duration of action, better compliance and reduced side-effects[4],[10],[38]. Usually, regulatory approval of a controlled release product requires demonstration of bio-availability, controlled release characteristics, reproductibility of in vivo performance and evidence of clinical efficacy and safety[10]. Only such stringent guidelines can provide safe and effective drug delivery systems.

Balanced outlook: The new therapeutic systems have provided an opportunity to maximise efficacy, selectivity and safety. It has been possible to match drug release rate with expected therapeutic activity[34]. However, the unwanted effects seen with conventional formulations are not totally avoided. OROS indomethacin has been withdrawn due to severe and fatal GI side-effects[4]. Transdermal scopolamine can cause not only the more common anticholinergic side-effects but (rarely) psychosis[32],[33]. Severe contact dermatitis has been reported after the use of nitroglycerine patches[32]. Local and generalised skin reactions are known with transdermal clonidine[35]. Plasma level fails much more slowly after removal of clonidine patch than after discontinuing oral treatment and is clearly a disadvantage when the drug needs to be discontinued[35]. An interesting case of “person-to-person transfer” has recently been reported in which accidental application of a clonidine patch to an infant proved to be toxic[32]. Another interesting phenomenon is tolerance to constant nitroglycerine levels [32],[38]. The current recommendation is to apply the nitroglycerine patch for 12 hours only[38].

Despite these problems and rather stringent physiochemcial and pharmacodynamic requirements, the transdermal systems are already gaining ground. Patient's reference for nitroderm TTS was significantly better than their preference for oral nitrates[38]. The unit cost of nitroglycerine patch appears higher than oral therapy. However, the cost/benefit analysis considering the overall costs of consultations, technical services, other concomitant antianginal therapies showed that Nitroderm TTS led to a reduction in cost of 23% per patient per month[4].

Today, there is a large gap in the prospects for diagnostic vs therapeutic developments. Newer therapeutic systems can help to match the diagnostic accomplishments. These systems must be recognised as therapeutic milestone, which may open a new era of drug treatment. Attempt to develop indigenous and superior drug delivery systems for old drugs must be applauded. However, theory will continue to need empirical substitution by clinical experience, which provides the final verdict on safety and efficacy[32].

  ::   Conclusions Top

The article has considered the two important aspects of drugs (1) bioavailability and (2) drug delivery systems from a clinician's perspective. The focus of discussion are the aspects which are necessary for a clinician to understand, to interpret and to judge with an objective to utilise the knowledge in improving therapeutics and patient care.

  ::   Acknowledgments Top

Published with permission from Editors NA Kshirsagar and KC Gupta of "Selected Topics in Clinical Pharmacology", 1990, published by Indian Council of Medical Research.

 :: References Top

1. Breckenridge A, Orme MLE. Principle of clinical pharmacology and therapeutics. In: Weatheral DJ, Lendingham JGG, Warrell DA, editors. Oxford Text Book of Medicine, 1st ed. Oxford: Oxford University Press; 1984; 7:3-7, 18.  Back to cited text no. 1    
2.Dettelbach H. A time to speak out on bioequivalence and therapeutic equivalence. J Clin Pharmacol 1986; 26:307-308.  Back to cited text no. 2    
3.Spiker B. Guide to Clinical Interpretation of Data. New York: Raven Press; 1986.  Back to cited text no. 3    
4.Heilmann K. Therapeutic Systems Rate Controlled Drug Delivery: Concept and Development. 2nd ed. Stuttgart: Georg Thieme Verlag; 1984.  Back to cited text no. 4    
5.Greenblatt DJ, Smith TW, Koch Wester J. Bioavailability of drugs: The digoxin dilemma. Clin Pharmacokinetics 1976; 1:36-51.  Back to cited text no. 5    
6.Bochner F, Hooper WD, Tyrer JH, Eadie MJ. Factors involved in an outbreak of phenytoin intoxication. J Neuro Sci 1972; 16:481-487.  Back to cited text no. 6    
7.Scrip 1988; No. 1292:19.  Back to cited text no. 7    
8.Nightingale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA 1987; 258:1200-1204.   Back to cited text no. 8    
9.Lamy PP. Generic equivalents: Issues and concerns J 24. Clin Pharmacol 1986; 26:309-16.  Back to cited text no. 9    
10.Chien YW. Novel Drug Delivery System. New York: Marcel Dekker Inc; 1982.  Back to cited text no. 10    
11.Benet LZ, Massoud N, Gambertoglio JC. Pharmacokinetic Basis for Drug Treatment. New York: Raven Press; 1984.  Back to cited text no. 11    
12.Pachla LA, Scott WD, Reynold DL. Bioanalytic considerations for pharmacokinetic and biopharmaceutic studies. J Clin Pharmacol. 1986; 26:332-335.  Back to cited text no. 12    
13.Boreus LO. The role of therapeutic drug monitoring in children. Clin Pharmacokinetics 1989; 17:45-125.   Back to cited text no. 13    
14.Marino MR, Dey M, Garg D. Pharmacokinetics and pharmacodynamics of long acting propranolol 60 mg capsules. A comparative evaluation J Clin Pharmacol 1987; 27:885-891.  Back to cited text no. 14    
15.Koch-Weser J. Serum drug concentrations in clinical perspective. In: Richens A, Marks V, editors. Therapeutic Drug Monitoring. Edinburgh: Churchill Livingstone; 1987, pp 1-22.  Back to cited text no. 15    
16.Greenblatt DJ, Shader RJ. Drug absorption rate. A critical component of bioequivalence assessment in psychopharmacology. J Clin Pharmacol 1987; 27:85-86.  Back to cited text no. 16    
17.Bhatia SC, Bhatt AD, Bakshi RJ,. Comparative bioavailability with two brands of carbamazepine, Tegretol and Mazetol in healthy volunteers. J Assoc Phys Ind 1988; 36:611-612.  Back to cited text no. 17    
18.Sachdeo RC, Belendiuk G. Generic versus branded carbamazepine. Lancet 1987; 1:1432.  Back to cited text no. 18    
19.Hurwitz A, Karim A, Burns TS. Theophylline absorption from sustained release products. Comparative steady state bioavailabhty of one daily Theo-dur. Theo-24 and Uniphyl. J Clin Pharmacol 1987; 27:855-861.  Back to cited text no. 19    
20.Channer KS, Virjee JP. The effect of size and shape of tablets on their esophageal transit. J Clin Pharmacol 1986; 26:141-146.  Back to cited text no. 20    
21.Ghosh SS, Bhatt AD, Bhatia SC. Effect of food on the absorption and pharmacokinetics of sulphadi-azine and trimethoprim after administration of Aubril To health human volunteers. J Assoc Phys Ind 1988; 36:607-610.  Back to cited text no. 21    
22.Tulpule A, Krishnaswamy K. Effect of food on bioavailability of chloroquine. Europ J Clin Pharmacol 1982; 23: 271-273.  Back to cited text no. 22    
23.Bhatt AD, Vaidya AB. Pharmacokinetics and practising physican. Drugs & Therapeutics. 1986; 2:2-3.  Back to cited text no. 23    
24.Smith RB, Krobath PD, Paul PJ. Temporal variation in triazolam pharmacokinetics and pharmacodynamics after oral administration. J Clin Pharmacol 1986; 26:120-124.  Back to cited text no. 24    
25.Vessell ES. On the significance of host factors that affect drug disposition. Clin Pharmacol Ther 1982; 31:1-7.  Back to cited text no. 25    
26.Ablad B. Abrahmsson T, Adler G. Cardiac antirschaemic effect of metoprolol: role of P Blockade within the ischaemic region. J Cardiovasc Pharmacol 1987; 10:S117-125.  Back to cited text no. 26    
27.Ghosh SS, Bhatt Ad, Sheode J. Tonsil levels of trimethoprim and sulphadiazine after administration of cotrimazine. Therapeutics and Drugs. 1989; 6:10-111.  Back to cited text no. 27    
28.Rheinstein PH. Therapeutic inequivalence. Drug Safety 1990; 5:S114-119.  Back to cited text no. 28    
29.Azarnoff DL, Huffman DH. Therapeutic implications of bioavaiiability. Ann Rev Pharmacol Toxical 1976; 16:53-67.  Back to cited text no. 29    
30.Koch-Weser J. Bioavailability of drugs N Engl J Med 1974; 291:503-506.  Back to cited text no. 30    
31.Zaffaroni A. Towards a new concept in drug administration Pharm J 1979; 205:400-402.  Back to cited text no. 31    
32.Lasagna L, Greenblatt DS. More than skin deep trasdermal drug delivery systems N Engl J Med 1986; 314:1638-1639.  Back to cited text no. 32    
33.Clissold SP, Heel RC. Transdermal Hyoscine (Scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985; 29:189-207.  Back to cited text no. 33    
34.Muller P, Imhof PR, Burkart F, Chu L-C, Geradin A. Human pharmacological studies of a new transdermal system containing nitroglycerin. Eur J Clin Pharmacol 1982; 22:473-480.  Back to cited text no. 34    
35.Anonymous Transdermmal anti hypertensive drugs (Editorial). Lancet 1987; 1:79-80.  Back to cited text no. 35    
36.Dunn J. Controlled release formulations of propranolol and verapamil. J Clin Pharmacol 1987; 27:22-31.  Back to cited text no. 36    
37.Ridout G, Santus GC, Guy RH. Pharmacokinetic considerations in the use of newer transdermal formulations. Clin Pharmacokinetics 1988; 15:114-131.  Back to cited text no. 37    
38.Brady EM, Gold OG, Rosenback HJ. Antiangianal efficacy of trandermal nitroglycerin and oral nitrates: the ACTION study. Cardiovasc Rev Resp 1988; 10:40-44.   Back to cited text no. 38    


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