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Oral prolonged-action drugs
J. chron. Dis. 1963, Vol. 16, pp. 1039-1041. Pergamon Press Ltd. Printed in Great Britain
Editorial
ORAL PROLONGED-ACTION
DRUGS
LEO E. HOLLISTER, M.D.*’ Veterans Administration Hospital, Palo Alto, California (Received
8 April
1963)
patients, including physicians, have difficulty following an exact dosage schedule. In fact, about the only thing one can really be sure of when prescribing a drug is that it will not be taken exactly as prescribed. Any preparation which would simplify dosage by requiring fewer doses would be welcome. Simplicity of dosage is only one advantage claimed for oral prolonged-action drugs. Another is that a sustained therapeutic level of drug is attained, avoiding peaks of concentration with unwanted side-effects or valleys with diminished therapeutic effects. Less than a decade after the introduction of the first prolonged-action drug for oral use, the sales volume for such preparations in 1959 represented 4 per cent of the pharmaceutical market [l]. Approximately 180 different products were available in oral prolonged-action form, two-thirds of all anorectics and 40 per cent of all anti-histaminics being of this type. Further proliferation of such preparations in the past three years indicates a considerable increase in present estimates of use. The various types of preparations are also increasing. They may take the form of tablets-within-tablets (repeat action), slowly disintegrating tablets, pellets in capsules, special slowly-dissolving salts of drugs, or drugs embedded in ion-exchange or inert plastic matrices. Almost without exception, prolonged-action dose forms are more expensive than the same doses in capsule or tablet-form. To begin with, some situations obviously make the use of prolonged-action medications irrational. If the drug is intrinsically long-acting (many barbiturates, phenothiazines, reserpine, thyroid extract, digitalis glycosides), why try to improve upon the natural pharmacology ? If immediacy of effect is desired, as with antiangina1 agents, a prolonged-action form might defeat this aim. A similar situation exists where the dose of drug lies within a narrow range and rapid reversal of effects might be desirable, as with anticoagulants or ganglionic blocking agents. If tolerance is likely ta be a factor, as with nitrates or ephedrine, acute doses as needed would be preferable, since sustained levels of many seem to facilitate the development of tolerance. Finally, one would hesitate to use prolonged-action forms containing 2-4 times the usual single dose of a drug if this amount might be dangerous if absorbed immediately. Until recently, comparatively little investigative work has been done to verify claims made for oral prolonged-action medications, a lack which has been decried MOST
.~_____ *Associate
Chief of Staff. 1039
1040
LEO. E. HOLLISTER
editorially [2, 31. Quantitative studies by the Canadian Food and Drug Laboratories have established that for complete availability, tablets should dissolve in vitro in less than 60 minutes, that physiologic availability is best measured by urinary output of drug over timed periods and that by measuring rates of urinary excretion one can demonstrate the presence or absence of prolonged action [4-61. With so little time for effective absorption of drug, any preparation delaying this process might very likely result in a smaller actual dose of the drug being absorbed than predicted from the total amount present in the capsule or tablet. It is generally agreed that in vitro tests of prolonged release of drug are completely inadequate for testing these preparations. Clinical studies have usually been limited to uncontrolled assessments of efficacy. While therapeutic results from prolonged-action preparations have often been reported to be favorable, the lack of comparison with conventional forms of the drugs or accounting for placebo effects has provided little verification for their claimed advantages. Even attempts to use quantitative methods in clinical studies have consistently fallen into the same error: Single large doses of the prolongedaction form have been compared with’divided doses of the same drug in conventional form. Thus, studies of trimeprazine using both chemical determinations of urinary excretion and determinations based on Y5 activity in blood and urine revealed that a single dose of the prolonged-action form was equivalent to three doses of the tableted form given at 4-hour intervals [7]. A similar result was obtained for phenylpropylamine, based on urinary excretion [8]. Because with most drugs a larger dose acts over a longer period than a smaller dose, it has been pointed out that valid comparison requires that identical amounts of each form of the drug be administered in the same way [3]. Using the technique of comparing equal single doses,of drugs both as prolongedaction preparations and conventional tablet or capsule forms, I have studied a number of drugs using quantitative clinical and chemical measurements. Meprobamate was administered in single 800 mg doses as compressed tablets and as two kinds of prolonged-action capsules to 16 volunteer subjects. Plasma levels of drug were significantly higher 8 hr and 12 hr later following both prolonged-action capsules. Urinary excretion of the drug also confirmed the slight prolonged-action suggested by plasma levels. However, the differences were minor and of little importance as judged by clinical effects [93. A similar study of two phenothiazine derivatives failed to demonstrate prolonged-action of either preparation (capsuled pellets in the case of chlorpromazine, tablets with retarding agents in the case of Both of these phenothiazine derivatives have an intrinsically thioridazine). prolonged-action regardless of formulation. Further, the evidence is suggestive in the case of chlorpromazine and definite in the case of thioridazine that prolongedaction formulations are a less efficient method of administering the dose as judged by total urinary recovery [lo]. Essentially similar results have been found in a study of sodium pentobarbital [ll]. In the latter study, two separate trials of each preparation were made in the same subjects. Oddly, a comparison of the two trials indicated that when conventional capsules were given, serum levels of drug were significantly less on the second trial at 4 hr, 8 hr and 24 hr than on the first trial. These data suggest considerable variability of drug absorption in the same subject when given successive doses of the same preparation, so that intra-
Editorial
1041
individual variability of absorption may overshadow any differences due to pharmaceutical formulation. It is apparent that some prolonged-action preparations available for clinical use do in fact what they purport to do. One would hope that in the future all prolonged-action preparations would be routinely subjected to quantitative in viva studies prior to being placed on the market so that clinicians could know with some assurance what to expect from them. In any case, the wise clinician would do well to question the need for such preparations for specific drugs, to consider their relative advantages and disadvantages, and to weigh the importance of their greater expense to the patient as a consumer.
1.
2. 3. 4. 5. 6. 7. 8.
REFERENCES LAZARUS,J. and COOPER, _I.: Absorption, testing and clinical evaluation of oral prolongedaction drugs, J. phcrrm. Sci. 50,715, 1961. EDITORIAL: Drugs with delayed and prolonged action, New Engl. 1. Med. 254, 963, 1956. DRUXXEDT, C.: Oral medication with preparations for prolonged action, 1. Amer. med. Ass. 168, 1652, 1958. CAMPBELL, J., CHAPMAN, D. and CHAT~EN, L.: Timed disintegration medication: need for more quantitative criteria, Canad. med. Ass. 1. 77,602, 1957. CHAPMAN, D., CHASTEN, L. and CAMPBELL, .I.: Physiological availability of drugs in tablets, Canad. med. Ass. J. 76, 102, 1957. CAMPBELL,J., NELSON, E. and CHAPMAN,D.: Criteria for oral sustained release medication with particular reference to amphetamine, Canad. med. Ass. J. 81, 15, 1959. ROSEN, E. and SWINTOSKY,J.: Preparation of an S3” labelled trimeprazine tartrate sustained action product and its evaluation in man, 1. Pharm. Pharmacol. 12, 237~. 1960. HEIMLICH, K., MACDONNELL,D., FLANAGAN, T. and O’BRIEN, P. : Evaluation of a sustained release form of phenylpropanolamine hydrochloride by urinary excretion studies, 1. pharm.
9.
Sci. 50,232,
1961.
HOLLISTER, L.: Studies of delayed-action medication. 1. Meprobamate administered as compressed tablets and as two delayed-action capsules, New Engl. J. Med. 266, 281, 1962. 10. HOLLISTER, L.: Studies of prolonged-action medication. II. Two phenothiazine tranquilizers (thioridazine and chlorpromazine) administered as coated tablets and prolongedaction preparations, Cur-r. ther. Res. 4,471, 1962. 11. HOLLISTER, L., KANT~R, S. and CLYDE, D.: Studies of prolonged-action medication. 111. Sodium pentobarbital in prolonged-action ‘gradumets’ compared with conventional capsules. Serum levels of drug and clinical effects following acute doses, C’lin. Pharmacol. Ther. In press.
Editorial
ORAL PROLONGED-ACTION
DRUGS
LEO E. HOLLISTER, M.D.*’ Veterans Administration Hospital, Palo Alto, California (Received
8 April
1963)
patients, including physicians, have difficulty following an exact dosage schedule. In fact, about the only thing one can really be sure of when prescribing a drug is that it will not be taken exactly as prescribed. Any preparation which would simplify dosage by requiring fewer doses would be welcome. Simplicity of dosage is only one advantage claimed for oral prolonged-action drugs. Another is that a sustained therapeutic level of drug is attained, avoiding peaks of concentration with unwanted side-effects or valleys with diminished therapeutic effects. Less than a decade after the introduction of the first prolonged-action drug for oral use, the sales volume for such preparations in 1959 represented 4 per cent of the pharmaceutical market [l]. Approximately 180 different products were available in oral prolonged-action form, two-thirds of all anorectics and 40 per cent of all anti-histaminics being of this type. Further proliferation of such preparations in the past three years indicates a considerable increase in present estimates of use. The various types of preparations are also increasing. They may take the form of tablets-within-tablets (repeat action), slowly disintegrating tablets, pellets in capsules, special slowly-dissolving salts of drugs, or drugs embedded in ion-exchange or inert plastic matrices. Almost without exception, prolonged-action dose forms are more expensive than the same doses in capsule or tablet-form. To begin with, some situations obviously make the use of prolonged-action medications irrational. If the drug is intrinsically long-acting (many barbiturates, phenothiazines, reserpine, thyroid extract, digitalis glycosides), why try to improve upon the natural pharmacology ? If immediacy of effect is desired, as with antiangina1 agents, a prolonged-action form might defeat this aim. A similar situation exists where the dose of drug lies within a narrow range and rapid reversal of effects might be desirable, as with anticoagulants or ganglionic blocking agents. If tolerance is likely ta be a factor, as with nitrates or ephedrine, acute doses as needed would be preferable, since sustained levels of many seem to facilitate the development of tolerance. Finally, one would hesitate to use prolonged-action forms containing 2-4 times the usual single dose of a drug if this amount might be dangerous if absorbed immediately. Until recently, comparatively little investigative work has been done to verify claims made for oral prolonged-action medications, a lack which has been decried MOST
.~_____ *Associate
Chief of Staff. 1039
1040
LEO. E. HOLLISTER
editorially [2, 31. Quantitative studies by the Canadian Food and Drug Laboratories have established that for complete availability, tablets should dissolve in vitro in less than 60 minutes, that physiologic availability is best measured by urinary output of drug over timed periods and that by measuring rates of urinary excretion one can demonstrate the presence or absence of prolonged action [4-61. With so little time for effective absorption of drug, any preparation delaying this process might very likely result in a smaller actual dose of the drug being absorbed than predicted from the total amount present in the capsule or tablet. It is generally agreed that in vitro tests of prolonged release of drug are completely inadequate for testing these preparations. Clinical studies have usually been limited to uncontrolled assessments of efficacy. While therapeutic results from prolonged-action preparations have often been reported to be favorable, the lack of comparison with conventional forms of the drugs or accounting for placebo effects has provided little verification for their claimed advantages. Even attempts to use quantitative methods in clinical studies have consistently fallen into the same error: Single large doses of the prolongedaction form have been compared with’divided doses of the same drug in conventional form. Thus, studies of trimeprazine using both chemical determinations of urinary excretion and determinations based on Y5 activity in blood and urine revealed that a single dose of the prolonged-action form was equivalent to three doses of the tableted form given at 4-hour intervals [7]. A similar result was obtained for phenylpropylamine, based on urinary excretion [8]. Because with most drugs a larger dose acts over a longer period than a smaller dose, it has been pointed out that valid comparison requires that identical amounts of each form of the drug be administered in the same way [3]. Using the technique of comparing equal single doses,of drugs both as prolongedaction preparations and conventional tablet or capsule forms, I have studied a number of drugs using quantitative clinical and chemical measurements. Meprobamate was administered in single 800 mg doses as compressed tablets and as two kinds of prolonged-action capsules to 16 volunteer subjects. Plasma levels of drug were significantly higher 8 hr and 12 hr later following both prolonged-action capsules. Urinary excretion of the drug also confirmed the slight prolonged-action suggested by plasma levels. However, the differences were minor and of little importance as judged by clinical effects [93. A similar study of two phenothiazine derivatives failed to demonstrate prolonged-action of either preparation (capsuled pellets in the case of chlorpromazine, tablets with retarding agents in the case of Both of these phenothiazine derivatives have an intrinsically thioridazine). prolonged-action regardless of formulation. Further, the evidence is suggestive in the case of chlorpromazine and definite in the case of thioridazine that prolongedaction formulations are a less efficient method of administering the dose as judged by total urinary recovery [lo]. Essentially similar results have been found in a study of sodium pentobarbital [ll]. In the latter study, two separate trials of each preparation were made in the same subjects. Oddly, a comparison of the two trials indicated that when conventional capsules were given, serum levels of drug were significantly less on the second trial at 4 hr, 8 hr and 24 hr than on the first trial. These data suggest considerable variability of drug absorption in the same subject when given successive doses of the same preparation, so that intra-
Editorial
1041
individual variability of absorption may overshadow any differences due to pharmaceutical formulation. It is apparent that some prolonged-action preparations available for clinical use do in fact what they purport to do. One would hope that in the future all prolonged-action preparations would be routinely subjected to quantitative in viva studies prior to being placed on the market so that clinicians could know with some assurance what to expect from them. In any case, the wise clinician would do well to question the need for such preparations for specific drugs, to consider their relative advantages and disadvantages, and to weigh the importance of their greater expense to the patient as a consumer.
1.
2. 3. 4. 5. 6. 7. 8.
REFERENCES LAZARUS,J. and COOPER, _I.: Absorption, testing and clinical evaluation of oral prolongedaction drugs, J. phcrrm. Sci. 50,715, 1961. EDITORIAL: Drugs with delayed and prolonged action, New Engl. 1. Med. 254, 963, 1956. DRUXXEDT, C.: Oral medication with preparations for prolonged action, 1. Amer. med. Ass. 168, 1652, 1958. CAMPBELL, J., CHAPMAN, D. and CHAT~EN, L.: Timed disintegration medication: need for more quantitative criteria, Canad. med. Ass. 1. 77,602, 1957. CHAPMAN, D., CHASTEN, L. and CAMPBELL, .I.: Physiological availability of drugs in tablets, Canad. med. Ass. J. 76, 102, 1957. CAMPBELL,J., NELSON, E. and CHAPMAN,D.: Criteria for oral sustained release medication with particular reference to amphetamine, Canad. med. Ass. J. 81, 15, 1959. ROSEN, E. and SWINTOSKY,J.: Preparation of an S3” labelled trimeprazine tartrate sustained action product and its evaluation in man, 1. Pharm. Pharmacol. 12, 237~. 1960. HEIMLICH, K., MACDONNELL,D., FLANAGAN, T. and O’BRIEN, P. : Evaluation of a sustained release form of phenylpropanolamine hydrochloride by urinary excretion studies, 1. pharm.
9.
Sci. 50,232,
1961.
HOLLISTER, L.: Studies of delayed-action medication. 1. Meprobamate administered as compressed tablets and as two delayed-action capsules, New Engl. J. Med. 266, 281, 1962. 10. HOLLISTER, L.: Studies of prolonged-action medication. II. Two phenothiazine tranquilizers (thioridazine and chlorpromazine) administered as coated tablets and prolongedaction preparations, Cur-r. ther. Res. 4,471, 1962. 11. HOLLISTER, L., KANT~R, S. and CLYDE, D.: Studies of prolonged-action medication. 111. Sodium pentobarbital in prolonged-action ‘gradumets’ compared with conventional capsules. Serum levels of drug and clinical effects following acute doses, C’lin. Pharmacol. Ther. In press.