Correspondence
`
`Case history of a pharmaceutical
`formulation failure
`To the Editor:
`The formulation of pharmacologically
`active substances ( drugs) into therapeuti-
`cally effective pharmaceutical dosage forms
`requires considerable scientific skill, one
`which is not shared equally by all manu-
`facturers. Consequently, certain pharma-
`ceutical dosage forms containing the same
`drug may differ appreciably in therapeutic
`efñcacy.4' 6' 9 Two and three years ago, re-
`ports from this and other laboratories di-
`rected attention to the lack of adequate
`physiologic availability (i.e., absorbability)
`of aspirin from a widely used enteric -
`coated tablet product produced by a major
`pharmaceutical manufacturer.', 8 In our
`own study, absorption of aspirin ranged
`from 0 to 25 per cent of the administered
`dose in 3 out of 4 subjects.8 The tablets
`were noted on occasion to appear intact
`in the stool and yielded poor therapeutic
`results.' Nevertheless,
`they passed the
`U.S.P. tablet disintegration test and con-
`tained the labeled amount of aspirin.8 Sig-
`nificantly, there was an indication that at
`least one other enteric- coated tablet prep-
`aration ( thyroid) made by the same manu-
`facturer was also clinically ineffective and
`that intact tablets were passed in the stool.'
`
`The manufacturer did not withdraw either
`product from the market, nor was there
`any apparent action by the Food and Drug
`Administration, despite the several adverse
`reports from different laboratories.
`The recent adoption by this manufac-
`turer of a tablet identification imprint for
`his products presented an opportunity to
`re- evaluate the physiologic availability of
`his enteric- coated aspirin tablets with the
`certainty that the particular tablets used
`in the study were of recent manufacture.
`They were obtained directly from a whole-
`sale house and there was no indication that
`they had been exposed to adverse storage
`conditions. The determination of physio-
`logic availability was carried out in G
`healthy male volunteers, 23 to 29 years
`old. The experimental design and methods
`were the same as in the previous study,8
`except that single tablets and 0.32 Gm.
`aspirin in solution were given. Results are
`summarized in Fig. 1 and show that ab-
`sorption occurred only 7 to 19.5 hours
`( average, 13.6 hours) after administration
`and that it was so slow as to be thera-
`peutically ineffective. After 24 hours an
`average of only 28 per cent (range, 2 to
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`888
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`Correspondence
`
`Clinical Pharmacology
`and Therapeutics
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`SUBJECT 3
`
`SUBJECT 4
`
`SUBJECT 6
`
`more than one hour and disintegrated
`within 20 to 25 minutes in simulated intes-
`tinal fluid ( U.S.P. limit, 125 minutes ).
`The results of this study illustrate sev-
`eral important but not generally appre-
`ciated facts which have bearing on the
`present controversy concerning generic vs.
`brand name prescribing:
`L The therapeutic efficacy of a pharma-
`ceutical product is a function not only of
`its active ingredient( s) but also of the de-
`sign and properties of the dosage form.
`2. Different
`pharmaceutical
`products
`containing the same kind and amount of
`drug may differ appreciably in efficacy.
`3. Ineffective ( improperly formulated)
`products are marketed occasionally ( the
`incidence presently being unknown due to
`lack of sufficient studies) by major "brand
`name" pharmaceutical manufacturers'', 6' e
`as well as by smaller companies specializ-
`ing in low cost generic products.
`(For
`other examples, see references 4, 6, and 9
`and 5, 7, and 11.)
`4. At present, the U.S.P. and N.F. do
`not provide suitable standards to assure
`the physiologic availability of the products
`listed in these compendia.10
`5. There is now at least one example of
`lack of appropriate action by a major phar-
`maceutical manufacturer as well as the
`Food and Drug Administration during
`more than two years after reports in the
`literature which demonstrated clearly the
`lack of adequate absorption and the result-
`ing therapeutic ineffectiveness of a clearly
`identified pharmaceutical product.
`Gerhard Levy, Pharm.D.
`Professor of Pharmaceutics
`William J. Jusko, B.S.
`Graduate Assistant
`Department of Pharmaceutics
`School of Pharmacy
`State University of New York at Buffalo
`Buffalo, New York 14214
`
`References
`1. Clark, R. L., and Lasagna, L.: How reliable
`are enteric -coated aspirin preparations?, CLIN.
`PHARMACOL. áz THERAP. 6:568 -574, 1965.
`
`10
`
`30
`
`40
`
`50
`
`20
`TIME, hours
`Fig. 1. Urinary excretion rate of total salicylates
`as a function of time after oral administration of
`0.32 Gm. aspirin in solution (Q ) and in an
`) to 6 healthy adult male
`enteric -coated tablet (
`subjects.
`
`64 per cent) of the administered dose had
`been recovered in the urine from the en-
`teric- coated tablets; recovery of salicylate
`from solution was
`essentially complete
`by that time ( average, 95 per cent; range,
`92 to 98 per cent) . The relatively constant
`and prolonged rate of salicylate excretion
`from the enteric -coated tablets suggests
`that the drug diffused slowly through an
`essentially intact coating ( i.e., a surface of
`relatively constant area), and that the tab-
`lets did not disintegrate in the intestinal
`tract. Properly formulated enteric -coated
`tablets do not release drug in the stomach
`but do so promptly after passage into the
`small intestine and yield measurable sali-
`cylate levels in the plasma within 2 hours
`after administration.3 The tablets used in
`the present study passed the U.S.P. tablet -
`disintegration test in that they resisted dis-
`integration in simulated gastric fluids for
`
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`Volume 8
`Number 6
`
`Correspondence
`
`889
`
`2. Hollister, L. E., and Kanter, S. L.: Studies of
`delayed- action medication.
`IV.
`Salicylates,
`CLIN. PHARMACOL. & THERAP. 6:5 -11, 1965.
`3. Leonards, J. R., and Levy, G.: Absorption and
`metabolism of aspirin administered in enteric -
`coated tablets, J. A. M. A. 193:99 -104, 1965.
`4. Levy, G.: The therapeutic implications of brand
`interchange, Am. J. Hosp. Pharmacol. 17:756-
`759, 1960.
`5. Levy, G.: Availability of spironolactone given
`by mouth, Lancet 2:723 -724, 1962.
`6. Levy, G.: Effect of dosage form on drug ab-
`sorption---a frequent variable in clinical phar-
`macology, Arch. internat. pharmacodyn. 152:
`59 -68, 1964.
`7. Levy, G., Hall, N. A., and Nelson, E.: Studies
`on inactive prednisone tablets, U. S. P. XVI,
`Am. J. Hosp. Pharmacol. 21:402, 1964.
`
`8. Levy, G., and Hollister, L. E.: Failure of
`U. S. P. disintegration test to assess physiologic
`availability of
`enteric -coated tablets, New
`York State J. Med. 64:3002 -3005, 1964.
`9. Levy, G., and Nelson, E.: Pharmaceutical
`formulation and therapeutic efficacy, J. A. M.
`A. 177:689 -691, 1961.
`10. Levy, G., and Nelson, E.: U.S.P. and N.F.
`standards, F.D.A. regulations, and the quality
`of drugs, New York State J. Med. 61:4003-
`4008, 1961.
`11. Searl, R. O., and Pernarowski, M.: The bio-
`pharmaceutical
`properties
`dosage
`of
`solid
`forms: I. An evaluation of 23 brands of phenyl -
`butazone tablets, Canad. M. A. J. 96:1513-
`1520, 1967.
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