Buccal Absorption of Ergotamine

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.10.1116 on 1 October 1974. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry, 1974, 37, 1116-1120

Buccal absorption of ergotamine

J. M. SUTHERLAND, W. D. HOOPER, M. J. EADIE, AND J. H. TYRER From the Department of Medicine, Royal Brisbane Hospital, University of Queensland, Brisbane, Australia

SYNOPSIS The rate of disappearance of ergotamine from the mouth after buccal administration has been studied in seven subjects. Allowance has been made for non-absorptive losses of the drug due to experimental technique. The absorption of ergotamine across the buccal mucosa appears to be a passive process, pH-dependent but independent of ergotamine concentration or the simultaneous presence of caffeine. Because of the low solubility of ergotamine at the pH of saliva, it is unlikely that therapeutically useful amounts of the drug would have absorbed across the buccal mucosa even after the drug had been in the mouth for five minutes. guest. Protected by copyright.

Ergotamine, widely used in treating attacks of than oral administration but less effective than migraine, may be administered by injection intravenous, intramuscular, subcutaneous, rectal, (intravenous, intramuscular, or subcutaneous), or aerosol therapy (Kelly, 1937; von Storch, taken rectally, buccally or sublingually, swal- 1938; Graham et al., 1960; Sutherland and lowed, inhaled as an aerosol, or applied to the Eadie, 1961; Crooks et al., 1964; Cristol and nasal mucosa. The oral route of administration Unger, 1971). is the most convenient and simple. However, Ergotamine is often combined with caffeine in vomiting often tends to occur in migraine and preparations used for the treatment of migraine. ergotamine may increase this tendency. Vomit- Clinical studies have indicated that the combined ing may cause partial or total loss of the dose of preparations were more effective than ergotamine ergotamine swallowed. Therefore, alternative alone when given orally or rectally (Horton et al., routes of ergotamine intake may be preferred 1948; Cohen and Criep, 1949; Bercel, 1950; when the drug is to be self-administered. Rectal Friedman and von Storch, 1951). Zoglio et al. administration has been shown to be effective (1969) suggested that at least part ofthe effective- (Kadish, 1950; Graham, 1954), though it may ness of the combined oral preparations may be lead to problems such as immediate defaecation due to complex formation between caffeine and with loss of a of the ergotamine leading to enhanced alimentary portion dose, constipation, http://jnnp.bmj.com/ or poor patient acceptance. absorption of ergotamine. The relative effective- Absorption across the mucous membranes ness of the combined preparation as compared of the mouth might circumvent these problems with ergotamine alone when administered by and would appear to be of great potential value. the buccal route does not appear to have been Ergotamine might enter the circulation faster if studied. absorbed from the mouth rather than from lower The lack of a sensitive and specific assay for portions of the alimentary tract, and a greater ergotamine has considerably hampered studies proportion of the dose might by-pass the portal of the clinical pharmacology of the drug, so that on October 2, 2021 by circulation (and possible metabolism in the hitherto its absorption in man has had to be liver) to reach the cranial blood vessels. How- assessed in terms of subjective criteria. However, ever, buccal and sublingual absorption of ergot- with the development of a sensitive fluorimetric amine has not been extensively studied. Clinic- assay of ergotamine by Hooper et al. (1974), a ally, there is some evidence that sublingual or greater understanding of the use of ergotamine buccal absorption of ergotamine is more effective may be attained. 1116 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.10.1116 on 1 October 1974. Downloaded from

Buccal absorption of ergotamine 1117

In the present study, an attempt was made to as the pH 4 3, the pH 6 3, and the pH 8 2 solutions measure the buccal absorption of ergotamine, despite ± 0 1 pH unit range. Subsequent measure- alone and in the presence of caffeine, to try to ment showed that these buffers satisfactorily main- assess the potential effectiveness of the drug in tained pH after exposure to the buccal mucosa. The given by this route. buffer solutions containing the drug(s) stood over- migraine when night at 20-220C and were then filtered twice through Whatman No. 42 filter paper to avoid the presence of METHODS undissolved drug. The concentrations of ergotamine SUBJECTS Three healthy female volunteers (17, 26, tartrate studied ranged from 0-7 jug/ml to 90 1 ,g/ml and 31 years of age) and four healthy male volun- (pH 4 3), 0-6 jtg/ml to 9 3 ,tg/ml (pH 6-3) and 0-28 teers (23, 25, 28, and 34 years of age) participated in Mtg/ml to 4 4 /g/ml (pH 8-2). the study. BUCCAL ABSORPTION TEST The technique used was a SOLUTIONS USED Two buffer systems were used to modification of the buccal absorption test of Beckett maintain the pH of the ergotamine solution during and Moffat (1968). Twenty millilitres of a buffered buccal contact-namely, 0-2 M acetate buffer (pH solution of the drug(s) was circulated around the sub- 4 3 ± 0 1) and 0 2 M phosphate buffer (pH 6 3 ± 0 1 ject's mouth by movement of the tongue and cheeks and pH 8-2 ± 0 1). These solutions will be referred to for a predetermined time, and then expelled into a guest. Protected by copyright.

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A1- I I I 0 1 2 3 4 5 0 1 2 3 4 5 TIME (minutes) TIME (minutes) FIG. 1. Mean percentage of ergotamine lost for the seven subjects at pH 4-3 (top), pH 6-3 (lower left), andpH 8-2 (lower right). Results in the absence (-U-) and presence (-----) ofcaffeine are shown; the bars indicate SD on either side of the points for the mean value at each time of buccal contact J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.10.1116 on 1 October 1974. Downloaded from

1118 J. M. Sutherland, W. D. Hooper, M. J. Eadie, and J. H. Tyrer beaker. The subject then quickly rinsed his mouth low solubility of ergotamine, there was no statis- for 5 s with a 5 ml aliquot of the same buffer without tically significant effect of concentration on per ergotamine, but containing caffeine citrate (5 mg/ml) cent of ergotamine lost at any of the pH's. when appropriate. Both expelled solutions were combined and the pH measured. This solution was then EFFECT OF CAFFEINE Figure 1 shows the time diluted as necessary for assay. The interval between course of the loss of ergotamine from the mouth successive tests in each subject was at least 15 of caffeine at pH minutes. Buccal absorption was measured after i, in the presence and absence one, two, and five minutes of drug contact with the 4-3, 6-3, and 8-2. For each of the three pHs buccal mucosa. Each subject was given ergotamine studied a two-way hierarchial analysis of vari- solutions of various concentrations at each of three ance (Croxton and Cowden, 1965) was performed different pHs, both with and without added caffeine on the data. These analyses showed that the citrate (5 mg/ml) on one or more occasions. Further- presence of caffeine had no statistically signifi- more, each subject was given ergotamine solutions cant effect on the percentage of the ergotamine of at least one of the pHs on a minimum of two dose lost at any of the three pHs studied. occasions. Where more than one solution was studied in one day in a subject the order of exposure was randomized. DISCUSSION While Gibaldi and Kanig (1965) drew a distinc- ANALYTICAL METHOD Ergotamine concentration in the buccal and the sublingual tion between guest. Protected by copyright. saliva and the other solutions used was measured by in practice the technique of Hooper et al. (1974). To provide a routes of drug administration, 'blank' solution for these assays, each subject kept ergotamine for buccal administration is first in his mouth for five minutes, on at least two chewed and the disintegrating material is then occasions, a non-ergotamine containing buffer, with often allowed to move about the mouth. There- or without caffeine citrate (5 mg/ml). After expulsion, fore, the drug is likely to absorb through both this solution was assayed by the routine technique to the buccal and the sublingual mucosae. In the provide blank values for ergotamine determination present experimental study the solution of in saliva with, and without, caffeine citrate. ergotamine was presented to both buccal and sublingual mucosae. RESULTS EFFECT OF TIME Figure 1 shows the mean percentage of ergotamine lost at 41, one, two, and 20 five minutes for the seven subjects when exposed to ergotamine at each of the three pHs. The correlation coefficient for linear regression of percentage of drug lost against time was signifi- I- cant at the 0-001 level for pH 4*3 and 6-3 and at LI- hence ergotamine ce 10 the 001 level for pH 8-2; http://jnnp.bmj.com/ losses increase with time. However, at the most, less than 4000 of the ergotamine dose was lost after five minutes' exposure. A/ EFFECT OF PH Analysis of covariance showed line for pH that the elevation of the regression 1 2 3 4 5 4-3 in Fig. 1 differed at a statistically significant 0 level of confidence (P < 0.01) from the elevations TIME (minutes) on October 2, 2021 by of the regressions for pH 6-3 and 8-2. Thus pro- FIG. 2. Differences between observed values for portionately less ergotamine was lost at pH 4*3 percentage of ergotamine lost at various times (mean than at the higher pH values studied. of seven subjects) and extrapolated zero time values (see text) plotted against time for pH 4-3 EFFECT OF CONCENTRATION Over the range of --0--), pH 6-3 ( * ), and pH 8-2 concentrations studied, which was limited by the (-----). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.10.1116 on 1 October 1974. Downloaded from

Buccal absorption of ergotamine 1119

As measured in the present study, the percent- pH 4 3, whereas much more would be non- age of ergotamine lost is not necessarily equal to ionized at higher pH. The present study has the true percentage of the drug dose absorbed shown better ergotamine absorption at the across the buccal mucosa. Non-absorptive losses higher pH values, in accordance with the pH due to spillage, swallowing, binding to mucosal partition hypothesis of passive absorption surfaces, and perhaps teeth, and possible (Levine, 1971). Also ergotamine absorption is metabolism might have occurred while ergot- not concentration-dependent, which again is amine was in the mouth, and would have been consistent with passive absorption, though we included in the percentage of drug lost. A more satisfactory method would have been to measure the appearance of ergotamine in plasma after absorption, but the method of assay used, 20 though very sensitive (limit of detection 0-002 ,ug/ml), was not capable of measuring the drug concentration in plasma. Alternatively, a non- absorbable marker compound could have been V) 10 kept in the mouth together with the ergotamine, CD and measured after expulsion from the mouth, but this might not have accounted for all the fac- guest. Protected by copyright. tors that could be involved in non-absorptive ergotamine loss. Two possible methods of more nearly estimating the true absorption of ergotamine are considered below. 0 1 2 Figure 1 shows that ergotamine is lost faster in TIME (minutes) the first half minute of buccal contact than in the FIG. 3. Data obtained for mean percentage of subsequent 4j minutes, during which time the ergotamine lost plotted against time after the values rate of loss is approximately linear. This high at pH 43 are subtracted from those at pH 6-3 initial rate of loss, irrespective of ergotamine ( * ) and pH 82 (----A---). concentration, may reflect the combined effects of both drug absorption and of most of the non- absorptive loss due to the various factors men- tioned above. Consequently, a better estimate of cannot be certain that the range of concentration buccal ergotamine absorption might be obtained studied was wide enough to exclude an active by extrapolating the linear regression between process obeying Michaelis-Menten kinetics. per cent of ergotamine lost and time (over the Since so little ergotamine is ionized at pH 4*3, if interval half to five minutes) back to zero time, the drug's absorption is passive, the data ob- and taking the differences between this zero-time tained for ergotamine loss at pH 4-3 in the present loss and the observed losses at subsequent times study may represent almost entirely non-absorp- http://jnnp.bmj.com/ as more realistic estimates of ergotamine absorptive losses of the drug due to the experimental tion. When these values are plotted against time technique. Therefore subtraction of percentage (Fig. 2), absorption is greater at pH 6-3 and 8-2 of ergotamine lost at pH 4-3 from the losses at than at pH 4-3. For instance, after five minutes higher pH values (Fig. 3) may provide a reason- of buccal contact with ergotamine, 700 of the able estimation of true ergotamine absorption at dose would have been absorbed at pH 4*3, 160/O pH 6-3 and pH 8-2. The mean percentage at pH 6-3, and 10% at pH 8-2. absorbed, calculated in this way, appears to in- on October 2, 2021 by The data of the present study are consistent crease slightly with time and, after five minutes' with ergotamine being absorbed passively across buccal contact, 18% of the dose would be ab- the buccal mucosa. Ergotamine is a base with a sorbed at pH 6-3 and 13% at pH 8-2. Personal Pka of 6-25 (Maulding and Zoglio, 1970). Conse- unpublished studies indicate that saliva pH quently only about 10% of the drug would be varied in the range pH 6 to 8, and that after non-ionized, and likely to absorb passively, at chewing a buccal ergotamine tablet containing J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.37.10.1116 on 1 October 1974. Downloaded from

1120 J. M. Sutherland, W. D. Hooper, M. J. Eadie, and J. H. Tyrer

caffeine for five minutes the saliva pH varied Ergotamine tartrate was supplied by Sandoz between 7-1 and 7-4. Australia, North Ryde, New South Wales. From the above data, it appears that only about one-sixth ofan ergotamine dose in solution REFERENCES Beckett, A. H., and Moffat, A. C. (1968). The influence of might absorb from saliva across the buccal alkyl substitution in acids on their performance in the mucosa in five minutes. This is probably as long buccal absorption test. Journal of Pharmacy and Pharma- as a patient would keep a chewed ergotamine cology, 20, Suppl. 239S-247S. Bercel, N. A. (1950). Treatment of migraine; results with tablet in his mouth. Does this represent the dihydroergocornine methane sulfonate (DHO-180) and absorption of a therapeutically useful dose? An other ergot derivatives. California Medicine, 72, 234-238. ergotamine preparation administered in tablet Cohen, S. G., and Criep, L. H. (1949). Observations on the symptomatic treatment of chronic vascular headache with form would have to disintegrate and the drug Cafergone (ergotamine tartrate and caffeine). New England dissolve before absorption could begin, so that in Journal of Medicine, 241, 896-900. Cristol, J. L., and Unger, L. (1971). Allergic migraine and five minutes there might be less drug absorbed sublingual ergotamine tartrate. In Proceedings of the from a tablet than from a previously prepared International Headache Symposium, Elsinore, 1971. pp. solution of the drug. Crooks et al. (1964) found 55-56. Edited by D. J. Dalessio, T. Dalsgaard-Nielsen and S. Diamond. Sandoz: Basle. that the average 'dissolution time', which Crooks, J., Stephen, S. A., and Brass, W. (1964). Clinical trial appears to be actually the average 'disintegra- of inhaled ergotamine tartrate in migraine. British Medical tion time' of the sublingual ergotamine tablets Journal, 1, 221-224.

Croxton, F. E., and Cowden, D. J. (1965). Applied Generalguest. Protected by copyright. used in their clinical trial, was five minutes. Fur- Statistics, 2nd edn, pp. 714-720. Pitman: London. ther, Zoglio et al. (1969) found that, at pH 6 65 Friedman, A. P., and von Storch, T. J. C. (1951). Recent 9 advances in treatment of migraine. Journal ofthe American only about ,ug ergotamine would dissolve per Medical Association, 145, 1325-1329. ml of water at 30°C. It is unlikely that 20 ml of Gibaldi, M., and Kanig, J. L. (1965). Absorption of drugs saliva would be produced in the mouth in five through the oral mucosa. Journal of Oral Therapeutics and Pharmacology, 1, 440-450. minutes, but even assuming this amount of saliva Graham, J. R. (1954). Rectal use of ergotamine tartrate and were present when a patient chewed an ergot- caffeine alkaloid for the relief of migraine. New England amine tablet, it is improbable that more than a Journal of Medicine, 250, 936-938. Graham, J. R., Malvea, B. P., and Gramm, H. F. (1960). total of 0-2 mg of the drug would be in solution Aerosol ergotamine tartrate for migraine and Horton's at any one time. Of this, about one-sixth-that syndrome. New EnglandJournal ofMedicine, 263, 802-804. is, 0 03 be expected to absorb across Hooper, W. D., Sutherland, J. M., Eadie, M. J., and Tyrer, mg-might J. H. (1974). Fluorimetric assay of ergotamine. Analytica the buccal mucosa in five minutes. Comparison Chimica Acta, 69, 11-17. of this 0-03 mg intake of ergotamine with the Horton, B. T., Ryan, R., and Reynolds, J. L. (1948). Clinical observations on the use of E.C. 110, a new agent for the intravenous drug dose of 0 25 to 050 mg, which treatment of headache. Proceedings of the StaffMeetings of itself does not always relieve migraine, suggests the Mayo Clinic, 23, 105-108. that it is scarcely an adequate intake. Kadish, A. H. (1950). Clinical observations on the rectal and oral use of various ergot derivatives in headache. New The present study also suggests that con- England Journal of Medicine, 242, 581-582. Kelly, T. W. G. (1937). Ergotamine tartrate in migraine. currently administered caffeine would be un- Lancet, 1, 777-778. likely to enhance the buccal absorption of Levine, R. R. (1971). Intestinal absorption. In Topics in http://jnnp.bmj.com/ ergotamine. However, it should be noted that Medicinal Chemistry, vol. 4, pp. 27-95. Edited by J. L. Rabinowitz and R. M. Myerson. Wiley: New York. caffeine may still be of benefit with other routes Maulding, H. V., and Zoglio, M. A. (1970). Physical chemistry of administration where different physico- of ergot alkaloids and derivatives. 1. Ionization constants chemical environments would be encountered. of several medicinally active bases. Journal of Pharma- ceutical Sciences, 59, 700-701. These results suggest that therapeutically use- Sutherland, J. M., and Eadie, M. J. (1961). The drug therapy of migraine. Medical Journal of Australia, 2, 740-742. ful quantities of ergotamine are unlikely to be von Storch, T. J. C. (1938). Complications the use following on October 2, 2021 by absorbed from commercial ergotamine prepara- of ergotamine tartrate. Their relation to the treatment of migraine headaches. Journal of the American Medical tions across the buccal mucosa in a tolerable Association, 111, 293-300. period of time. It might be suspected that ergot- Zoglio, M. A., Maulding, H. V., Jr, and Windheuser, J. J. amine, intended for buccal absorption, is often (1969). Complexes of ergot alkaloids and derivatives. 1. The interaction of caffeine with ergotamine tartrate in helpful in migraine only ifthe drug is accidentally aqueous solution. Journal of Pharmaceutical Sciences, 58, swallowed. 222-225.