COMMUNICA TlONS
`
`Nasal Absorption of Propranolol in Humans
`
`Table I-Mean Area under Serum Level-Time Curve for
`Propranolol Administered by Three Routes
`
`Keyphrases 0 Propranolol-nad absorption in humans a Absorption,
`nasal-Dropranolol, humans
`
`To the Editor:
`Propranolol, an adrenergic 8-receptor-blocking drug,
`is widely used for hypertension management and treat-
`ment of angina pectoris. However, the drug is absorbed
`inefficiently and variably from oral dosage forms. A study
`in humans showed that the oral administration of pro-
`pranolol results in considerable variation in plasma drug
`levels. Peak plasma levels in five subjects given 80-mg oral
`doses varied sevenfold, while those in the same subjects
`given 10-mg iv doses varied only twofold (1). Furthermore,
`drug bioavailability of an 80-mg oral dose in some subjects,
`as calculated from the ratio of the area under the curve, was
`as low as 16% of the bioavailability of a 10-mg iv dose, The
`variations in the blood levels as well as the low bioavail-
`ability for oral doses have been attributed to extensive drug
`metabolism in the GI tract during absorption and to the
`first-pass effect (2,3).
`Previous studies in rats (4) and dogs (5) showed that
`propranolol is absorbed rapidly and completely from the
`nasal mucosa. We now report the results of a study of the
`nasal absorption of propranolol in humans.
`Six healthy male subjects, 21-35 years old, were selected
`for participation in a randomized crossover study after
`providing written informed consent. The subjects were
`admitted to the clinical facility following an 8-hr fast, and
`dosing commenced in the morning (7:OO am).
`
`-
`Intravenous (10 mg)
`Nasal (10 mg)
`Oral (80 mg)
`
`175.4 5 20.4
`190.3 f 17.6
`349.5 f 35.2
`
`-
`1-09
`0.25
`
`For the oral administration, two 40-mg propranolol
`hydrochloride tablets' were dissolved in 30 ml of water,
`followed by 150 ml of water. For the intravenous admin-
`istration, 10 ml of propranolol hydrochloride injection2
`(each milliliter contained 1 mg of propranolol hydrochlo-
`ride) was infused at a rate of 0.73 mg/min. For the nasal
`administration, 10 mg of propranolol hydrochloride in 0.2
`ml of WO methylcellulose~ gel was placed in the nasal cavity
`using a 1-ml syringe while the subjects were in a sitting
`position.
`Blood samples were obtained periodically after drug
`administration, and the serum was separated immediately
`and frozen until analysis. The serum drug levels were de-
`termined spectrophotofluorometrically (3,4).
`Figure 1 shows the mean serum propranolol levels for
`the three administration routes. Table I lists the area
`under the serum level-time curve (AUC) and the adjusted
`AUC ratio.
`As shown in Fig. 1, the serum drug levels after intrave-
`nous and nasal administration of 10-mg doses were iden-
`tical. The oral bioavailability calculated from the adjusted
`A UC ratio was 25%.
`The results also indicate that propranolol hydrochloride
`is absorbed rapidly from the nasal mucosa. The nasal route
`for propranolol administration appears to be superior to
`the oral route and as effective as the intravenous route.
`
`(1) D. C. Shand, E. M. Nuckolls, and J. A. Oaks, Clin. Phorrnocol.
`Ther.. 11.112 (1970).
`(2) C. T. Dollerj and D. S. Davies. Ann. N. Y. Acad. Sci., 179, 109
`(1971).
`(3) T. Suzuki, Y. Saitoh, S. Isozaki, and R. Ishida, Cham. Pharm. Bull.,
`20,2731 (1972).
`(4) A. Hussain, S. Hirai, and R. Bawarshi, J . Pharm. Sci., 68,1196
`(1979).
`(5) Ibid., in press.
`
`A. Hussain
`T, Foster
`S. Hirai
`T, Kashihara
`R. Batenhorst
`M. Jones
`Colleges of Pharmacy and Medicine
`University of Kentucky
`Lexington, KY 40506
`
`Received April 21,1980.
`Accepted for publication July 14,1980.
`
`1 Indeml tubleu, lot IJRB, AyeMt hboretories.
`2 lnderal injection, 1 mg/cma, lot ILAF, Ayerst Laboratories.
`3 Methocel, Dow Chemical Co.
`
`0
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`2
`
`4
`
`6
`HOURS
`Figure 1-Time course of the average serum propranolol levels in six
`male subjects following nasal administration of JO mg/subject (A), in-
`travenous administration of 10 mglsubject (01, and oral administration
`of 80 mgleubject (U).
`
`8
`
`10
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`12
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`1240 I Journal of PhannecWfcal Sclences
`Vol. 69. No. 10, October 1980
`
`0022-3549/811/ 1000- 1240$0 1.Wd
`0 1980, American Phamceutlcal Association
`
`Neurelis - EX. 2008
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
`
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