April 1999
`
`Notes
`
`Biol. Pharm. Bull, 22(4) 425-—427 (1999)
`
`425
`
`Intranasal Administration of Diazepam Aiming at the Treatment of Acute
`Seizures: Clinical Trials in Healthy Volunteers
`Sveinbjérn Gizurarson,*”” Fridrik K. GupsraNnpsson,” Helgi Jonsson,‘ and Erik BECHGAARD?
`Department of Pharmacy, University of Iceland,* PO. Box 7171, 127 Reykjavik, Iceland, Department of ENT, Reykjavik
`Hospital,” 108 Reykjavik, Iceland, Department ofMedicine, University ofIceland,° Vatnsmyrarveg, 101 Reykjavik, Iceland,
`and Department of Pharmaceutics, The Royal Danish School of Pharmacy," Universitetsparken 2, 2100 Copenhagen @,
`Denmark. Received August 17, 1998; accepted December 23, 1998
`
`Intranasal administration of diazepam may be a practical alternative to the conventional acute medication
`of seizures, such as status epilepticus. Nine healthy students participated in an open crossover study on in-
`tranasal versus intravenous administration of diazepam (2 mg). Blood samples were collected, pharmacodynamic
`tests were performed, and the volunteersfilled out questionnaire. Peak concentration was achieved after 18+11
`min and the bioavailability was 50.4+23,3%. A pharmacodynamic effect was observed after about 5 min, but the
`dose, even for i.v. administration, was too low to generate a strong measurable effect. The results indicate that in-
`tranasally administered diazepam may bean effective alternative to i.y. administration in relief of seizures, e.g. in
`an acute situation when a physician or nurseis not available on location.
`intranasal administration; diazepam; volunteers; bioavailability
`Key words
`
`Treatment of epileptic seizures should be controlled with-
`out causing adverse reactions and in such a way that it pro-
`motes a good quality of life. The preferred drugs for the
`treatment of epileptic seizures are diazepam or clonazepam
`intravenously (i.v.), followed by phenytoin or phenobarbi-
`tal.) These drugs are effective for hospitalized or institu-
`tionalized patients. They are, however, not applicable to pa-
`tients living at home with their families, becausei.v. adminis-
`tration of these drugs to a patient in seizure requires skilled
`personnel and an acute care facility, since the treatment may
`be associated with hypotension, cardiac dysrhythmiasor cen-
`tral nervous system depression.
`Rectal administration of diazepam as a clysmais an alter-
`native in pediatric therapy. Parents and other caregivers may
`easily be trained to give these drugs rectally. Such therapy,
`however,
`is not that convenient in adults, though clinical tri-
`als show that this treatmentresults in less psychological, so-
`ciological and financial stress for the family,
`including re-
`duced hospitalizations, and it improves the quality oflife*—
`In a study by Kriel ef a/.’) it was shownthat rectal adminis-
`tration of diazepam waseffective in controlling seizures in
`85% of the patients and improved quality of life in 58% of
`the patients.
`The intranasal administration of drugs may be an alterna-
`tive to the rectal delivery. Drugs are absorbed rapidly from
`the nasal cavity, due to the highly vascularized nasal tissue
`andtherelatively leaky epithelium. This rapid absorption is a
`benefit for acute medication. The absorption should also be
`fast, since drugs that are not absorbed within 10—30 min are
`cleared down to the nasopharynx and swallowed, due to the
`mucociliary clearance mechanism.”
`A non-toxic intranasal delivery system for water-insoluble
`substances, such as benzodiazepines, has been developed.’®
`Whena clinically relevant dose of diazepam and clonazepam
`was administered to rabbits, both peak concentration and
`the pharmacodynamic response were achieved within 5 and
`31/2 min, respectively.” The aim of the present study is to
`compare the pharmacokinetic and pharmacodynamic para-
`meters after intranasal and intravenous administration ofdi-
`azepam to humans.
`
`% To whom correspondence should be addressed.
`
`MATERIALS AND METHODS
`
`Diazepam was kindly provided by Lyfjaverslun Islands
`(Reykjavik, Iceland), polyethylene glycol 200 by Union Car-
`bide (Charleston, U.S.A.) and glycofurolum 75 by Hofman-la
`Roche (Basle, Switzerland). The intranasal diazepam formu-
`lation (20 mg/ml) consisted of a mixture 5% glycofurol
`in
`polyethylene glycol 200. The subjects received 100 441into
`one nostril. For comparison, a commercial
`intravenous di-
`azepam formulation was used (Stesolid®, Dumex-Alpharma
`A/S, Copenhagen, Denmark).
`The protocol was an open crossovertrial, approved by the
`local ethics committee and the National Health Authorities
`of Iceland and the State Committee on Pharmaceuticals.
`Nine healthy volunteers, between 20—30 years old (weigh-
`ing 58—80kg), were chosen among 20 caucasian students
`who applied for participation, on the basis of normal
`liver
`and kidney function and no sign of a cold within the last two
`weeksprior to the first experimental day. They could not use
`any drugs that may interact with diazepam nor sedatives such
`as tranquilizers or alcohol, 3d prior and during the experi-
`ment, Blood samples were withdrawn at time 0, 2, 5, 10, 30,
`105, 300 min after administration. The serum diazepam con-
`centration was measured by means of a fluorescence polar-
`ization immunoassay (FPIA) from Abbott A/S (Copenhagen,
`Denmark). Prior to and 30min after application, the nasal
`mucous membranes in both nostrils were inspected by an
`evaluator, and the volunteers were asked to note all adverse
`reactions at 1, 10 and 30min after the administration. After
`0, 5, 30 and 90 min, the subjects were tested for some phar-
`macological tests (short time memory, catching, vigilance,
`concentration and tension) and recorded by the investigators.
`Short time memory was measured by reading 10 single num-
`bers with a fixed speed followed by allowing the participants
`to repeat the numbers. The number of right numbers was
`recorded. Catching was measured by asking the participants
`to catch a pencil dropping 1.5m from above. Vigilance, con-
`centration and tension were based on a questionnaire.
`Standard methods were used to calculate the pharmacoki-
`netic parameters. Intraindividual comparison was carried out
`
`© 1999 Pharmaceutical Society of Japan
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`426
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`for all subjects. The area-under-the-curve (AUC) was calcu-
`lated using the trapezoidal method, the time to #,,, was read
`from the plasma concentration profiles F,,,,, was calculated
`as the percent of AUC,,.,, over AUC,,. Standardstatistical
`techniques were used throughout the study. For the evalua-
`tion of significance, one way ANOVAwasused.
`
`RESULTS AND DISCUSSION
`
`Intranasal administration of diazepam resulted in a rapid
`absorption of the drug. Peak concentration was achieved
`after about 18+11 min (5 out of 9 had #,,,=10 min), provid-
`ing 32.9+21.6% of the concentration, compared to the serum
`concentration obtained 10min after an intravenous injection
`(Fig. 1, Table 1). The rate of absorption (k,,,) was found to
`be 0.43+0.19 min”'. The mostimportanttime(clinically) for
`a successful treatment of seizure are the first 10 min. When
`this study was compared with other studies in the literature,
`32.9+21.6% concentration is achieved after 10min, com-
`pared with 12—27% in other studies after 10 min?°—*) and
`46.5£19,1% after 30min. The dose was kept at minimum
`(only 2 mg), since this study was the first clinical trial for this
`formulation. Sampling of plasma wasonly carried out over a
`5h period because the treatment of seizures is an acute treat-
`ment. Apparent half-life for diazepam was about 16h since
`its terminal half-life ranges over 24h. A six-fold increasein
`the dose should be possible using these vehicles, although
`the solubility of benzodiazepines is very low. The results in-
`dicate that clinically relevant amounts of diazepam can be
`absorbed within !0 min after the administration. This form
`for administration has the advantage that problems such as
`respiratory depression, efc. associated with intravenous injec-
`tion are eliminated, providing a safer delivery system.
`Several
`studies have been conducted where benzodi-
`azepines have been administered intranasally to animals and
`41
`
`o So
`
`100
`
`
`
`Concentration(ng/ml
`
`Vol. 22, No. 4
`
`humans. The most common is midazolam, administered in
`the form of undiluted parenteral solution for inducing seda-
`tion in children.'*—'”) These studies show solely pharmaco-
`dynamic data but not clinical pharmacokinetic information.
`Few pharmacokinetic studies have been performed where
`plasma concentration profiles are presented. Time to maxi-
`mal plasma concentration was between 12—15 min in those
`studies (except for one, where ¢,,,, was 83 min),!and the
`concentration around 15 min was about 12—27%,relative to
`an iv, dose. Studies on rectal administration of diazepam
`show that 12 min onset timeis sufficient for improving qual-
`ity of life and effective in controlling seizures in the majority
`ofpatients, suffering from multiple seizures.”
`Even after i.v. administration, the pharmacological effects
`were small, duc to the low dose used, However, someeffects
`were measured. Table 2 shows a summary of the pharmaco-
`dynamic responses after the administration. Intravenously
`administered diazepam waseffective in decreasing the ability
`to concentrate and decreased vigilance, but the effect was not
`strong dueto the low dose administered.
`Intranasally administered diazepam, however, was effec-
`tive in decreasing tension andthe ability to memorize (short-
`time memory). The onset of effect on short-time memory
`wasrapid andsignificantly different after nasal application as
`compared to the intravenous group, indicating that some of
`the diazepam may have been transported directly from the
`nasalcavity to the brain throughthe olfactory area.’
`Nosigns ofirritation were seen on the nasal mucosa, ex-
`cept for one volunteer who had a minor redness 30 min after
`the administration. The majority of subjects felt some irri-
`tation immediately after the administration. Thirty minutes
`later, however, all subjects had no or only minorsenseofirti-
`tation, Eight out of nine participants would prefer nasally to
`intravenously administered diazepam for the treatment of
`acute seizures in themselves or in their child. It may be con-
`cluded that intranasal delivery of diazepam may bean alter-
`native to i.v. and rectal treatment of acute seizures.
`
`Table 1. Kinetic Parameters of Diazepam in Humans after Single Admin-
`istration (2 mg) Intranasally and Intravenously
`
`
`
` Parameter Intravenous Intranasal
`
`
`
`2
`2
`Dose (mg)
`0.434£0.19
`_
`Kong (min™')
`0.189+0.077
`0.064+0.017
`A (Wy
`17.8415.5
`14.4+7.0
`ti. (n) (apparent)
`I8+Il
`—
`tax (Min)
`S07
`_
`Cnax (01g/ml)
`1,0954412
`2,972+980
`AUC)_som(NG* min/ml)
`
`Fata(%)
`— 50.4423.3
`
`Time (min)
`
`Plasma Concentration-Time Profile (+S$.D.} for Diazepam after
`|.
`Fig.
`Intranasal (@) and Intravenous (Ml) Administration of 2mg Diazepam to
`Healthy Human Volunteers
`
`Table 2. The Onset of Individual Pharmacodynamic Tests, afler Single Intranasal or Intravenous Administration of Diazepam (2 mg) to Healthy Volun-
`teers,
`Test
`Intravenous
`Intranasal
`Significance
`Comments
`onset (min)
`onset (min)
`(p)
`
`
`No
`5
`§
`Decreased ability to concentrate
`Strongereffect afteri.v.
`0.1
`5—30
`>
`Decreased vigilance
`Strongereffect after i.n.
`0.17
`30
`30
`Decreased tension
`Strongereffectafter i.n.
`0.05
`5
`5—30
`Decreased ability to memorise
`
`
`
`Noeffect No effectDecreasedability to catch No
`
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`9)
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`10)
`11)
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`12)
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`(3)
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`14)
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`15)
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`AQUESTIVE EXHIBIT 1030 page 0003
`AQUESTIVE EXHIBIT 1030
`e 0003
`NII-Electronic Tae € rvice
`ag
`
`April 1999
`
`Acknowledgements This study was kindly supported by
`Peptech Europe A/S (Hillerod, Denmark). The FPIA was
`partly sponsored by Abbott A/S (Vedbak, Denmark). The au-
`thors thank Dorthe Seir Petersen and Henriette Bierregaard
`Sorensen for skillful technical assistance and the students for
`participating in this study.
`
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