International Journal of Pharmaceutics, 54 (1989) 171-174
`Elsevier
`
`IJP 01860
`
`171
`
`Absorption of diazepam
`and lorazepam following intranasal administration
`
`S.W.J. Lau and John T. Slattery
`Department of Pharmaceutics, University of Washington, Seattle, WA 98195 (U.S.A.)
`
`(Received 15 August 1988)
`(Modified version received 5 December 1988)
`(Accepted 17 April 1989)
`
`Key words: Diazepam; Lorazepam; Absorption; Nasal administration; Bioavailability; Epilepsy
`
`Summary
`
`The absorption characteristics of diazepam and lorazepam following intranasal administration were determined in order to assess
`the suitability of this approach for the treatment of status epilepticus in children. Due to the limited aqueous solubility of these drugs,
`a series of non-ionic surfactants were evaluated for drug solubility and nasal irritation. Cremophor EL (Blagden, U.K.) was selected
`as the least irritating. The diazepam and lorazepam studies were carried out in 2 and 4 healthy adults, respectively, in cross-over
`fashion. Diazepam was found to be 84% and 72% absorbed in the two subjects, peak concentration following nasal administration
`was observed at approximately 1 h and was approximately 27% of that following i.v. administration. Lorazepam bioavailability
`ranged from 35% to 63%, peak time from 0.5 to 4 h, and peak concentration from 33% to 94% that following i.v. administration (even
`though the i.v. dose of lorazepam was 1/2 the intranasal dose). Although both drugs are absorbed following intranasal application,
`this route of administration would appear to have limited potential for the acute treatment of seizures.
`
`International JournalofPharmaceutics, 54 (1989) 171-174 171 Elsevier IJP 01860 Absorption of diazepam and lorazepam following intranasal administration S.W.J. Lau and John T. Slattery Department of Pharmaeeutics, University of Washington, Seattle, WA 98195 (U.S.A.) (Received 15 August 1988) (Modified version received 5 December 1988) (Accepted 17 April 1989) Key words: Diazepam; Lorazepam; Absorption; Nasal administration; Bioavailability; Epilepsy Summary The absorption characteristics of diazepam and lorazepam following intranasal administration were determined in order to assess the suitability of this approach for the treatment of status epilepticus in children. Due to the limited aqueous solubility of these drugs, a series of non-ionic surfactants were evaluated for drug solubility and nasal irritation. Cremophor EL (Blagden, U.K.) was selected as the least irritating. The diazepam and lorazepam studies were carried out in 2 and 4 healthy adults, respectively, in cross-over fashion. Diazepam was found to be 84% and 72% absorbed in the two subjects, peak concentration following nasal administration was observed at approximately 1 h and was approximately 27% of that following i.v. administration. Lorazepam bioavailability ranged from 35% to 63%, peak time from 0.5 to 4 h, and peak concentration from 33% to 94% that following i.v. administration (even though the i.v. dose of lorazepam was 1/2 the intranasal dose). Although both drugs are absorbed following intranasal application, this route of administration would appear to have limited potential for the acute treatment of seizures. Diazepam and lorazepam are well accepted drugs for the treatment of status epilepticus (Ho- man and Walker, 1983; Leppik et al., 1983). Status epilepticus is a serious and often life-threatening emergency, which requires prompt treatment to minimize mortality as well as reducing neurologi- cal sequelae caused by prolonged seizure activity (Oxbury and Whitty, 1971; Meldrum, 1978). Cur- rent therapy requires rectal or i.v. administration of drugs to achieve the rapid onset of effect re- quired. In the last decade, the intranasal route of drug administration for systemic effects has re- ceived attention due to its convenience and relia- Correspondence to: J.T. Slattery, Department of Pharmaceutics, BG-20, University of Washington, Seattle, WA 98195, U.S.A. bility (Freestone and Weinberg, 1976; Parr, 1983; Su, 1986). Intranasal administration of proprano- lol has been shown to result in drug concentration in blood similar to those observed after i.v. admin- istration (Hussain et al., 1980). Both nasal nicotine solution and intranasal aerosolized insulin have demonstrated efficacy (Russell et al., 1983; Salz- man et al., 1985). Given the promise this route of administration seems to hold, this investigation was initiated to determine whether diazepam and lorazepam can be administered intranasally to promptly achieve the therapeutic concentrations required to treat status epilepticus. Benzodiazepines are poorly water-soluble (di- azepam 0.05 mg/ml; lorazepam 0.08 mg/ml). Organic vehicles are therefore necessary for the formulation of nasal drops. A series of non-aque- 0378-5173/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)
`
`bility (Freestone and Weinberg, 1976; Parr, 1983;
`Su, 1986). Intranasal administration of proprano-
`lol has been shown to result in drug concentration
`in blood similar to those observed after i.v. admin-
`istration (Hussain et al., 1980). Both nasal nicotine
`solution and intranasal aerosolized insulin have
`demonstrated efficacy (Russell et al., 1983; Salz-
`man et al., 1985). Given the promise this route of
`administration seems to hold, this investigation
`was initiated to determine whether diazepam and
`lorazepam can be administered intranasally to
`promptly achieve the therapeutic concentrations
`required to treat status epilepticus.
`Benzodiazepines are poorly water-soluble (di-
`azepam 0.05 mg/ml; lorazepam 0.08 mg/ml).
`Organic vehicles are therefore necessary for the
`formulation of nasal drops. A series of non-aque-
`
`Diazepam and lorazepam are well accepted
`drugs for the treatment of status epilepticus (Ho-
`man and Walker, 1983; Leppik et al., 1983). Status
`epilepticus is a serious and often life-threatening
`emergency, which requires prompt treatment to
`minimize mortality as well as reducing neurologi-
`cal sequelae caused by prolonged seizure activity
`(Oxbury and Whitty, 1971; Meldrum, 1978). Cur-
`rent therapy requires rectal or i.v. administration
`of drugs to achieve the rapid onset of effect re-
`quired. In the last decade, the intranasal route of
`drug administration for systemic effects has re-
`ceived attention due to its convenience and relia-
`
`Correspondence to: J.T. Slattery, Department of Pharmaceutics,
`BG-20, University of Washington, Seattle, WA 98195, U.S.A.
`
`0378-5173/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)
`
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`

`172
`
`TABLE 1
`
`Intranasal bioavailability of diazepam
`
`Subject
`
`Peak time
`(h)
`
`Peak conc. (ng/ml)
`i.v. a
`
`Nasal
`
`Bioavailability b
`
`1
`2
`Mean
`
`1.25
`1.50
`1.38
`
`110
`240
`175
`
`650
`644
`647
`
`(%)
`
`72
`84
`78
`
`a Estimated by least-square regression.
`b Estimated from 0-50 h area under the plasma—concentration
`time curve (see Fig. 1).
`
`curves using standard methods (Gibaldi and
`Perrier, 1982). Peak time and concentration after
`intranasal administration were read from the
`concentration vs time plots. Peak concentration
`after i.v. administration was estimated by least-
`square linear regression analysis.
`The results for diazepam are shown in Table 1
`and data from a representative subject are shown
`in Fig. 1. Peak time following intranasal adminis-
`tration of diazepam was comparable in both sub-
`jects; the mean value was 1.38 h. Peak concentra-
`tion following i.v. administration was similar in
`the two subjects, with a mean value of 647 ng/ml.
`On the other hand, peak concentration following
`intranasal administration differed substantially
`between subjects with values of 110 ng/ml and
`240 ng/ml in the two individuals.
`
`700
`
`600
`
`E
`
`-
`
`0
`
`400
`
`C'q
`
`200
`
`100-
`
`172 ous solvents apparently acceptable on the basis of toxicity, irritability and carcinogenicity (Spiegel and Noseworthy, 1963; Lewis and Tatken, 1980) were evaluated. Since the volume which can be instilled is limited to about 100/~1 for each nostril, a series of solubility tests for diazepam (10 mg) and lorazepam (4 mg) was carried out on these vehicles. Seven non-aqueous vehicles, triacetin, di- methyl sulfoxide, polyethylene glycol 400 (all from Sigma Chemical Co., St. Louis, MO), Cremophor EL (polyoxyethylated castor oil), Lipal-9-LA (laureth-9(polyoxyethylene-9 lauryl ether)) (PVO Research, Boonton, N J), isopropyl adipate (Union Carbide, New York, NY), and azone 1-dodecy- lazacycloheptane-2-one (Nelson Laboratories, Irvine, CA) had acceptable solubility (i.e., could deliver the desired dose in < 250 /~1 solvent). These 7 vehicles were subjectively tested for acceptability by administering 100 #1 of each vehicle separately to each nostril of two human subjects at different times. Cremophor EL was quite well tolerated and has been used as a vehicle for parenteral diazepam formulation in Europe. The other 6 vehicles were found to be irritating and unsuitable for intranasal application. Cremo- phor EL was therefore selected for bioavailability studies. The subjects were 4 male and one female healthy volunteers, 26-37 years of age, weighing 60-85 kg, and receiving no other medication. The protocols for the two drugs were similar, except that 10 mg diazepam (both i.v. and intranasal) and 2 mg (i.v.)/4 mg (intranasal) lorazepam were adminis- tered. The subject received an i.v. dose of 10 mg/2 ml Valium or 2 mg/rnl Ativan; and blood samples were obtained serially through a heparin lock. Plasma was stored at -20 °C until analyzed by GC for diazepam (Rutherford, 1977) or lorazepam (Greenblatt et al., 1978). One to two weeks later, the same procedures were repeated except that the drug was administered as nose drops; 10 mg di- azepam in 220/~1 Cremophor EL or 4 mg loraze- pam in 100 #1 Cremophor EL. The dose was divided between the two nostrils and was adminis- tered with a positive-displacement pipette (SMI) while the subject was supine. Bioavailability was calculated for each subject from the area under plasma concentration-time TABLE 1 lntranasal bioavailability of diazepam Subject Peak time Peak conc. (ng/ml) (h) Nasal i.v. a Bioavailability (%) 1 1.25 110 650 72 2 1.50 240 644 84 Mean 1.38 175 647 78 a Estimated by least-square regression. b Estimated from 0-50 h area under the plasma-concentration time curve (see Fig. 1), curves using standard methods (Gibaldi and Perrier, 1982). Peak time and concentration after intranasal administration were read from the concentration vs time plots. Peak concentration after i.v. administration was estimated by least- square linear regression analysis. The results for diazepam are shown in Table 1 and data from a representative subject are shown in Fig. 1. Peak time following intranasal adminis- tration of diazepam was comparable in both sub- jects; the mean value was 1.38 h. Peak concentra- tion following i.v. administration was similar in the two subjects, with a mean value of 647 ng/ml. On the other hand, peak concentration following intranasal administration differed substantially between subjects with values of 110 ng/ml and 240 ng/ml in the two individuals. soo 4oo 8 100 0 , - Time (hr') e0 Fig. 1. Time course of diazepam concentration in plasma of subject 1 following i.v. (o) and intranasal (D) administration.
`
`ous solvents apparently acceptable on the basis of
`toxicity, irritability and carcinogenicity (Spiegel
`and Noseworthy, 1963; Lewis and Tatken, 1980)
`were evaluated. Since the volume which can be
`instilled is limited to about 100 µI for each nostril,
`a series of solubility tests for diazepam (10 mg)
`and lorazepam (4 mg) was carried out on these
`vehicles. Seven non-aqueous vehicles, triacetin, di-
`methyl sulfoxide, polyethylene glycol 400 (all from
`Sigma Chemical Co., St. Louis, MO), Cremophor
`EL (polyoxyethylated castor oil), Lipal-9-LA
`(laureth-9(polyoxyethylene-9 lauryl ether)) (PVO
`Research, Boonton, NJ), isopropyl adipate (Union
`Carbide, New York, NY), and azone 1-dodecy-
`lazacycloheptane-2-one (Nelson Laboratories,
`Irvine, CA) had acceptable solubility (i.e., could
`deliver the desired dose in < 250 µI solvent).
`These 7 vehicles were subjectively tested for
`acceptability by administering 100 µ1 of each
`vehicle separately to each nostril of two human
`subjects at different times. Cremophor EL was
`quite well tolerated and has been used as a vehicle
`for parenteral diazepam formulation in Europe.
`The other 6 vehicles were found to be irritating
`and unsuitable for intranasal application. Cremo-
`phor EL was therefore selected for bioavailability
`studies.
`The subjects were 4 male and one female healthy
`volunteers, 26-37 years of age, weighing 60-85 kg,
`and receiving no other medication. The protocols
`for the two drugs were similar, except that 10 mg
`diazepam (both i.v. and intranasal) and 2 mg
`(i.v.)/4 mg (intranasal) lorazepam were adminis-
`tered. The subject received an i.v. dose of 10 mg/2
`ml Valium or 2 mg/ml Ativan; and blood samples
`were obtained serially through a heparin lock.
`Plasma was stored at — 20 ° C until analyzed by
`GC for diazepam (Rutherford, 1977) or lorazepam
`(Greenblatt et al., 1978). One to two weeks later,
`the same procedures were repeated except that the
`drug was administered as nose drops; 10 mg di-
`azepam in 220 µI Cremophor EL or 4 mg loraze-
`pam in 100 id. Cremophor EL. The dose was
`divided between the two nostrils and was adminis-
`tered with a positive-displacement pipette (SMI)
`while the subject was supine.
`Bioavailability was calculated for each subject
`from the area under plasma concentration—time
`
`0
`
`0
`
`20
`
`30
`Time (hr)
`Fig. 1. Time course of diazepam concentration in plasma of
`subject 1 following i.v. (o) and intranasal (Li) administration.
`
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`173
`
`TABLE 2
`
`Intranasal bioavailability of lorazepam
`
`Subject
`
`Peak time
`(h)
`
`Peak conc. (ng/ml)
`
`Nasal
`
`i.v. a
`
`Bioavailability
`(%)
`
`3
`4
`5
`6
`Mean
`S.D.
`
`4.0
`0.5
`2.0
`2.5
`2.25
`1.44
`
`15.5
`27.5
`15.8
`15.8
`18.7
`5.90
`
`46.2
`29.4
`24.3
`31.2
`32.7
`9.42
`
`35
`63
`56
`51
`51
`11.9
`
`Estimated by least-square regression.
`
`The peak concentration and peak time for di-
`azepam after intranasal administration are quite
`comparable to those found after 10 mg rectal
`suppository (Moolenaar et al., 1980), about 200
`ng/ml and 1.5 h respectively. When 10 mg di-
`azepam was administered as a rectal solution
`(Moolenaar et al., 1980), the peak concentration
`(290 ng/ml) was observed at 0.25 h and the
`concentration was approximately constant from
`the time of the peak to 3 h. Absorption from
`rectal solution achieved higher concentrations
`more quickly than we observed following in-
`tranasal administration.
`The results for lorazepam are shown in Table 2,
`and data from a representative subject in Fig. 2.
`The mean peak time of lorazepam concentration
`
`35
`
`25 -
`
`3
`
`15-
`
`1p_
`
`TABLE 2 Intranasal bioavailability of lorazepam Subject Peak time Peak conc. (ng/ml) (h) Nasal i.v. a Bioavailability 3 4.0 15.5 46.2 35 4 0.5 27.5 29.4 63 5 2.0 15.8 24.3 56 6 2.5 15.8 31.2 51 Mean 2.25 18,7 32.7 51 S.D. 1.44 5,90 9.42 11.9 a Estimated by least-square regression. The peak concentration and peak time for di- azepam after intranasal administration are quite comparable to those found after 10 mg rectal suppository (Moolenaar et al., 1980), about 200 ng/ml and 1.5 h respectively. When 10 mg di- azepam was administered as a rectal solution (Moolenaar et al., 1980), the peak concentration (290 ngJml) was observed at 0.25 h and the concentration was approximately constant from the time of the peak to 3 h. Absorption from rectal solution achieved higher concentrations more quickly than we observed following in- tranasal administration. The results for lorazepam are shown in Table 2, and data from a representative subject in Fig. 2. The mean peak time of lorazepam concentration 2s 8 lo 10 2o 3o 4O so Time [hr) Fig. 2. Time course of lorazepam concentration in plasma of subject 6 following i.v. (o) and intranasal ([3) administration. 173 in plasma of the 4 subjects following intranasal administration was 2.25 h, but varied from 0.5 to 4 h. Mean peak concentration was 18.7 ng/ml following intranasal administration and 32.7 ng/ml following i.v. administration. In one sub- ject (number 4), peak concentration was compara- ble following intranasal and i.v. administration. This subject also had the shortest peak time, 0.5 h. Bioavailability ranged from 35% to 63% with a mean of 51%. The peak concentration (20.7 mg/ml) and time (2.2 h) reported by Greenblatt et al. (1982) for sublingual administration is simi- lar to that observed here for intranasal administra- tion. The mean peak time for intranasal diazepam absorption is shorter than for lorazepam, 1.38 h vs. 2.25-3 h, and the extent of absorption is greater for diazepam, the more lipophilic drug. The rate of intranasal absorption of both drugs is rather slow for the treatment of a medical emer- gency such as status epilepticus. It is generally recognized that the high peak concentration fol- lowing i.v. administration of benzodiazepine is essential for action. It may be possible to improve the intranasal absorption of benzodiazepines through the use of another solvent, use of a cosolvent, or use of an aerosol to maximize con- tact of the solution with the biological barrier, although the poor aqueous solubility of these drugs is likely to limit the success of this route. Due to the poor aqueous solubility of the benzodi- azepines, the surfactant Cremophor was used neat in this study, and may have promoted absorption through the undesirable effect of disrupting the mucosal barrier (mild irritation was observed in some subjects). It appears that there is little room between the poor aqueous solubility of these com- pounds and the potential for solvent irritation (and toxicity, not addressed in this study) to achieve a satisfactory formulation. Although diazepam and lorazepam cross the nasal mucosa and are absorbed into the systemic circulation, absorption is rather slow and peak concentration is low relative to that found after i.v. administration. It would appear that this route of administration may be of limited utility for benzodiazepines in the treatment of status epi- lepticus where rapid onset of effect is essential.
`
`in plasma of the 4 subjects following intranasal
`administration was 2.25 h, but varied from 0.5 to
`4 h. Mean peak concentration was 18.7 ng/ml
`following
`intranasal administration and 32.7
`ng/ml following i.v. administration. In one sub-
`ject (number 4), peak concentration was compara-
`ble following intranasal and i.v. administration.
`This subject also had the shortest peak time, 0.5 h.
`Bioavailability ranged from 35% to 63% with a
`mean of 51%. The peak concentration (20.7
`mg/ml) and time (2.2 h) reported by Greenblatt
`et al. (1982) for sublingual administration is simi-
`lar to that observed here for intranasal administra-
`tion.
`The mean peak time for intranasal diazepam
`absorption is shorter than for lorazepam, 1.38 h
`vs. 2.25-3 h, and the extent of absorption is
`greater for diazepam, the more lipophilic drug.
`The rate of intranasal absorption of both drugs is
`rather slow for the treatment of a medical emer-
`gency such as status epilepticus. It is generally
`recognized that the high peak concentration fol-
`lowing i.v. administration of benzodiazepine is
`essential for action. It may be possible to improve
`the
`intranasal absorption of benzodiazepines
`through the use of another solvent, use of a
`cosolvent, or use of an aerosol to maximize con-
`tact of the solution with the biological barrier,
`although the poor aqueous solubility of these drugs
`is likely to limit the success of this route. Due to
`the poor aqueous solubility of
`the benzodi-
`azepines, the surfactant Cremophor was used neat
`in this study, and may have promoted absorption
`through the undesirable effect of disrupting the
`mucosal barrier (mild irritation was observed in
`some subjects). It appears that there is little room
`between the poor aqueous solubility of these com-
`pounds and the potential for solvent irritation
`(and toxicity, not addressed in this study) to
`achieve a satisfactory formulation.
`Although diazepam and lorazepam cross the
`nasal mucosa and are absorbed into the systemic
`circulation, absorption is rather slow and peak
`concentration is low relative to that found after
`i.v. administration. It would appear that this route
`of administration may be of limited utility for
`benzodiazepines in the treatment of status epi-
`lepticus where rapid onset of effect is essential.
`
`0
`
`10
`
`20
`
`30
`Time (hr)
`Fig. 2. Time course of lorazepam concentration in plasma of
`subject 6 following i.v. (0) and intranasal (0) administration.
`
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`

`174
`
`References
`
`174 References Freestone, D.S. and Weinberg, A.L., The administration of drugs and vaccines by the intranasal route. Br. J. Clin. Pharmacol., 3 (1976) 827-830. Gibaldi, M. and Pettier, D., Pharmacokinetics, 2nd edn., Marcel Dekker, New York, 1982. Greenblatt, D.J., Divoll, M., Harmatz, J.S. and Shader, R.I., Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular and oral lorazepam. J. Pharm. Sci., 71 (1982) 248-252. Greenblatt, D.J., Franke, K. and Shader, R.I., Analysis of lorazepam and its glucuronide metabolite by electron-cap- ture gas-liquid chromatography. J. Chromatogr., 146 (1978) 311-320. Homan, R.W. and Walker, J.E., Clinical studies of lorazepam in status epilepticus. A.V. Delgado-Escueta and C.G. Wasterlain (Eds.), Advances in Neurology, Vol. 34, Status Epilepticus, Raven, New York, 1983, pp. 493-498. Hussain, A., Foster, T., Hirai, S., Kashihara, T., Batenhorst, R. and Jones, M., Nasal absorption of propranolol in humans. J. Pharm. Sci., 69 (1980) 1240. Leppik, I.E., Derivan, A.T., Homan, R.W., Walker, J.W., Ramsay, R.E. and Patrick, B., Double-blind study of lorazepam and diazepam in status epilepticus. J. Am. Med. Assoc., 249 (1983) 1452-1454. Lewis, R.J. and Tatken, R.L., Registry of Toxic Effects of Chemical Substances, Vols. 1, and 2, U.S. Dept. of Health and Human Services, 1980. Meldrum, B., Physiological changes during prolonged seizures and epileptic brain damage. Neuropaediatrie, 9 (1978) 203-212. Moolenaar, F., Bakker, S., Visser, J. and Huizinga, T., Bio- pharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int. J. Pharm., 5 (1980) 127-137. Oxbury, J.M. and Whitty, C.W.M., Causes and consequences of status epilepticus in adults. Brain, 94 (1971) 733-744. Parr, G.D., Nasal delivery of drugs. Pharm. Int., 4 (1983) 202-205. Russell, M.A.H., Javis, M.J., Feyerabend, C. and Fern/5, O., Nasal nicotine solution: a potential aid to give up smoking? Br. Med. J., 286 (1983) 683-684. Rutherford, D.M., Rapid micro-method for the measurement of diazepam and desmethyldiazepam in blood plasma by gas-liqnid chromatography. J. Chromatogr., 137 (1977) 439-448. Salzman, R., Manson, J.E., Griffing, G.T., Kimmerle, R., Ruderman, N., McCall, A., Stoltz, E.J., Mallin, C., Small, D., Armstrong, J. and Melby, J.C., Intranasal aerosolized insulin mixed-meal studies and long-term use in type I diabetes. N. Engl. J. Med., 312 (1985) 1078-1084. Spiegel, A.J. and Noseworthy M.M., Use of nonaqueous solvents in parenteral products. J. Pharm. Sci., 52 (1963) 917-927. Su, K.S.E., Intranasal delivery of peptides and proteins. Pharm. lnt., 7 (1986) 8-11.
`
`Meldrum, B., Physiological changes during prolonged seizures
`and epileptic brain damage. Neuropaediatrie, 9 (1978)
`203-212.
`Moolenaar, F., Bakker, S., Visser, J. and Huizinga, T., Bio-
`pharmaceutics of rectal administration of drugs in man IX.
`Comparative biopharmaceutics of diazepam after single
`rectal, oral, intramuscular and intravenous administration
`in man. Int. J. Pharm., 5 (1980) 127-137.
`Oxbury, J.M. and Whitty, C.W.M., Causes and consequences
`of status epilepticus in adults. Brain, 94 (1971) 733-744.
`Parr, G.D., Nasal delivery of drugs. Pharm. Int., 4 (1983)
`202-205.
`Russell, M.A.H., Javis, M.J., Feyerabend, C. and Ferno, 0.,
`Nasal nicotine solution: a potential aid to give up smoking?
`Br. Med. J., 286 (1983) 683-684.
`Rutherford, D.M., Rapid micro-method for the measurement
`of diazepam and desmethyldiazepam in blood plasma by
`gas-liquid chromatography. J. Chromatogr., 137 (1977)
`439-448.
`Salzman, R., Manson, J.E., Griffing, G.T., Kimmerle, R.,
`Ruderman, N., McCall, A., Stoltz, E.J., Mallin, C., Small,
`D., Armstrong, J. and Melby, J.C., Intranasal aerosolized
`insulin mixed-meal studies and long-term use in type I
`diabetes. N. Engl. J. Med., 312 (1985) 1078-1084.
`Spiegel, A.J. and Noseworthy M.M., Use of nonaqueous
`solvents in parenteral products. J. Pharm. Sci., 52 (1963)
`917-927.
`Su, K.S.E., Intranasal delivery of peptides and proteins. Pharm.
`Int., 7 (1986) 8-11.
`
`Freestone, D.S. and Weinberg, A.L., The administration of
`drugs and vaccines by the intranasal route. Br. J. Clin.
`Pharmacol, 3 (1976) 827-830.
`Gibaldi, M. and Perrier, D., Pharmacokinetics, 2nd edn., Marcel
`Dekker, New York, 1982.
`Greenblatt, D.J., Divoll, M., Harmatz, J.S. and Shader, R.I.,
`Pharmacokinetic comparison of sublingual lorazepam with
`intravenous, intramuscular and oral lorazepam. J. Pharm.
`Sci., 71 (1982) 248-252.
`Greenblatt, D.J., Franke, K. and Shader, RI., Analysis of
`lorazepam and its glucuronide metabolite by electron-cap-
`ture gas-liquid chromatography. J. Chromatogr., 146 (1978)
`311-320.
`Homan, R.W. and Walker, J.E., Clinical studies of lorazepam
`in status epilepticus. A.V, Delgado-Escueta and C.G.
`Wasterlain (Eds.), Advances in Neurology, Vol. 34, Status
`Epilepticus, Raven, New York, 1983, pp. 493-498.
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`Neurelis - EX. 2009
`Aquestive Therapeutics, Inv. v. Neurelis, Inc. - IPR2019-00451
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