November 1986
`November 1986
`Volume 75, Number 11
`Volume 75, Number 11
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`[
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`Sharon G. Boots
`Sharon G. Boots
`Editor
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`Karen L. Langridge
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`Journal of Pharmaceut-ical Sciences
`Journal of Pharmaceutical Sciences
`
`® ~!~~ of the .
`® ~~~~of the.
`
`American
`American
`Pharmaceutical
`Pharmaceutical
`Association
`Association
`
`November 1986
`November 1986
`Volume 75, Number 11
`Volume 75, Number 11
`
`Coden :75(11) 1017-1116 (1986)
`Coden:75(11) 1017-'1'6 (1986)
`ISSN: 0022-3549
`ISSN: 0022-3549
`
`Time in Review. Sliarori G. Boots . . ... . . .. ... ... .. .. . . .. .. . . . ... ...... . .. . .. . ... . ...... .. . ... ·. . . . . . . . . . . . . . . . . 1017
`. 1017
`Time in Review. Sharon' G. Boots
`
`EDITORIAL
`EDITORIAL
`
`SYMPOSIUM ARTICLES
`SYMPOSIUM ARTICLES
`
`Similarity Principles and Intrinsic Geometries: Contrasting Approaches to Interspecies Scaling. F . Eugene
`Similarity Principles and Intrinsic Geometries: Contrasting Approaches to Interspecies Scaling. F. Eugene
`Yates and Peter N . Kugler .. ... .. . .. .... .... .. .... . . .. ... . . .. ... .. ...... . ...... · ... . . . . . . ..... .... ... .. . .. .. .. . 1019
`Yates and Peter N. Kugler
`, . . . . . .. 1019
`
`Man versus Beast: Pharmacokinetic Scaling.in Mammals. Joyce Mordenti .· .. . . . ... .. . . . . .. .. . .. . .... . ....... . . 1028
`ScalingIn Mammals. Joyce Mordenti
`Man versus Beast: Pharmacokinetic
`.'
`1028
`
`Animal Extrapolation and the Challenge of Human Heterogeneity. Edward J . Calabrese .. . . .. . ... .. ... . .. ... .. 1041
`1041
`Animal Extrapolation and the Challenge of Human Heterogeneity. Edward J. Calabrese
`
`Interspecies Scaling of Regional Drug Delivery. Robert L. Dedrick . ....... . ....... .. .... . .. . ... . .. . ........... 1047
`Interspecies Scaling of Regional Drug Delivery. Robert L. Dedrick
`1047
`,
`
`Time Concepts in Physics, Biology, and Pharmacokinetics. Harold Boxenbaum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
`1053
`in Physics, Biology, and Pharmacokinetics. Harold Boxenbaum
`Time Concepts
`
`ARTICLES
`ARTICLES
`
`A Pharmacodynamic Model for the Activity of Antibiotics Against Microorganisms under Nonsaturable
`under Nonsaturable
`A Pharmacodynamic Model for the Activity of Antibiotics Against Microorganisms
`Conditions. Jianguo Zhi, Charles H. Nightingale, and Richard Quintiliani .. ... ..... . ......... . . . .... . . ... . ... . . . 1063
`1063
`Conditions. Jianguo Zhi, Charles H. Nightingale,
`'
`'
`and Richard Quintiliani
`,
`
`In Vitro Binding of Chloroquine to Rat Muscle Preparations. Anna C. MacIntyre and David J . Cutler .. .. : .. . . . .. 1068
`1068
`In Vitro Binding of Chloroquine to Rat Muscle Preparations. Anna C. MacIntyre and David J. Cutler
`: . . .
`
`Effects of Combined Administration of Diazepam and Imipramine Hydrochloride in Rats. Masahiko Okiyama,
`in Rats. Masahiko Okiyama,
`of Diazepam and Imipramine Hydrochloride
`Effects of Combined Administration
`Koichi Ueno, Satoshi Ohkawara, Shigeru Ohmori, Takcishi lgarashi, and Haruo K itagawa . . . . . . . . . . . . . . . . . . . . . . . . 1071
`Koichi Ueno, Satoshi Ohkawara, Shige.Tu Ohmori, Takcishi Igarashi, and Haruo Kitagawa
`1071
`_
`_
`_
`
`Thermal Chemistry of Podophyllotoxin in Ethanol and a Comparison of the Cytostatic Activity of the
`Thermal Chemistry of Podophyllotoxin in Ethanol and a Comparison of the Cytostatic Activity of the
`Thermolysis Products. Ole Buchardt, Roald Boe J ensen, Henrik F. Hansen, Peter E . Nielsen, Dorrit Andersen, and
`Thermolysis Products. Ole Buchardt, Roald Roe Jensen, Henrik F. Hansen, Peter E. Nielsen, Dorrit Andersen, and
`Ildiko Chinoin . .. .. .. . .. . . .. . .. . . .. . ... ..... . . . . .. . . ... ... .. ..... . . . '. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
`1076
`Ildiko Chinoin
`,
`, . . . . . . .
`.
`,
`
`S-Acylation of Cysteine by 0-Acetylsalicylic Anhydride: A Possible Mechanism for Aspirin Hypersensitivity? H.
`S-Acylation of Cysteine by O-Acetylsalicylic Anhydride: A Possible Mechanism for Aspirin Hypersensitivity? H.
`Dannan, M. N. Khawam, J.B. Bogardus, A. A. Hussain, and P.A. Crooks ....... .. .. .. .... . .. .. .... : .. .... . . . . . . 1081
`J. B. Bogardus, A. A. Hussain, and P. A. Crooks
`1081
`Dannan, M. N. Khawam,
`, . '"
`
`Intranasal Administration of Peptides: Nasal Deposition, Biological Response, and Absorption of
`Intranasal Administration of Peptides: Nasal Deposition, Biological Response, and Absorption of
`Desmopressin. A. S . Harris, I. M. N ilsson, Z. G-. Wagner, and U. Alkner .... . . . . .. . .. . . . . . . ....... .. .. ... ... . . .. 1085
`1085
`Desmopressin. A. S, Harris, 1. M. Nilsson, Z. G-. Wagner, and U. Alkner
`'"
`
`Dermal Penetration Enhancement Profile of Hexamethylenelauramide and Its Homologues: In Vitro Versus In
`and Its Homologues: In Vitro Versus In
`Dermal Penetration Enhancement Profile of Hexamethylenelauramide
`Vivo Behavior of Enhancers in the Penetration of Hydrocortisone. Dorla Mirejousky and Harun Takruri . . . . . . . . 1089
`Vivo Behavior of Enhancers in the Penetration of Hydrocortisone. Dorlo Mirejovsky and Harun Takruri
`1089
`
`Methods for In Vitro Percutaneous Absorption Studies VII: Use of Excised Human Skin. Robert L . Bronaugh,
`Methods for In Vitro Percutaneous Absorption Studies VII: Use of Excised Human Skin. Robert L. Bronaugh,
`Raymond F . Stewart, and Morton Simon . ..... ..... . . . . .. .. . ... . . . ... .. ... : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
`, .. 1094
`Raymond F. Stewart, and Morton Simon
`
`Permeation of Mouse Skin and Silicone Rubber Membranes by Phenols: Relationship to In Vitro Partitioning.
`Permeation of Mouse Skin and Silicone Rubber Membranes by Phenols: Relationship to In Vitro Partitioning.
`Walter E. J etzer, Abu S. Huq, Norman F . H. Ho, Gordon L. Flynn, Nandini Duraiswamy, and Lyman Condie, Jr . .. . 1098
`Walter E. Jetzer, Abu S. Hug, Norman F. H. Ho, Gordon L. Flynn, Nandini Duraiswamy,
`1098
`and Lyman Condie, Jr ....
`
`Determination of the Dissolution Rate Controlling Process for Isomeric Amides in Alkane Solvents. Dale Eric
`Determination of the Dissolution Rate Controlling Process for Isomeric Amides in Alkane Solvents. Dale Eric
`Wurster, Ho -Lun Weng, and Douglas R . Flanagan . . . . . .. .. . .. . .. . .. . . . .. .. . .. .. .... .. .... . . . ; . . .... . . . .. . .. .... 1104
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1104
`Wurster, Ho-Lun Weng, and Douglas R. Flanagan
`, . . . . . . . . . . ..
`
`Contents continued on III
`Contents continued on III
`
`Journal of Pharmaceutical Sciences I I
`Journal of Pharmaceutical Sciences / I
`Vol. 75, No. 11, November 1986
`Vol. 75. No. 11, November
`1986
`
`

`

`Contents continued from I
`Contents continued from 1
`
`Plasma Levels of the Prodrug, Arbaprostil, [(15R)-15-Methylprostaglandin E 2], and its Active, Antiulcer (15S)
`E,l, and its Active, Antiulcer
`[(lSR)-lS-Methylprostaglandin
`Plasma Levels of the Prodrug, Arbaprostil,
`(ISS)
`Epimer in Humans after Single Dose Oral Administration. J. W. Cox, W. M. Bothwell, R.H. Pullen, M.A.
`J. W. Cox, W. M. Bothwell, R. H. Pullen, M. A.
`Epimer
`in Humans after Single Dose Oral Administration.
`Wynalda, F. A . Fitzpatrick, and J. T. VanderLugt ... . .. . ... . ..... ... .. .. ............. . ........ . .......... . ..... 1107
`Wynalda, F. A. Fitzpatrick, and J. T. VanderLugt
`1107
`
`Comparison of Ultraviolet and Liquid Chromatographic Methods for Dissolution Testing of Sodium Phenytoin
`and Liquid Chromatographic Methods for Dissolution Testing of Sodium Phenytoin
`Comparison of Ultraviolet
`Capsules. Vinod P. Shah and Kathryn E. Ogger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
`Capsules. Vinod P. Shah and Kathryn E. Ogger . . . . . . . . . . . . . . . . . .. . ...
`. .. . . .. . . . .. . . . . . . . . . . .. ...
`. . . . . . .. . .. .. 1113
`
`BOOK REVIEWS
`BOOK REVIEWS
`
`Economic and Medicinal Plant Research, vol. 1. Edited by H. Wagner, Hiroshi Hikino and Norman R. Farnsworth.
`Economic and Medicinal Plant Research, vol. 1. Edited by H. Wagner, Hiroshi Hikino and Norman R. Farnsworth.
`Review by James D. McChesney . ........ . . . . . ............... . .. .... .... · .......... . _. .... . . . . . . . . . . . . . . . . . . . . . . . 1116
`Review by James D. McChesney. . .. . . .. . .. . . . . . . . . . . . . . .. . .. . . . . . . .. .. ... . .. . . . . . . .. .. . . . . . . . . . .. . ...
`. ...
`. . . . .. 1116
`
`Current Books .............. · ......... · .......... ·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116
`Current Books
`'. .. . .. .. .. . . . . . . .. . .. . . . . . .. .. .. .. .. . . . . . .. . .. . . . .. .. . . . .. .. . . . . . . . . . .. 1116
`
`Journal of Pharmaceutical Sciences I Ill
`Journal of Pharmaceutical Sciences / III
`Vol. 75, No. 11, November 1986
`Vol. 75. No. II, November 1986
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Intranasal Administration of Peptides: Nasal Deposition,
`Intranasal Administration of Peptides: Nasal Deposition,
`Biological flesponse, and Absorption of Desmopressin
`Biological Response, and Absorption of Desmopressln
`
`A. s. HARRIS,*6 x I. M. NILSSON,§ z. G-. WAGNER,:t: AND U.-ALKNER11
`A. s. HARRIS:'X
`Received June 9, 1986, from the *Faculty of Pharmacy, Biomedical Centr~ S-751 23 Uppsala, §Department of Coagulation Disorders, Malmo
`from the -Faculty of Pharmacy, BiomedicElI Centr~ $-751 23 UppsaJa, §Department of Coagulation Disorders, Malmo
`June 9, 1986,
`Received
`General Hospital, S-214 01 Malmo, *Fyzikon AB, S-221 OOLund, and the Department of Pharmacology, Ferring Pharmaceuticals; S-200 62
`'Fyzikon AB, $-221 00 Lund, and the Department
`General Hospital, $-21401 Malmo,
`of Pharmacology, Ferring Pnetmeceutlcels,
`$-20062
`Present addre_ss: 6 Ferring Research, S:200 62 Malmo, Sweden.
`Accepted for publication September 2, 1986.
`.Malmo, Sweeten.
`. Malmo, Sweden.
`Present address: 6Ferring Research, 8:20062 Malmo, Sweden.
`Accepted for publication September 2,1986.
`
`I. M. NILSSON,§ Z. G-. WAGNER,* AND U. ALKNER~
`
`.
`
`'
`
`Abstract □ The nasal administration of desinopressin [1-(3-mercapto(cid:173)
`[1-(3-mercapto-
`0 The nasal administration of desmopressin
`Abstract
`propionic acid)-8-o-arginine-vasopressin] in humans was investigated.
`propionic
`acldj-g-o-arqmlne-vasopressjn]
`in humans was investigated.
`Desmopressin solutions containing 99mTc-labeled human serum albu(cid:173)
`Desmopressin
`solutions containing 99mTc_labeled human serum albu-
`min were administered intranasally as a spray, using two metered-dose
`min were administered intranasally
`as a spray, using two metered-dose
`or as drops, using a rhinyle catheter or a slnqle-doss
`pumps, or as drops, using a rhinyle catheter or a single-dose pipet.
`pumps,
`pipet.
`Images of the sites of deposition and rates of clearance were monitored
`Images of the sites of deposition and rates 'o~clearance were monitored
`quantitatively by gamma scintigraphy. Plasma levels of desmopre~sin
`quantitatively
`by gamma scintigraphy. Plasma levels of desrnopressin
`were measured using a highly sensitive and specific radioimmunoassay.
`were measured using a highly sensitive and specific radlojmrnunoassay.
`The biological response was 9etermined by measuring circulating levels
`The biological
`response was determined .by measuring circulating levels
`of F VIII, tlie antihemophilia factor. The sprays were deposited mainly
`of F VIII,
`the antihemophilia
`factor. The sprays were deposited mainly
`anteriorly, from which small portions were cleared slowly into the nasal
`anteriorly,
`from which small portions were cleared slowly into the nasal
`pharynx. In contrast, the drops were deposit~d mostly posteriorly and
`pharynx.
`In Contrast,
`the drops were deposited mostly posteriorly and
`cleared very rapidly in large portions; some were swallowed immediate(cid:173)
`cleared very rapidly in large portions; some were swallowed immedlate-
`ly. Plasma levels showed that desmopressin was absorbed to a greater
`Iy. Plasma levels showed that desmopressin was' absorbed to a greater
`extent after administration of the spray with a 2 to 3-fold increase in the
`of the spray wlth a 2 to 3-fold increase in the
`extent after administration
`relative bioavailability compared with the drops. The biological response
`relative bioavailability
`compared with the drops. The biological
`response
`was c!early enhanced after spray administration and produced similar
`was clearly enhanced -after spray administration
`and produced similar
`increases in F VIII activity. A linear correlation was observed betVleen
`increases
`in F VIII activity. A linear correlation was observed' between
`maximum plasma desmopressin levels and maximum F VIII activity. The
`maximum plasma desmopressin
`revels and maximum F VIII activity: The
`use of an intranasal spray device can deposit well-controlled doses
`use of an intranasal
`spray device can deposit well-controlled
`doses
`within the nasal cavity, which remain there sufficiently long to provide a
`within the nasal cavity, which remain there sufficiently long to provide a
`.
`clear enhancement in absorption and bioavailability.
`clear enhancement
`in absorption
`and bioavailability.
`.
`
`It has recently become evident that intranasal administra(cid:173)
`administra-
`intranasal
`It has recently become evident that
`tion is useful for delivering drugs to the systemic circulation.
`tion is useful for delivering drugsto the systemic circulation.
`In the past, the administration of drugs by the nasal route
`In the past, the administration of drugs by the nasal route
`has concentrated on local action on the muccis_a. The large
`has concentrated on local action on the mucosa. The large
`surface area of the nasal cavity, its highly vascularized bed of
`surface area of the nasal cavity, its highly vascularized bed of
`mucosa, and the fact that it appears to contain little metabo(cid:173)
`mucosa, and the fact that
`it appears to contain little metabo-
`lizing capacity,1 all contribute toward making it a useful site
`lizing capacity,' all contribute toward making it a useful site
`for drug absorption. Drugs which have hitherto only· been
`for drug absorption. Drugs which have hitherto only been
`administered parenterally have become the primary candi(cid:173)
`administered parenterally have become
`the primary candi-
`dates. In particular, polypeptides, such as insulin,2 luteiniz(cid:173)
`In particular,
`dates.
`polypeptides,
`such as insulin,» luteiniz-
`ing hormone releasing hormone (LHRH),3 secretin,4 and
`ing hormone
`releasing
`hormone
`(LHRH),3 secretin.s
`and
`growth releasing factor (GRF),5 have been investigated for
`growth releasing factor (GRF),' have been investigated for
`their therapeutic activity following intranasal administra(cid:173)
`their
`therapeutic
`activity .following intranasal
`administra-
`tion.
`tion.
`The standard method of administration has been in -the
`has been in the
`The standard method of administration
`form of sprays or drops which have been delivered using
`form of sprays or drops which have been delivered using
`rhinyle catheters, single-dose pipets, or metered-dose, pre(cid:173)
`rhinyle
`catheters,
`single-doss pipets, or metered-dose, pre-
`compression spray pumps. It has been postulated that the
`compression spray pumps. It has been postulated that
`the
`site of deposition and rate of clearance of the drug will
`site of deposition and rate of clearance of the drug will
`influence its absorption and, therefore, the therapeutic ef(cid:173)
`influence its absorption and,
`therefore,
`the therapeutic
`ef-
`fect. 6 Moreover, it has been demonstrated that the choice of
`fact." Moreover,
`it has been demonstrated that
`the choice of
`the delivery system, whether by spray or drops, will influ(cid:173)
`the delivery system, whether by spray or drops, wiil influ-
`ence the site of deposition and its subsequent clearance.6 •7 •8 A
`ence the site of deposition and its subsequent clearance.e.t-e A
`,study by Hardy et al. 6 compared the deposition and clearance
`.etudy by Harp,y et a1.6 compared the deposition and clearance
`of solut~ons administered by spray (100 µL) and by one (30
`of solutions administered by spray (100 I-'L)and by one (30
`µL) or three nasal drops (90 µ.L). The nasal spray was found
`I-'L)or three nasal drops (90 pL). The nasal spray was found
`to deposit anteriorly in the nasal atrium in contrast to the
`to deposit anteriorly in the nasal atriuni
`in contrast
`to the
`drops which dispersed throughout the length of the nasal
`drops which dispersed throughout
`the length of the nasal
`cavity. As a consequence, the spray was found to clear more
`cavity. As a consequence,
`the spray was found t() clear mOTe
`slowly than the drops, since most of the spray deposited on
`slowly than the drops, since most of the spray deposited on
`.
`nonciliated regions.
`nonciliated regions.
`
`Although these previous studies have investigated in some
`Although these previous studies have investigated in some
`detai1 the method and technique of nasal administration, no
`detail
`the method and technique of nasal administration,
`no
`work has been done on the relationship between depos_ition
`work has been done on the relationship 'between deposition
`and in vivo absorption and the effect of nasal delivery
`and in. vivo absorption and the effect of nasal delivery
`systems on resulting biological response. Using the peptide
`systems on resulting biological response. Using the peptide
`desmcipressin (DDAVP) as a model, we compared various
`desmopressin
`(DDA VP) as a model, we compared various
`methods of intranasal delivery by measuring the deposition
`methods of intranasal
`delivery by measuring the deposition
`and clearance of drugs in the nasal cavity using gamma
`of drugs in the nasal cavity using gamma
`and clearance
`scintigraphy and systemic absorption using a specific radio(cid:173)
`scintigraphy
`and systemic absorption using ~ specific radio-
`iminunoassay, and, by determining the effect on circulating
`immunoassay,
`and, by determining the effect on circulating
`·
`levels of the a.ntihem~phelia factor (F VIII).
`levels of the antihemophelia
`factor (F VIII).
`.
`
`Experimental Section
`Experimental Section
`Materials-Desmopressin [1-(3-mercaptopropionic acid)-8-o-argi(cid:173)
`[1.(3-mercaptopropionicacidl-Bcn-argi-
`Materials-c-Oesmopressin
`nine vasopressin; Minirin, lot no. 85K24, Ferring Pharmaceuticals;
`nine vasopressin; Minirin, lot no. 85K2.4, Ferring Pharmaceuticals;
`Malmo, Sweden] and 99mTc-label~d human serum albumin
`Malmo, Sweden] and 99mTc·labeled human serum albumin
`(TechneScan, Microspheres 20/40, Mallinckrodt Diagnostica, Hol(cid:173)
`(Technedcan, Microspheres 20/40, Mallirickrodt Diagnostica, Hal-
`iand) were·used. All reagents were analytical grade.
`land) were used. All reagents were analytical grade.
`· Nasal Formulations-The desmopressin (DDA VP) solutions were
`. Nasal Formulations-The desmopressin(DDAVP) solutionswere
`prepared under aseptic conditions.- Nasal _formulations were pre(cid:173)
`prepared under aseptic conditions. Nasal formulations were pre-
`pared containing either 1.5 or 3.0 mg/mL desniopressin in 0.9%
`pared containing either 1.5 or 3.0 mg!mL desniopressin in 0.9%
`.,
`sodium chloride (w/v) and 5% chlorobutanol (w/v).
`sodium chloride (w!v)and 5%chlorobutanol (w!v).
`..
`The rhiriyle delivery device was a calibrated plastic catheter
`The rhinyle delivery device was a calibrated plastic catheter
`designed to give a dose of 200 µL or 300 µg from a solution of 1.5 mg/
`designed to give a doseof200 ,uL or 300 p.gfrom a solution ofl.5 mgt
`mL desmopressin: The inti'l:!nasal single-dose pipet w_as supplied in
`mL desmopressin. The intranasal
`single-dosepipet was supplied in
`the commercial fonn, mamifactured using the "Bottelpack" (Rom(cid:173)
`the commercial form, manufactured
`using the "Bottelpack"
`(Rom-
`rnerlag GmbH, Switzerland) principle of fill, fonn, and seal in a
`merlag GmbH, Switzerland) principle of fill, form, and seal in a
`single operation. Each pipet contained 200 µLor 300 µg of 1.15 mg/
`single operation. Each pipet contained 200 p.Lor 300 p.gof 1.15mgt
`mL desmopressiri. Nasal sprays were supplied as precompressi<in,
`mL desmopressiri. Nasal sprays were supplied as precompressicn,
`metered dose, spray pumps (Pfeiffer GmbH, Radolfzell, West Germa(cid:173)
`metered dose,spray pumps (PfeifferGmbH,Radolfzell, West Genna-
`ny). Two pumps were tested: one gave a volume of 100 µ.Lor 150 µg
`ny). Twopumps were tested: one gave a volume,of 100 -p.L or 150 J-Lg
`of 1.5 mg/mL desmopressin; the either gave a volume of 50 µL or 150
`of 1.5mg/mLdesmopressin;the other gave a volume of 50 JLL or 150
`µg of 3.0 mg/mL drug per actuation. Radiolabeling · of each device
`JLg of 3.0 mg/mL drug per actuation. Radiolabeling
`·of each device
`was done by addition of 1 mg of human serum albumin radio labeled
`was done by addition of 1 mg of human serum albumin radiolabeled
`with 100:-200 MBq 99mlfc. Each dose contained 2-4 MBq 99°'Tc.
`with 100:-200MBq 99mTC. Each dose contained 2-4 MBq 99m1fC.
`Deposition Studies-The nasal solutions were administered to six
`Deposition Studies-The nasal solutions were administered to six
`heaithy male volunteers aged 30 years or more. None of the subjects
`healthy male volunteers aged 30 years or more. None ofthe subjects
`had nasal problems and all were free from colds. Separated by an
`had nasal problems and all were free from colds. Separated by an
`interval of at least 3 d, each subject received all four treatments
`interval of at least 3 d, each subject received all four treatments
`which were _allocated in a blind, randomized sequence using coded,
`which were .allocatedin a blind, randomized sequence using coded,
`sealed envelopes. In this way, a total of 24 administrations were
`sealed envelopes. In this way" a total of 24 'administrations were
`made. The study was approved by the hospital ethical committee and
`made. The study was approvedby the hospital ethical committee and
`radioisotope committee, and each subject gave written informed
`radioisotope committee, and each subject gave written informed
`·
`'
`consent prior to entry into the study.
`consent prior to entry into the study.
`.
`All nasal solutions were administered with the subjects sitting in
`All nasal solutions were administered with the subjects sitting in
`an upright position and into the same nostril oh each occasion. A
`an upright position and into the same nostril on each occasion. A
`standard dose of 300 µg of desmopi-essin was self-administered in
`standard dose of ,300 1J,gof desmopressin was self-administered in
`every case. The rhinyle drops were administered by first filling 0,2
`every case. The rhinyle drops were administered by first filling 0,2
`mL of solution into the tube: One end of the tube was then put into
`mL of solution into the tube; One end of the tube was then put into
`the mouth, the other end was introduced 5-10 mm into the nostril,
`the mouth, the other end was introduced 5-10 mm into the nostril,
`and delivery was accomplished by blowing. The dose from the pipet
`and delivery was accomplishedby blowing. The dose from the pipet
`was administered by the following procedure: the subject's head was
`was administered by the followingprocedure: the subject's head was
`tilted back and individual drops were dispensed into the nostril
`tilted back and individual drops were dispensed into the nostril
`during normal breathing. The head was turned to the right arid left
`during normal breathing. The head was turned to the right and left
`and then back to the original position before the subject assumed a
`and then back to the original position before the subject assumed a
`normal sitting position. The two nasal sprays were designed to give
`nonnal sitting position. The two nasal sprays were designed to give
`accurate doses of 50 and 100 µL, respectively. Prior to administra(cid:173)
`accurate doses of 50 and 100 JLL, respectively. Prior to administra-
`tion, each spray device was primed by activating the pump five
`tion, each spray device was primed by activating the pump five
`
`0022-3549/86/ 1100-1085$01.00/0
`0022-3549/86//100-1085$01.00/0
`© 1986, American Pharmaceutical Association
`© 1986, American Pharmaceutical
`Association
`
`Journal of Pharmaceutical Sciences / 1 085
`Sciences /1 085
`Journal of Pharmaceutical
`Vol. 75, No. 11, November 1986
`Voi. 75, No. 11, November
`1986
`
`

`

`times. The applicator tip was introduced 5 to 10 mm into the nostril,
`times. The applicator
`tip was introduced 5 to 10 rom into the nostril,
`and two doses of 100 or 50 µL were dispensed during normal
`and two doses of 100 or 50 ,uL were dispensed
`during: normal
`inhalation, with the contralateral nostril open. Throughout the
`inhalation,
`with the
`contralateral
`nostril
`open. Throughout
`the
`study, and at each monitoring period, the subjects continued to
`study,
`and at each monitoring
`period,
`the subjects
`continued
`to
`breath normally but did not blow their noses or sneeze. Food and
`breath
`normally
`bout did not blow their noses or sneeze. Food and
`drink were withheld for the first hour an