{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:13:51Z","timestamp":1774350831124,"version":"3.50.1"},"reference-count":11,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[1999,4,1]],"date-time":"1999-04-01T00:00:00Z","timestamp":922924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 \u03bcL, the maximum volume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formulations containing benzodiazepines and to document the effects to support clinical trials in man.<\/jats:p>\n               <jats:p>After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single-dose studies with examinations 5 or 10 min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)-glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14-day repeated-dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)-glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four-week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)-glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150-\u03bcL doses daily, but no abnormalities after one or three 100-\u03bcL doses daily.<\/jats:p>\n               <jats:p>It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non-irritating drugs for short-term use in man.<\/jats:p>","DOI":"10.1211\/0022357991772565","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T22:04:05Z","timestamp":1033509845000},"page":"377-383","source":"Crossref","is-referenced-by-count":17,"title":["Single- and Repeated-dose Local Toxicity in the Nasal Cavity of Rabbits after Intranasal Administration of Different Glycols for Formulations Containing Benzodiazepines"],"prefix":"10.1093","volume":"51","author":[{"given":"Rolf K","family":"Hjortkj\u00e6r","sequence":"first","affiliation":[{"name":"Danish Toxicology Centre, ATV , Kogle All\u00e9 2, DK-2970 H\u00f8rsholm,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Bechgaard","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, The Royal Danish School of Pharmacy , Universitetsparken 2, DK-2100 Copenhagen \u00d8,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sveinbj\u00f6rn","family":"Gizurarson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Iceland , Hagi vid Hofsvallagotu, PO Box 7171, 127 Reykjavik,","place":["Iceland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Suzdak","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S , Novo All\u00e9, DK-2880 Bagsv\u00e6rd,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Mcdonald","sequence":"additional","affiliation":[{"name":"Danish Toxicology Centre, ATV , Kogle All\u00e9 2, DK-2970 H\u00f8rsholm,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R J","family":"Greenough","sequence":"additional","affiliation":[{"name":"Inveresk Research , Tranent EH33 2NE,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[1999,4,1]]},"reference":[{"key":"2024103110023372800_cit1","volume-title":"Method of administering a biologically active substance","author":"Bechgaard","year":"1995"},{"key":"2024103110023372800_cit2","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/j.2042-7158.1997.tb06105.x","article-title":"Pharmacokinetic and pharmacodynamic response after intranasal administration of diazepam to rabbits","volume":"49","author":"Bechgaard","year":"1997","journal-title":"J. Pharm. Pharmacol."},{"key":"2024103110023372800_cit3","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3109\/10837459709031449","article-title":"Solubilization of various benzodiazepines for intranasal administration, a pilot study","volume":"2","author":"Bechgaard","year":"1997","journal-title":"Pharm. Dev. Technol."},{"key":"2024103110023372800_cit4","volume-title":"Glycofurol. Toxicity Profile","author":"BIBRA","year":"1992"},{"key":"2024103110023372800_cit5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0378-5173(94)00365-C","article-title":"Morphological examination of rabbit nasal mucosa after exposure to acetylsalicylic acid, glycofurol 75 and ephedrine","volume":"119","author":"Bindseil","year":"1995","journal-title":"Int. J. Pharm."},{"key":"2024103110023372800_cit6","first-page":"229","article-title":"Nasal drug delivery and delivery systems","volume-title":"Novel Drug Delivery Systems","author":"Chien","year":"1994","edition":"2nd"},{"key":"2024103110023372800_cit7","first-page":"67","article-title":"Intranasal drug delivery for systemic medication","volume":"4","author":"Chien","year":"1987","journal-title":"Crit. Rev. Ther. Drug Carrier Syst."},{"key":"2024103110023372800_cit8","first-page":"105","article-title":"Animal models for intranasal drug delivery studies","volume":"2","author":"Gizurarson","year":"1990","journal-title":"Acta Pharm. Nord."},{"key":"2024103110023372800_cit9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0300-483X(95)03201-P","article-title":"Evaluation of local toxicity after repeated intranasal vaccination of guinea-pigs","volume":"107","author":"Gizurarson","year":"1996","journal-title":"Toxicology"},{"key":"2024103110023372800_cit10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3109\/10611869609015963","article-title":"Nasal delivery. The use of animal models to predict performance in man","volume":"3","author":"Illum","year":"1996","journal-title":"J. Drug Target."},{"key":"2024103110023372800_cit11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1398-9995.1989.tb02268.x","article-title":"A new formulation of flunisolide for intranasal application reduces side-effects","volume":"44","author":"Nielsen","year":"1989","journal-title":"Allergy"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1211%2F0022357991772565","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/4\/377\/60262042\/0022357991772565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/4\/377\/60262042\/0022357991772565.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T10:32:45Z","timestamp":1730370765000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/51\/4\/377\/6157268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,4,1]]},"references-count":11,"journal-issue":{"issue":"4","published-online":{"date-parts":[[1999,4,1]]},"published-print":{"date-parts":[[1999,4,1]]}},"URL":"https:\/\/doi.org\/10.1211\/0022357991772565","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1999,4]]},"published":{"date-parts":[[1999,4,1]]}}}