53 JPP 2004, 56: 53–60 ß 2004 The Authors Received June 4, 2003 Accepted August 20, 2003 DOI 10.1211/0022357022377 ISSN 0022-3573 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX-79106, USA Tianzhi Yang, Fatima Mustafa, Fakhrul Ahsan Correspondence: F. Ahsan, Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX-79106, USA. E-mail: fakhrul.ahsan@ttuhsc.edu Funding: This work was supported in part by a New Investigator Award, 0265182Y, from the American Heart Association, Texas Affiliate, Austin, TX. Alkanoylsucroses in nasal delivery of low molecular weight heparins: in-vivo absorption and reversibility studies in rats Tianzhi Yang, Fatima Mustafa and Fakhrul Ahsan Abstract The efficacy of alkanoylsucroses in enhancing nasal absorption of low molecular weight heparin (LMWH) and the time span of action of these agents on the nasal membrane has been investigated. In this regard, LMWH formulated with alkanoylsucroses was administered nasally to anaesthetized male Sprague-Dawley rats and the absorption of LMWH was determined by measuring plasma anti- factor Xa activity. The duration of action of these agents at the site of administration was investi- gated by an in-vivo reversibility study. The potency and efficacy of dodecanoylsucrose was compared with that of sodium glycocholate. Alkanoylsucroses used in this study include dodecanoylsucrose, decanoylsucrose and octanoylsucrose. These agents enhance nasal absorption of enoxaparin in a dose-dependent and chain-length-dependent manner. Of the agents tested, dodecanoylsucrose was found to be the most potent in enhancing nasal absorption of LMWH. The bioavailability of enoxaparin formulated with alkanoylsucroses was increased by several folds compared with enox- aparin formulated in saline. The reversibility study with dodecanoylsucrose showed that the effect of alkanoylsucroses faded away with time and the duration of action of this agent at the site of administration was 120–140 min. Dodecanoylsucrose was found to be twice as potent as sodium glycocholate. Overall, the nasal absorption of LMWH was effectively enhanced by co-administration of alkanoylsucroses and the effect of alkanoylsucroses on nasal epithelium was found to be rever- sible. The potency of these agents depends on their hydrophobic chain lengths. Introduction Low molecular weight heparins (LMWHs) are fragments of natural heparin produced by enzymatic or chemical depolymerization of unfractionated heparins (UFH) (Thanou et al 2001). In recent years, LMWH has been used as an alternative to unfractionated heparin in the treatment of deep vein thrombosis and pulmonary embolism. LMWH therapy is preferred to conventional heparin therapy, because LMWHs can be delivered subcutaneously with a bioavailability greater than 90% and have a much longer half-life. In addition, LMWHs do not bind at secondary locations, as does UFH, and thus do not cause many of the untoward effects asso- ciated with UFH. However, one of the major disadvantages of LMWH therapy is that it needs to be administered by the subcutaneous or intravenous route. Concerns have been raised about patient compliance, longer hospital stay and requirement of skilled health professionals for therapeutic drug monitoring and administration. These con- cerns have prompted interest in developing alternative drug delivery systems including oral, transdermal and nasal delivery of LMWH (Mitragotri & Kost 2001; Thanou et al 2001; Arnold et al 2002). In recent years, the nasal route has emerged as a route of choice for the systemic administration of drugs that are ineffective orally and must be administered by injection. Because of rich vasculature, avoidance of first-pass effect and ease of self administration, the nasal route has been proposed as a convenient and safe route of administration for non-invasive delivery of peptide and protein drugs (Ishikawa et al 2002). However, nasal drug delivery has been plagued with several disadvantages, including toxicity of absorp- tion promoters to the nasal membrane and impermeability of the nasal mucosa to Downloaded from https://academic.oup.com/jpp/article/56/1/53/6147150 by guest on 13 August 2022