Anwar A. Hussain

Intranasal drug delivery

In recent years the nasal route has received a great deal of attention as a convenient and reliable method for the systemic administration of drugs. Although this route is currently being marketed for the systemic administration of several drugs, it has only recently been studied. This chapter deals with animal techniques to study nasal absorption and the effect of physico-chemical and biopharmaceutical properties of drugs on the rate and extent of absorption. It also discusses factors affecting peptide absorption and methods to improve the nasal bioavailability of peptides. In the last part of the chapter the utility of the nasal route for the delivery of drugs to the brain is discussed.

Enhancement of the Systemic and CNS Specific Delivery of L-Dopa by the Nasal Administration of Its Water Soluble Prodrugs

AbstractPurpose. To study the utility of the nasal route for thesystemic delivery of L-dopa using water soluble prodrugs of L-dopa and toexamine if this delivery method will result in preferential delivery to theCNS. Methods. Several alkyl ester prodrugs of L-dopa wereprepared and their physicochemical properties were determined. Invitro hydrolysis rate constants in buffer, rat plasma, rat brainhomogenate, rat CSF, and rat nasal berfusate were determined by HPLC. Invivo nasal experiments were carried out in rats. Levels of L-dopa anddopamine in plasma, CSF, and olfactory bulb were determined using HPLCmethod with electrochemical detection. Results. All the prodrugs showed improved solubility andlipophilicity with relatively fast in vitro conversion in ratplasma. Absorption was fast following nasal delivery of the prodrugs withbioavailability around 90%. Dopamine plasma levels did not changesignificantly following nasal administration of the butyl ester prodrug.Olfactory bulb and CSF L-dopa concentration were higher following nasaldelivery of the butyl ester prodrug compared to an equivalent intravenousdose. Conclusions. Utilization of water soluble prodrugs ofL-dopa via the nasal route in the treatment of Parkinsons disease may havetherapeutic advantages such as improved bioavailability, decreased sideeffects, and potentially enhanced CNS delivery.

Nasal absorption of naloxone and buprenorphine in rats

Abstract The nasal administration of naloxone (30 μg/rat) and buprenorphine (135 μg/rat) was studied in male rats following single doses and compared with intravenous and intraduodenal administration of the two drugs. The nasal bioavailabilities calculated from the ratio of the AUC (nasal/intravenous × 100) was 101% for naloxone and 95% for buprenorphine. The intraduodenal bioavailability for naloxone was only 1.5% of the intravenous bioavailability. These studies showed that the nasal route for the administration of these two drugs can be considered as effective as the parenteral route.

Hydrolysis of leucine enkephalin in the nasal cavity of the rat — A possible factor in the low bioavailability of nasally administered peptides

In order to investigate the utility of intranasal administration of peptides for systemic medication, the nasal absorption of the model peptide, leucine enkephalin (Tyr-Gly-Gly-Phe-Leu), was studied in the rat. At a concentration of 60 micrograms/ml in Ringers buffer the pentapeptide was found to undergo, extensive hydrolysis in the nasal cavity. The hydrolysis rather than the polarity of the pentapeptide appears responsible for limiting the nasal absorption of this model compound. In the presence of dipeptides, the hydrolysis of leucine enkephalin was significantly inhibited. These results suggest that the nasal administration of peptides may become an important route for drug administration provided that the peptidases in the nasal mucosa can be transiently inhibited via coadministration of pharmacologically inactive peptidase substrates.

Targeted brain delivery of 17β-estradiol via nasally administered water soluble prodrugs

The utility of the nasal route for the systemic delivery of 17β-estradiol was studied using watersoluble prodrugs of 17β-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17β-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17β-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17β-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17β-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17β-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimers disease.

Solubility enhancement of some developmental anti-cancer nucleoside analogs by complexation with nicotinamide

Abstract The use of the non-toxic vitamin, nicotinamide, as a solubilizing agent for the poorly water-soluble anti-cancer agents, erythro-9-(2-hydroxy-3-nonyl)adenine (NSC 263164), 3-deazauridine (NSC 126849) and thioquanine (NSC 752), is presented. NSC 263164 is shown to form 1:1 and 1:2 drug-nicotinamide complexes while NSC 126849 and NSC 752 probably form 1:1 complexes only. Nicotinamide complexation appears to be a useful approach to overcoming the most commonly encountered formulation problem in cancer chemotherapy, i.e. the lack of adequate solubility in physiologically acceptable Systems.

Thermogravimetric analysis of ethylene-vinyl acetate copolymers with Fourier transform infrared analysis of the pyrolysis products

Abstract Ethylene-vinyl acetate (EVAc) copolymers were examined using thermogravimetric analysis (TGA). The method permitted rapid and reproducible determination of the vinyl acetate content of the copolymer. The weight loss profile for low density polyethylene, i.e., ethylene-vinyl acetate with a 0% vinyl acetate content, showed a single-step decomposition from 460 to 560°C that accounts for 100% of the observed weight loss of the sample. The heating of ethylene-vinyl acetate with vinyl acetate contents from 9 to 40% resulted in a two-step decomposition in the ranges 360–450°C and 450–550°C. A TGA-Fourier transform infrared spectrometer (FTIR) coupled system permitted the identification of the pyrolytic products in the effluent gas as acetic acid for the first-step product, and a mixture of 1-butene, carbon dioxide, ethylene, methane, and carbon monoxide.

Nasal absorption of ondansetron in rats: an alternative route of drug delivery

Purpose: Ondansetron (OND) is a 5-HT3 receptor antagonist that is used therapeutically for the prevention of nausea and vomiting associated with emetogenic cancer therapy. There is a need for nasal drug delivery in specific patient populations where the use of commercially available intravenous and oral dosage forms may be inconvenient and/or unfeasible. Methods: OND (Zofran Injection, 2 mg/ml) was administered at a dose of 1 mg/kg to male Sprague-Dawley rats intravenously or intranasally (n = 3 in each group). A special surgical procedure was performed to ensure that the drug solution was held in the nasal cavity. OND was injected into the femoral vein for the intravenous group. Blood samples were collected at appropriate times for 60 min. An HPLC method was employed to determine OND in the plasma. Results: The results clearly showed that OND was readily and rapidly absorbed through the nasal mucosa of the rat. The peak plasma level was attained within 10 min. OND was also completely absorbed as the plasma concentration-time profiles for the two routes were comparable. The terminal elimination half-lives were also similar. Conclusions: The nasal administration route for OND is apparently as effective as the intravenous route. If one considers the limitations of delivering OND orally or intravenously to patients undergoing emetogenic cancer therapy, it becomes obvious that the intranasal route is a potential alternative modality to prevent nausea and vomiting associated with such therapy.

Design of novel prodrugs for the enhancement of the transdermal penetration of indomethacin

Abstract A series of esters of indomethacin containing tertiary amine functional groups and designed for transdermal delivery were synthesized. The rates of chemical hydrolysis of all the esters in pH 7.4 phosphate buffer were determined. For N,N-diethylaminopropyl N -(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indole acetate (ester 4), the rates of chemical hydrolysis in pH 5.5–11.25 buffers were investigated in detail. Ester 4 was chemically stable and had a higher n-octanol/water partition coefficient and a greater solubility in water at pH 7.4 than indomethacin. Furthermore, the rate of transdermal penetration of ester 4 through cadaver skin in Franz cells was found to be more than 10-times faster than that of indomethacin itself. Ester 4 was found to possess surface-active properties (CMC = 0.5 mg/ml). Assuming that micelles cannot penetrate biologic membranes, a corrected permeability coefficient was calculated for ester 4 using only the monomer concentration. This value, 3.6 × 10 −2 cm/h, was 100-times greater than that of indomethacin. These results suggest that prodrugs with structures similar to that of ester 4 may be useful for enhancing transdermal penetration of other carboxylic acid-containing anti-inflammatory agents.

Nipecotic acid : Systemic availability and brain delivery after nasal administration of nipecotic acid and n-butyl nipecotate to rats

No HeadingPurpose.The purpose of this research was to characterize nipecotic acid pharmacokinetics in blood and brain after intravenous (i.v.) and nasal administration of nipecotic acid and its n-butyl ester.Methods.Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized. Nipecotic acid concentration-time profiles were determined in blood by noncompartmental and compartmental methods. Nipecotic acid was also dosed i.v. and its n-butyl ester was dosed by nasal and i.v. routes, and brain levels of nipecotic acid over the subsequent 4 h (n = 5 rats/time point per route) were assessed.Results.The absolute systemic availability of nipecotic acid after nasal dosing was 14%. After i.v. and nasal dosing of the n-butyl ester, nipecotic acid systemic availability was 97% and 92%, respectively. Both i.v. and nasal administration of the n-butyl ester resulted in a significantly longer terminal half-life and larger mean resident time and volume of distribution for nipecotic acid than was observed after an i.v. nipecotic acid dose. Total brain exposure to nipecotic acid was not significantly different after nasal and i.v. dosing of the n-butyl ester. However, the brain/blood nipecotic acid ratio declined significantly with time after i.v. and nasal dosing of the ester prodrug. Nipecotic acid was not detectable in brain after i.v. dosing of nipecotic acid.Conclusions.The use of an ester formulation was crucial to delivering nipecotic acid to the brain. Preliminary evidence strongly suggests ester hydrolysis is rate limiting to nipecotic acid brain delivery. Once nipeoctic acid was formed, it displayed tissue trapping in brain. Parenteral dosing of nipecotic acid esters is unnecessary for systemic or brain delivery of nipecotic acid and possibly other CNS active zwitterion esters.