The usefulness of Caco-2 cell monolayers in determining the intestinal drug absorption of potential drug candidates as such and from delivery systems, elucidating the underlying mechanisms thereof, presystemic metabolism, cellular uptake and cytotoxicological assessment has been exemplified in this review. The role of Caco-2 cell monolayers in studying the effectiveness, involved mechanism and toxicity of various excipients for drug absorption promotion has also been discussed.

The aim of the investigation was to prepare and characterize microemulsion/mucoadhesive microemulsion of tacrine (TME/TMME), assess its pharmacokinetic and pharmacodynamic performances for brain targeting and for improvement in memory in scopolamine-induced amnesic mice. The TME was prepared by the titration method and characterized. Biodistribution of tacrine solution and formulations after intravenous and intranasal administrations were evaluated using 99m Tc as marker. From the data, the pharmacokinetic parameters, drug targeting efficiency, and direct nose-to-brain drug transport were calculated. To confirm drug localization in brain gamma scintigraphy in rabbits was performed. Lower Tmax values (60 min) after intranasal compared with intravenous administration (120 min) suggested selective nose-to-brain transport. The brain bioavailability of tacrine after intranasal TMME compared with intranasal tacrine solution was found to be 2-fold higher indicating larger extent of distribution of the drug to brain with intranasal TMME. Rabbit brain scintigraphy also showed higher uptake of drug into the brain after intranasal administration. The results demonstrated rapid and larger extent of transport of tacrine into the mice brain and fastest regain of memory loss in scopolamine-induced amnesic mice after intranasal TMME. Hence, results are suggestive of possible role of intranasal tacrine delivery in treating Alzheimer's patients.

A simple mathematical method to express the deviation in release profile of a test product following Higuchi's kinetics from an ideal Higuchi release profile was developed. The method is based on calculation of area under the curve (AUC) by using the trapezoidal rule. The precision of prediction depends on the number of data points. The method is exemplified for 2 dosage forms (tablets of diltiazem HCl and microspheres of diclofenac sodium) that are designed to release the drug over a 12-hour period. The method can be adopted for the formulations where drug release is incomplete (<100%) or complete (100%) at last sampling time. To describe the kinetics of drug release from the test formulation, zero-order, first-order, Higuchi's, Hixson-Crowell's, and Weibull's models were used. The criterion for selecting the most appropriate model was based on the goodness-of-fit test. The release kinetics of the tablets and microspheres were explained by the Higuchi model. The release profiles of the test batches were slightly below the ideal Higuchi release profile. For the test products, observed percentage deviation from an ideal Higuchi profile is less than 16% for tablets and less than 11% for microspheres. The proposed method can be extended to the modified release formulations that are designed to release a drug over 6, 18, or 24 hours. If the data points are not evenly separated, the ideal drug release profile and AUC are calculated according to the specific sampling time. The proposed method may be used for comparing formulated products during the research and development stage, for quality control of the products, or for promoting products by comparing performance of the test product with that of the innovator's product.

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In the treatment of Alzheimer's disease tacrine, a cholinesterase inhibitor, is not the drug of choice due to its low oral bioavailability, extensive hepatic first-pass effect, rapid clearance from the systemic circulation, pronounced hepatotoxicity, and the availability of drugs better than tacrine in the same pharmacological class. Hence, the aim of this investigation was to ascertain the possibility of direct nose-to-brain delivery of tacrine to improve bioavailability, to avoid the first-pass effect and to minimize hepatotoxicity. Tacrine solution (TS) in propylene glycol was radiolabelled with (99m)Tc (technetium) and administered in BALB/c mice intranasally (i.n.) and intravenously (i.v.). Drug concentrations in blood and brain were determined at predetermined time intervals post dosing. Drug targeting efficiency (DTE %) and the brain drug direct transport percentage (DTP %) were calculated to evaluate the brain targeting efficiency. Brain scintigraphy imaging in rabbits was performed to ascertain the uptake of the drug into the brain. Tacrine solution was effectively labelled with (99m)Tc and was found to be stable and suitable for in-vivo studies. Following intranasal administration tacrine was delivered quickly (T(max) 60 min) to the brain compared with intravenous administration (T(max) 120 min). The brain/blood ratios of the drug were found to be higher for [(99m)Tc]TS(i.n.) compared with [(99m)Tc]TS(i.v.) at all time points. The DTE (207.23%) and DTP (51.75%) following intranasal administration suggested that part of tacrine was directly transported to brain from the nasal cavity. Rabbit brain scintigraphy imaging showed higher uptake of the drug into the brain following intranasal administration compared with intravenous administration. The results showed that tacrine could be directly transported into the brain from the nasal cavity and intranasal administration resulted in higher bioavailability of drug with reduced distribution into non-targeted tissues. This selective localization of tacrine in the brain may be helpful in reducing dose, frequency of dosing and dose-dependent side effects, and may prove an interesting new approach in delivery of the drug to the brain for the treatment of Alzheimer's disease.

The treatment of brain disorders is the greatest challenge because of a variety of formidable obstacles in effective drug delivery and maintaining therapeutic concentrations in the brain for a prolonged period. The brain is a delicate organ, and evolution built very efficient ways to protect it. The same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Approximately, 100% of large molecule drugs and >98% of small molecule drugs do not cross the blood-brain barrier (BBB). Many advanced and effective approaches to brain delivery of drugs have emerged in recent years. Intranasal drug delivery is one of the important delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory/trigeminal route and via peripheral circulation. Realization of nose to brain transport and the therapeutic viability of this route can be traced from the ancient times and has been investigated for rapid and effective transport in the last two decades. Many patents have been filed in recent past, claiming enhanced delivery of intranasally administered therapeutics to the brain via olfactory/trigeminal neural pathways, use of novel devices for targeted delivery to olfactory region etc. Various models have been designed and studied by scientists to establish the qualitative and quantitative transport through nasal mucosa to brain. The development of nasal drug products for brain targeting is still faced with enormous challenges. A better understanding in terms of properties of the drug candidate, nose to brain transport mechanism, and transport to and within the brain is of utmost importance. A critical review of recent patents claiming different approaches for enhanced brain delivery through the nasal route will help in determining the focus of this promising area of research.

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