Microemulsion based intranasal delivery system for treatment of insomnia.

The aim of this investigation was to prepare and characterize microemulsions/mucoadhesive microemulsions of Diazepam (D), Lorazepam (L) and Alprazolam (A), evaluate their pharmacodynamic performances by performing comparative sleep induction studies in male albino rats to assess their role in effective management of insomnia patients. Microemulsions of Diazepam (DME), Lorazepam (LME) and Alprazolam (AME) were prepared by titration method and characterized for drug content, globule size distribution and zeta potential, nasal toxicity and sleep induction. DME, LME and AME were transparent and stable with mean globule size and zeta potential in the range of 95.6 nm to 141.7 nm and -2.205 to -0.111 mV respectively. The prepared microemulsions exhibited reversible nasal toxicity. Onset of sleep and duration of sleep were observed in the following order: Lorazepam > Alprazolam>Diazepam. Faster onset of sleep following intranasal administration of microemulsions (<20 min) compared to oral administration (29-33 min) and control group (>45 min) for all three drugs suggested selective nose-to-brain transport of drug(s). Intranasal administration of microemulsion based formulations resulted in even faster onset of sleep (<12 min) with intranasal mucoadhesive microemulsion(s) resulting in fastest onset of sleep (<9 min). Duration of sleep was longest with the intranasal mucoadhesive microemulsions. These results are suggestive of larger extent of distribution of drug(s) to brain after intranasal administration of mucoadhesive microemulsion(s). These results are further corroborated with by loss or rightening reflex and startle reflex at earlier time points (within 10 min and 15 min respectively) with mucoadhesive microemulsions. Thus, the results of this investigation indicated rapid and larger extent of drug transport to the rat brain resulting in rapid induction of sleep followed by prolonged duration of sleep in rats following intranasal administration of mucoadhesive microemulsion(s). However, the role of microemulsion based formulations developed in this investigation in clinical practice can only be established after animal studies in two different animal models followed by extensive clinical trials.

Recent patents review on intranasal administration for CNS drug delivery.

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.

Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting.

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.

In vitro assessment of acyclovir permeation across cell monolayers in the presence of absorption enhancers.

The aim of the investigation was to establish transepithelial permeation of acyclovir across Caco-2 and Madin-Darby canine kidney (MDCK) cell monolayers and attempt to improve its permeation by employing absorption enhancers (dimethyl beta cyclodextrin, chitosan hydrochloride and sodium lauryl sulfate) and combinations thereof. Caco-2 and MDCK cell monolayers have been widely employed in studying drug transport, mechanisms of drug transport, and screening of absorption enhancers and excipients. Transepithelial electrical resistance and permeation of 99mTc-mannitol were employed as control parameters to assess the tight junction and paracellular integrity. Permeation of acyclovir in the presence of absorption enhancers was found to be significantly higher compared with drug permeation in their absence when assessed as apparent permeability coefficients (Papp). Synergistic improvements in Papp values of acyclovir were obtained in case-selected combinations of absorption enhancers; dimethyl beta cyclodextrin-chitosan hydrochloride, chitosan hydrochloride-sodium lauryl sulfate, and dimethyl beta cyclodextrin-sodium lauryl sulfate, were used. Recovery and viability assessment studies of both cell monolayers suggested reestablishment of paracellular integrity and no damage to cell membranes. Significantly improved permeation of acyclovir in the presence of selected combinations of absorption enhancers may be used as a viable approach in overcoming the problem of limited oral bioavailability of acyclovir.

Nose-to-brain delivery of tacrine.

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.

Modulation of ganciclovir intestinal absorption in presence of absorption enhancers.

The purpose of this investigation was to study the influences of absorption enhancers in increasing oral bioavailability of Ganciclovir (GAN) by assessing the transepithelial permeation across cell monolayers in vitro and bioavailability in rats in vivo. The permeation of GAN across Caco-2 and MDCK cell monolayers in the absence/presence of dimethyl-beta-cyclodextrin (DMbetaCD), chitosan hydrochloride (CH), sodium lauryl sulphate (SLS), and their combinations was studied for a 2-h period. GAN was administered to rats in absence/presence of absorption enhancers and drug contents in plasma were estimated. We found that the apparent permeability coefficient (Papp) of GAN in absence of absorption enhancers (control) were 0.261 +/- 0.072 x 10(-6) and 0.486 +/- 0.063 x 10(-6) cm/s in Caco-2 and MDCK cell monolayers, respectively, whereas in the presence of DMbetaCD, CH, SLS, and their combinations, Papp of GAN increased by 5- to 25-fold and 7- to 33-fold as compared to control in Caco-2 and MDCK cell monolayers, respectively. However, in rats, the maximum enhancement in bioavailability of GAN during coadministration of these absorption enhancers was only fivefold compared to GAN control. To conclude, the absorption enhancers-DMbetaCD, CH, SLS, and their combinations demonstrated significant improvement in transepithelial permeation and bioavailability of GAN.

Role of 99mTc-mannitol and 99mTc-PEG in the assessment of paracellular integrity of cell monolayers.

AIM: To assess the role of 99mTc-mannitol and 99mTc-polyethylene glycol 4000 in the evaluation of paracellular integrity of Caco-2 and Madine-Darby canine kidney (MDCK) cell monolayers, and confirm it in the presence of absorption promoters. METHODS: Radiolabelling of mannitol and polyethylene glycol was performed by a simple reduction method. Transepithelial electrical resistance values were measured to gain information regarding the integrity of tight junctions of Caco-2 and MDCK cell monolayers. Permeabilities of 99mTc-mannitol/99mTc-polyethylene glycol across cell monolayers were studied in the absence and presence of absorption promoters, namely dimethyl-beta-cyclodextrin, chitosan hydrochloride and sodium lauryl sulfate, and during recovery studies to assess paracellular integrity. RESULTS: Values for the apparent permeability coefficient (Papp) of Tc-mannitol were found to be 0.286 x 10 cm x s(-1) and 0.507 x 10 cm x s(-1) in Caco-2 and MDCK cell monolayers, respectively, whereas corresponding values for 99mTc-polyethylene glycol were 0.046 x 10 cm x s(-1) and 0.065 x 10 cm x s(-1). The insignificant Papp values of the marker molecules demonstrated the paracellular integrity of the cell monolayers. Significant increases in the Papp values in the presence of absorption promoters and their combinations due to opening of paracellular pathways and a return of Papp values to almost baseline values during recovery studies confirm the role of these marker molecules in the assessment of paracellular integrity of cell monolayers. CONCLUSION: 99mTc-labelled marker molecules can be attractive, useful and viable alternatives to the conventionally used markers in the assessment of paracellular integrity because of the absence of tissue-damaging corpuscular radiation and the ease of production of radiochemically pure and stable molecules at a reasonable cost.

Role of Caco-2 cell monolayers in prediction of intestinal drug absorption.

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.