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Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15POTENTIAL CLINICAL ADVANTAGES OF NANOCRYSTALSApplication for Oral Drug DeliveryThe oral route is the most important and preferred route of administration. The formulation of drugnanocrystals can impressively improve the bioavailability of perorally administered poorly soluble drugs. In 1995,Liversidge and Cundy reported an increase in bioavailability for the drug Danazol from 5.1 ± 1.9% for theconventional suspension to 82.3 ± 10.1% for the nanosuspension. [30] The increased dissolution velocity andsaturation solubility lead to fast and complete drug dissolution, an important prerequisite for drug absorption.Whenever a rapid onset of a poorly soluble drug is desired, the formulation of drug nanocrystals can be beneficial.If absorption windows limit the drug absorption or by food effects, drug nanocrystals have advantages incomparison to conventional suspensions. Another important advantage of drug nanocrystals is their adhesivenessand the increased residence time, which canpositively influence the bioavailability. The mucoadhesiveness can beraised by the use of mucoadhesive polymers in the dispersion medium. Additionally the utilized mucoadhesivepolymers can prevent the drug from degradation. The reduced particle size can be also exploited for improveddrug targeting, as reported for inflammatory tissues. [31] Nanosuspensions enable incorporation of all hydrophobicdrugs in well established sustained release technologies. However whole doing so,the effect and interaction ofdosage form excipients with the nanocrystalline drug must be critically investigated. Drug nanosuspensions can beincorporated into dosage forms, such as tablets, capsules, and fast melts by means of standard manufacturingtechnologies. A ketoprofen nanosuspension has been successfully incorporated into pellets to release drug over aperiod of 24 hrs. [32]Intravenous drug deliveryIn principle aqueous nanosuspensions are an ideal formulation approach to overcome side effectsof i. v. formulations due to not very well tolerated excipients (example: Paclitaxel formulated with Cremophor EL inthe product Taxol®; Itraconazole formulated with cyclodextrine in the product Sporanox®).However, injection ofnanosuspensions leads to a different pharmacokinetics compared to injecting the drug solutions. Nanocrystalsabove 200 nm do not dissolve fast enough; they are taken up by the macrophages of the liver, potentially targetingtoxicity to the liver. In case nanosuspensions of very small nanocrystals are injected, they dissolve much faster dueto their nanocrystals size well below 100 nm. Therefore they are considered to be better suited to minimize/avoiduptake by the liver and to mimic intravenously injected solutions. [33]Pulmonary drug deliveryAs an alternative to dry powders for inhalation, nanosuspensions can be used in case of poorly solubledrugs. Application can simply be performed by placing aqueous nanosuspensions in an aqueous nebulizer. Thenebulizer generates an aerosol, with a droplet size suitable for pulmonary administration, e.g. 1–5 μm droplets.The nanocrystals are contained inside these droplets. The nanocrystals cannot be inhaled as a powder. First of all,the nanocrystals are highly adhesive with a tendency to agglomerate, and in addition particles below 0.5–1 μm arebeing exhaled. The advantage of nanocrystals is that they show an increased dissolution velocity compared toInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 201110
Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15micronsized crystals. When the aerosol droplets deposit in the lung, as fine particles they should spread moreevenly on the lung surface, especially when stabilized with surfactants with good spreadability. Budesonide(corticosteroid) nanosuspensions for pulmonary delivery have been successfully formulated. [34] Intensive studiesfor pulmonary delivery of nanosuspensions were performed [35] by comparing different commercial portablenebulizers regarding their ability to nebulize nanosuspensions. [36] All of them were suitable, showing thatnebulisation of well-stabilized nanosuspensions can be performed successfully.Ocular drug deliveryNanosuspensions have not been yet exploited for this route of drug administration. The general problem isthat solutions are relatively fast cleared from the eye , adhesive nanoparticulate suspensions can show prolongedrelease due to their adhesion properties. Polymeric (Eudragit RS 100 and Eudragit RL 100) nanoparticulatesuspensions of flurbiprofen and ibuprofen [37] revealed superior in vivo performance over the existing marketedformulations and could sustain drug release for 24 h. Drug nanosuspensions can also be used for drugs that exhibitpoor solubility in lachrymal fluids providing advantages of prolonged residence time in a cul-de-sac. Currentlythere are few studies are investigating NSAIDs in the form of nanocrystals for ophthalmic application. [38] Anincreased rate and extent of drug absorption and intensity of drug action was reported for ocular nanosuspensionsof hydrocortisone, prednisolone and dexamethasone. [39] In contrast to the polymeric nanoparticles,nanosuspensions have a clear regulatory advantage. The particles are drained via the lipophilic channels to thenose, from here to the pharynx. That means, the materials used in formulation need to be approved for occularadministration. As many polymers are not approved by official authorities. As nanosuspensions do not contain anymatrix material, and are purely composed of drug and comparatively small amount of stabilizer. [15]Dermal drug deliveryNanocrystals can increase the penetration of poorly soluble cosmetic and pharmaceutical actives into theskin.The increased saturation solubility leads to an increased concentration gradient, thus promoting passivepenetration. Molecules penetrated into the skin are very fast replaced by new molecules dissolving from thenanocrystal depot in the cream. The first four cosmetic nanocrystal products with rutin were launched by Juvena.Compared to the water-soluble rutinglucoside, the original rutin molecule as nanocrystal formulation possesses a500 times higher bioactivity (as measured by sun protection factor (SPF) [40] Of course the same principle can beapplied to poorly soluble pharmaceutical drugs of interest for dermal application.Targeted Drug DeliveryNanosuspension can be used for targeted delivery as their surface properties & changing of the stabilizercan easily alter in vivo behaviour. Their versatility and ease of scale up and commercial production enables thedevelopment of commercially viable nanosuspensions for targeted drug delivery. The natural targeting processcould pose obstacles when macrophages are not the desired targets.Hence, in order to bypass the phagocyticuptake of drugs,its surface potential needs to be altered. Kayser developed the formulation of aphidicolin as ananosuspension to improve the drug targeting effect against Leishmania-infected macrophages. He stated thatInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 201111
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