Current Drug Delivery - Volume 9, Issue 2, 2012

Colon-targeted delivery of natural products has recently gained importance in addressing specific needs in the therapy of colon-based diseases, such as irritable bowel syndrome, Crohn's disease and ulcerative colitis, and cancer. For the treatment or chemoprevention of these pathologies many drugs and chemopreventive agents were introduced and are currently at disposition. Many approaches have been attempted for the development of colon-specific delivery systems, but many failed in the past. Recent research in the exploitation of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in the design of novel colon-targeted delivery systems based on natural products. The most part of orally administered drugs are absorbed in the upper gastrointestinal tracts (e.g. stomach and small intestine) leading to several side effects. Colon targeting is much attractive for delivery on natural products and colonic delivery of this specific drugs may also be useful when intentional delayed drug absorption is required such as asthma, gastric ulcer or arthritis….

A pro-drug is a substance administered in a pharmacologically inactive structure that, once administered, is metabolised in vivo into the corresponding active principle. The rationale for the design of prodrugs is the optimisation of absorption, distribution, metabolism, and excretion (ADME). Moreover these compounds are frequently synthesized to improve bioavailability. 5-Amino salicylic acid (5-ASA) represents one of the most efficient agents for ColoRectal Cancer (CRC) treatment. Its inclusion in natural or semi-synthetic cyclodextrins (CDs) has been extensively studied to enhance drug properties as solubility, stability, and bioavailability. On the other hand, very recently naturally occurring 4'- geranyloxyferulic acid and auraptene were found as novel promising agents for the treatment of colon diseases, like adenomas and adenocarcinomas. In this review we will focus our attention on the reported pharmacological activity and analytical assays for the most representative 5-ASA pro-drugs already in a therapy for the treatment of CRC and on novel prodrugs of 4'-geranyloxyferulic acid and auraptene that were shown to be efficient in vivo as dietary feeding colon cancer chemopreventers in mice.

Camptothecins are a family of alkaloids originally extracted from the Chinese tree Camptotheca acuminata, Nyssaceae, exhibiting a strong activity against colorectal cancer (CRC). CRC is a common malignancy worlwide. Despite significant developments in the treatment of this disease, it still causes considerable morbidity and mortality. Recent advances include both newer cytotoxic chemotherapies and novel biological agents including the more hydrosoluble camptothecin derivative, namely irinotecan. Camptothecin and irinotecan are selective human topoisomerase I inhibitors but their application for curing CRC is compromised by their intrinsic high toxicity, insolubility and instability. Furthermore, pharmacology studies have determined that continuously and prolonged schedules of administration are required. The aim of this work is to review the state of the art of camptothecin and its derivative irinotecan's delivery methods.

The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

In the field of pharmaceutical science and drug development, there are important and particular challenges related to the selection of suitable and compatible ingredients as well as the design of successful formulations. As plasticization is a phenomenon widely exploited in all formulation fields, plasticizers should be recognized as a critical aspect for drug delivery. The choice of an appropriate plasticizer requires a wide background of information. This is because they are incorporated into drug delivery systems containing an assortment of ingredients which may have different reactions to the presence of plasticizers. Concurrently, there are numerous pharmaceutical plasticizers and various environmental issues dictating favored solutions. To address these encumbrances, an extensive information concerning plasticizers; their types, properties, pharmaceutical roles, etc. is discussed. Additionally, the specific objective of this review is to substantiate the safety and performance of newly discovered plasticizers.

The aim of this study was to characterize the nanostructures formed from assembly of poly(ethylene oxide)-bpoly( α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) in water, determine the effect of weight fraction of the hydrophilic block( fEO) on their morphology, and to investigate their potential for solubilization and delivery of P-glycoprotein (P-gp) inhibitor, valspodar. Three PEO-b-PBCL block copolymers having fEO ranging from 0.18-0.40 were synthesized. Assembly of PEO-b-PBCL was triggered through a co-solvent evaporation method. The average critical aggregation concentration (CAC) for PEO114-b-PBCL30, PEO114-b-PBCL60, and PEO114-b-PBCL95 was found to be 62, 41, and 23 nM, respectively. A lower rigidity of the hydrophobic domain in nanostructures formed from the assembly of PEO114-b- PBCL60 and PEO114-b-PBCL95 in comparison to PEO114-b-PBCL30 was observed. The morphology of the assembled structures was characterized by transmission electron microscopy (TEM). The TEM images of PEO114-b-PBCL30 (fEO = 0.40) showed the formation of spherical micelles with high polydispersity, whereas the assembly of PEO114-b-PBCL60 (fEO = 0.25) and PEO114-b-PBCL95 (fEO = 0.18) resulted in a mixed population of spherical micelles and vesicles. Valspodar achieved high loading in all the three PEO-b-PBCL nanocarriers reaching aqueous solubility of nearly 2 mg/mL. The morphology of PEO-b-PBCL carrier did not seem to influence the pharmacokinetics of the encapsulated valspodar in rats following intravenous administration. In conclusion, the results show a potential for PEO-b-PBCL nanocarriers as efficient solubilizing agents for delivery of valspodar.

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm2/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

The main aim of the present investigation is to develop and characterize the self-nanoemulsifying drug delivery systems (SNEDDS) of atorvastatin calcium (ATV) for improving the dissolution thereby oral bioavailability and to minimize the gastric degradation. Naturally occurring different vegetable oils, various surfactants and co-surfactants were studied for ATV solubility to identify the components of SNEDDS. Ternary phase diagrams comprising surfactant, cosurfactant and oil were plotted. In the ternary phase diagrams the area of self-nanoemulsifying region was marked for the compositions that are giving dispersion with a globule size ≤S200 nm. Effect of drug loading on the phase behavior of selected system was studied. A series of SNEDDS were prepared by selecting from the nanoemulsifying area of 2.5% ATV system. Prepared SNEDDS were evaluated for visual observations, turbidity, effect of pH of the dispersion media on globule size and zeta potential, robustness to dilution and in vitro dissolution study and optimized. FT-IR and DSC were studied for interaction between drug and excipients if any. Forced degradation and accelerated stability studies were conducted for optimized SNEDDS. ATVF 04 and 11 were selected as optimized SNEDDS due to their smaller mean globule size (75.2 and 85.8 nm respectively), lower turbidity values, faster drug release and higher DE values among the other SNEDDS. The optimized ATV SNEDDS were not affected by the pH of dissolution medium. FT-IR study revealed no interaction between drug and excipients used. Forced degradation studies indicated the stability of ATV in the gastric environment. Accelerated stability studies showed no significant changes in the mean globule size, zeta potential, drug content and drug release before and after storage of optimized SNEDDS.

The poor bioavailability and therapeutic response exhibited by conventional eye drops due to rapid precorneal elimination of the drug may be overcome by the use of an in situ gelling systems that are instilled as drops into the eye and undergo a sol-to-gel transition in the cul-de-sac which improves patient compliance as the dosage regimen is one drop of the dosage form twice a day. The loss of drug overcomes due to the immediate gel formation between the eye membrane and the drug being entrapped simultaneously in sol-gel transition in the cul de sac. The present work describes the formulation and evaluation of an ophthalmic delivery system of an antiglaucomal agent, brimonidine tartrate based on the concept of ion-activated in situ gelation. Gelrite was used as the gelling agent, which gels in the presence of mono or divalent cations present in the lacrimal fluid. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in-vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing. In the developed formulations Gelrite Brimonidine-3 (GB3) exhibited sustained release of drug from formulation over a period of 8hrs thus increasing residence time of the drug, non-irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva, stable and sterile. These results demonstrate that the developed system is an alternative to conventional ophthalmic drops, with better patient compliance, and is industrially oriented and economical.

The objective of this investigation was to prepare mucoadhesive microspheres of ketorolac for nasal delivery to avoid gastrointestinal side effects of conventional dosage form. Mucoadhesive microspheres were prepared using carbopol, polycarbophil and chitosan as polymer by spray drying method. The process and formulation parameters were varied to study the effect on the yield and particle size. Microspheres were characterized for surface morphology, encapsulation efficiency, swelling behavior, mucoahesion properties, interaction studies using FTIR and DSC, in vitro drug release, ex vivo nasal cilio toxicity studies and in vivo anti-inflammatory and analgesic activity. Prepared microspheres were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 79-92%. The results showed that the process parameters significantly affect the particle size (10.29-16.75 μm) and yield of microspheres (36.53-56.69%). Interaction studies revealed that there were no drug to polymer interactions. Prepared microspheres exhibited good swelling and mucoadhesion strength which confined the strong mucoadhesive property of microspheres. Ketorolac release from the microspheres was extended up to 8 h and exhibited fickian drug release kinetics with best fit to higuchi model. The drug loaded microspheres were found to be nontoxic to nasal mucosa. The anti-inflammatory and analgesic effects of formulation showed a significant increase (p < 0.05) in percent inhibition value of up to 8 h when compared with ketorolac. In conclusion, spray dried microspheres based on chitosan could be suitable nasal delivery system for the administration of ketorolac.

The use of topical formulation is popular over the past decade due to extensive researches made in the field of transdermal drug delivery. As a result, an increasing number of drugs are being added to the list of therapeutic agents that can be delivered to systemic circulation through the skin. Commonly available dosage forms for the topical application are creams, ointments, gels, patches etc. The therapeutic benefits of the above topical formulations are limited due to barrier property of stratum corneum (SC). The use of chemical penetration enhancers (CPEs) is one of the long standing approach to overcome the barrier property of SC. Numerous class of novel compounds have been evaluated for penetration enhancement activity, including soft enhancement for percutaneous absorption (SEPA), for example, 2 N-nonyl-1,3- dioxolanes, N-acetyle prolinate esters (such as pentyl- and octyl-N-acetyle prolinate), alkyldiloxanes (e.g., 1-Alkyl-3-b-D glucopyranosyl-1,1,3,3-tetramethyl disiloxanes), transcarbam (such as 5-(dodecyloxycarbonyl) pentylammonium-5- (dodecyloxycarbonyl) pentylcarbamate), iminosulfurane (like N-hexyl,N-benzoyl-S,S-dimethylimino-sulfuranes), capsaicin derivatives (e.g., Nonivamide), cinnamene compounds (such as cinnamic acid, cinnamaldehyde etc), terpenes (like clove and basil oil) and synergestic combination of penetration enhancers (SCOPE). We briefly describe about the anatomy of skin. Potential mechanisms of action of above novel PEs along with adverse reactions associated with traditional PEs are also considered in this review.